The association between intestinal microbiome and autoimmune uveitis | Archivos de la Sociedad Española de Oftalmología (English Edition)

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Kalogeropoulos, R. Barry, C. Kalogeropoulos" "autores" => array:3 [ 0 => array:4 [ "nombre" => "D." "apellidos" => "Kalogeropoulos" "email" => array:1 [ 0 => "dkalog1990@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "R." "apellidos" => "Barry" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "C." "apellidos" => "Kalogeropoulos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Ophthalmology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Institute of Clinical Sciences, University of Birmingham, College of Medical and Dental Sciences, Birmingham, United Kingdom" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Ophthalmology, Birmingham & Midland Eye Centre, Sandwell & West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La asociación entre microbioma intestinal y uveítis autoinmune" ] ] "textoCompleto" => "IntroductionMicrobiome is an umbrella term that encompasses a community of microorganisms and their genetic material. The target of the Human Microbiome Project, originally launched by the National Institutes of Health in 2007, was to recognize the microorganisms that normally populate the human body in healthy individuals, as well as to identify alterations related to specific pathologies.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Some of the cardinal roles of the gut bacteria include the breakdown of food remnants, immunomodulation, biosynthesis of vitamins and amino acids, drug metabolism etc. These bacteria are affiliated to the affiliated to the phyla Bacteroidetes and Firmicutes, which together with Actinobacteria and Proteobacteria constitute 90% of intestinal microbiota. Fluctuations in the core microbiome in abundance, diversity and functionality with reference to the healthy-control microbiome is referred to as ‘dysbiosis’ (i.e. imbalance of commensal organisms).<a class="elsevierStyleCrossRef" href="#bib0010">2</a> In particular, intestinal dysbiosis has been linked with immune system disorders that eventually lead to various diseases, such as spondyloarthropathies, rheumatoid arthritis (RA), ankylosing spondylitis (AS) and multiple sclerosis (MS).<a class="elsevierStyleCrossRefs" href="#bib0015">3–6</a> Many of these clinical entities are also associated with uveitis, but the pathogenesis of non-infectious (or immune-mediated) uveitis remains obscure. Actually, most cases of uveitis not attributed to surgical or accidental trauma consist manifestations of infectious or immune mediated clinical entities. Approximately 30% to 45% cases with uveitis are associated with an underlying systemic disease.<a class="elsevierStyleCrossRefs" href="#bib0035">7,8</a> In particular, autoimmune uveitis is a group of intraocular inflammatory pathologies that occur without known infectious etiology. Inflammation of the uveal tract can occur in the context of a systemic autoimmune syndrome such as Behçet’s disease, systemic sarcoidosis and Vogt-Koyanagi-Harada disease. However, in other conditions, such as idiopathic uveitis, sympathetic ophthalmia and birdshot retinochoroidopathy, the eye may be the only target. Individuals with autoimmune uveitis often present recognizable memory responses to specific retinal proteins (e.g. retinal arrestin and interphotoreceptor retinoid binding protein - IRBP), which are expressed in photoreceptor cells and take part in the visual process. Various types of uveitis have been correlated with particular HLA haplotypes (e.g., A29, B27, B51, DR4, DQ4), enhancing the concept of the autoimmune pathogenetic mechanisms.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Although it has been suggested that some types of uveitis may be related with systemic microbial infections, our knowledge remains limited. Previous studies with data deriving from humans and animal models proposed a causative role of gut microbiota in the pathogenesis of autoimmune diseases and uveitis.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> The scope of this report is to review the evidence that gut microbiome can trigger immune-mediated mechanisms leading to the development of non-infectious (or autoimmune) uveitis and how it can be potentially targeted for developing therapeutic approaches.Materials and MethodsA thorough literature search was performed in the PubMed database. An additional search was made in Google Scholar to complete the collected items. The following keywords were used: “microbiome/microbiota and autoimmunity”, “microbiome/microbiota and autoimmune uveitis”, “microbiome/microbiota and autoimmune disease”, “gut/intestinal microbiome/microbiota and uveitis/autoimmune uveitis”. Studies that were written in any other language than English were excluded. We also excluded irrelevant studies and those that the full article could not be found. Overall we included 118 references dated from 1989 to 2020; the vast majority of them were published after 2004 (109 out of 118). An increasing interest in the correlation between the gut microbiome and autoimmune uveitis is noted after 2016. Special emphasis was given to those studies that focus on autoimmune uveitis. However, other studies that approach the role of intestinal microbiota in the pathogenesis of autoimmune disorders, as well as data from experimental studies, were also analyzed and included in our review to support our study.Understanding UveitisUveitis is associated with around 10–15% of all cases of blindness in the United States, and consists the fifth cause of visual loss in the developed world, accounting for up to 20% of legal blindness.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Impairment of vision has a crucial impact on the quality of life and productivity of individuals suffering from uveitis worldwide. Therefore, there is an immediate need of improvement in the understanding of uveitis, so as to develop more efficient and sophisticated diagnostic and therapeutic approaches.The uveal tract is defined as a pigmented, highly vascular loose fibrous tissue that can be divided into three distinct anatomical regions: the iris (anteriorly), the ciliary body (in the middle) (subdivided into pars plicata anteriorly and pars plana posteriorly), and the choroid (posteriorly). Uveitis is a general term describing a group of inflammatory disorders affecting any of these structures, and may also involve other surrounding tissues such as sclera, retina, and optic nerve. Classifying uveitis according to the predominant site of inflammation can contribute in narrowing the differential diagnosis. As established by the SUN (Standardization of uveitis nomenclature) Working group, the anatomic division of the uveal tract facilitates the classification of uveitis into anterior uveitis (iritis, anterior cyclitis, iridocyclitis), intermediate uveitis, posterior uveitis (focal, multifocal, or diffuse choroiditis, retinochoroiditis, or neuro-uveitis with optic nerve inflammation), and panuveitis (generalized intraocular inflammation).<a class="elsevierStyleCrossRef" href="#bib0060">12</a>The unique anatomical and physiological features of the human eye makes the management of uveitis even more complicated.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Currently, despite the available diagnostic resources, more than 30% of cases do not have a definitive etiologic diagnosis.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> The clinical manifestations of uveitis can provide crucial clues into setting diagnosis and detecting the infectious, inflammatory, or neoplastic etiologies. Thus, uveitis calls for a thorough ophthalmologic assessment. Slit-lamp biomicroscopy remains the cornerstone of clinical evaluation,<a class="elsevierStyleCrossRef" href="#bib0070">14</a> but retinal imaging (e.g. Optical Coherence Tomography – OCT, Fluorescein Angiography – FA, or Fundus Photography) can provide significant information not only during the first assessment but also for patient’s follow-up.Understanding the microbiomeBorn devoid of microorganisms, human gut becomes gradually heavily colonized by a complex spectrum of bacteria, archaea, eukaryotes and viruses that form communities, which are collectively mentioned as the intestinal microbiota. Its presence is crucial in several aspects of host physiology, including the acquisition and provision of nutrients, resistance to invading pathogens and education of the immune system.<a class="elsevierStyleCrossRefs" href="#bib0075">15,16</a> Although there has been a climax of interest in the microbes that colonize our body, it appears that this field has gained scientific attention for more than a century. Indeed, Elie Metchnikoff was fascinated by the potential effect of this complex ecosystem on physiological and pathological states of our immune system. This notion is correlated with how health-promoting bacteria (probiotics) have been implemented in therapeutic approaches in the early twentieth century.<a class="elsevierStyleCrossRef" href="#bib0085">17</a>The concept of microbiome is very important, especially if we take into account that commensal microorganisms colonize all exposed surfaces of the human body and outnumber human cells by at least 10 to 1.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> If we translate this in terms of genetic information, it means that there is a greater than 100-fold difference, since a single human comprises 23.000 host genes, whereas the microbes residing in our body encompass more than 3.000.000 genes.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> A significant amount of the human microbiome is found in the gastrointestinal tract, where a substantial proportion of the human body’s immune system is also settled.The immune system of the human body is significantly influenced by the development of the early microbiota, whereas the insufficient normal colonization of the gastrointestinal tract in infants (as occurs in C-section delivery in comparison to vaginal delivery) can predispose to immune-mediated diseases at later stages of life.<a class="elsevierStyleCrossRefs" href="#bib0100">20,21</a>As mentioned above, the pathogenesis of non-infectious (or immune-mediated) uveitis is not completely understood. Many uveitic entities are associated with specific inflammatory cytokine pathways. Data deriving from the study of the serum or ocular fluids of immune-mediated uveitis individuals of various causes have shown increased levels of interleukin-6 (IL- 6), IL-17, IL-23 or tumor necrosis factor-alpha. Interestingly, over the last decade, the vast majority of therapeutic targets have involved these pathways with various degrees of success but still calling for further investigation of their efficacy. The triggering factors of uveitis and pathogenetic mechanisms that lead to the elevation of cytokine levels are not always obvious. Moreover, treatments targeting at the restoration of immune homeostasis remain inadequately explored.Commensal microbiota has been found to play a pivotal role in immune-mediated disorders either by promoting or by inhibiting inflammatory process. Thus, an improved understanding and manipulating of the microbiome may contribute in recognizing novel pathogenetic mechanisms and consequently new therapeutic approaches.The complex interactions between the human immune system and the microbiome of the gastrointestinal tract can occur even at the level of strain-specific changes of immune cell repository. For example, the differentiation of T helper 17 cells (Th17) in the gut can be promoted by certain bacterial strains, segmented filamentous bacteria f detected in rodents<a class="elsevierStyleCrossRef" href="#bib0110">22</a> and analogous bacterial strains detected in humans.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> When Th17 become pathogenic, they are significantly associated with autoimmune diseases including uveitis. On the other hand, other bacteria (e.g. certain types of Clostridia, and the bacterial species, Bacteroides fragilis) can augment the differentiation of colonic Tregs therefore contribute to immune homeostasis.<a class="elsevierStyleCrossRefs" href="#bib0120">24,25</a>Although the equilibrium of microbiota can conduce to the pathogenesis of immune disorders, it has been found that host genetics, such as HLA-type, can affect the microbial framework of the gut.<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a> Other aspects of the human microbiome (e.g. oral, skin, pulmonary or ocular microbiome) may indeed be substantial for the pathogenesis of disease but will not be analyzed in the context of this review.Gut microbiota and immune system developmentThe mucosal immune system is defined by high-specialization and many of its functions are quite independent of the systemic immune system,<a class="elsevierStyleCrossRef" href="#bib0140">28</a> whereas it goes through significant alterations after bacterial colonization of the intestinal tract.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> Commensal microorganisms contribute to the maturation of the immune system, which is “trained” to distinguish commensal bacteria from pathogenic bacteria.<a class="elsevierStyleCrossRefs" href="#bib0150">30,31</a> This differential recognition is mediated by Toll-like receptors (TLRs), which are detected in the membrane of the epithelial and lymphoid cells of the small intestine and play a pivotal role in the development of the normal intestinal mucosal immune system. TLRs suppress the inflammatory responses and promote immunological tolerance to normal microbiota components. TLRs identify different general microbe-associated molecular patterns (MAMPs) that contain several bacterial antigens (such as capsular polysaccharides and lipopolysaccharides, peptidoglycan components-muramic acid, flagellin and unmethylated bacterial DNA CpG motifs) and trigger the innate intestinal immunity.<a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a> After stimulation, a complex surge of signals leads to the release of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), activating a wide spectrum of genes coding acute phase proteins, cytokines, chemokines and other components of the humoral immune response.<a class="elsevierStyleCrossRefs" href="#bib0170">34,35</a> TLR activity declines gradually during the first weeks of life, allowing the formation of a constant gut bacterial community. Moreover, activation of TLRs by antigens of the normal gut microbiota is signaling the repression of inflammatory responses, and is therefore necessary for maintaining intestinal homeostasis.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> Furthermore, NOD-like receptors (NLRs) detect microbial specific molecules and trigger the group of inflammasomes, which can recognize damage-associated patterns. In particular, the deficiency of NLPRP6 has been correlated to alterations of immune response, dysbiosis, and intestinal hyperplasia.<a class="elsevierStyleCrossRefs" href="#bib0185">37,38</a> Microbiota of the gastrointestinal tract has been found to regulate neutrophil migration and function,<a class="elsevierStyleCrossRef" href="#bib0190">38</a> as well as the differentiation of T cell populations into different types of helper cells (Th) (Th1, Th2, and Th17) or into regulatory T cells (Tregs).<a class="elsevierStyleCrossRef" href="#bib0195">39</a> The Th17 cells constitute a subset of TCD4+ cells that release various cytokines (IL-22, IL-17A, and IL-17F), with a tremendous effect on immune homeostasis and inflammation.<a class="elsevierStyleCrossRefs" href="#bib0200">40,41</a> Th1 and Th2 cells maintain a stable secretory profile after differentiation, whereas Th17 cells are defined by a divergent cytokine expression profiles and functions.<a class="elsevierStyleCrossRef" href="#bib0210">42</a> Interestingly, the administration of the purified capsular polysaccharide from the commensal bacterium B. fragilis reduces IL-17 production and stimulates TCD4+ lymphocytes to produce IL-10 in order to protect the colonic mucosa against inflammatory processes triggered by bacterial antigens.<a class="elsevierStyleCrossRef" href="#bib0215">43</a> On the other side, the colonic milieu also regulates the de novo differentiation and outspread of peripherally derived Tregs from naïve CD4+ T cells.<a class="elsevierStyleCrossRef" href="#bib0220">44</a> Tregs are essential for immune tolerance; they can suppress an inappropriately high inflammatory reaction,<a class="elsevierStyleCrossRef" href="#bib0225">45</a> whereas their dysregulation can lead to autoimmune diseases.<a class="elsevierStyleCrossRef" href="#bib0230">46</a> Secretory immunoglobulin A (sIgA) is an important component of the local immune response, shaping a first line of defense against toxins and pathogens. Production of sIgA specific to different mucosal antigens occurs after the captivation of these antigens by Peyer’s patches M cells, transformation by dendritic cells (DCs), T cells activation, and finally B cell class switching in gut-associated lymphoid tissue and mesenteric lymph nodes (MLNs). Production of small amounts of sIgA is induced by the commensal antigens via the configuration of their immune-dominant epitopes, providing a supremacy for the gut colonization.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> IgA production is stimulated by a cascade of cytokines, including IL-4, IL-5, IL-6, IL-10 and TGF-β. Particularly IL-10 and TGF-β, are important for the mucosal tolerance, indicating the strong link between sIgA secretion, immunity, and intestinal homeostasis.<a class="elsevierStyleCrossRef" href="#bib0235">47</a> Immune reactivity could be upregulated to enhance the establishment of a more favorable status in individuals with intestinal dysbiosis. This could be achieved through specific effects of sIgA, or less specific effects of innate immunity effectors (e.g. defensins) or local milieu alterations (i.e., diarrhea). In diarrhea, undesirable microbial communities are eliminated so as to reform intestinal niches for a re-colonization process with optimal microbial populations in order to promote healing.<a class="elsevierStyleCrossRef" href="#bib0240">48</a> Additionally, the commensal microbiota of the host initiates several responses from the epithelium, such as the production of various antibacterial lectins (e.g. RegIIIc, α-defensins, and angiogenins). These effectors restrict the volume of potential pathogens, providing protection against pathological immune responses.<a class="elsevierStyleCrossRefs" href="#bib0245">49,50</a> In overall, microbial products can lead to continuous immune responses and thus to chronic non-resolving inflammation and tissue destruction, especially after mucosal injury.Tools for investigating the intestinal microbiomeShedding more light in aspects regarding the composition and functional capacity of the gut microbiome is a great challenge. The research in this field is continuously developing and currently a number of approaches are being facilitated in order to determine the genetic background, the composition and function of intestinal microbiota. Culture-based techniques were traditionally used for defining the composition of the gut microbiome. However, this methods focused mainly on the “easy-to-culture” pathogens and gradually became less popular considering that approximately 10–50% of the gut bacteria are culturable.<a class="elsevierStyleCrossRef" href="#bib0255">51</a> These techniques have obviously limitations and cannot provide a pragmatic overview regarding the microbial composition of the gut. Despite these restrictions, some of the progress in this field can be attributed to the increased availability of specialized media for cultivating fastidious organisms.<a class="elsevierStyleCrossRef" href="#bib0260">52</a>A study by Lagier et al.<a class="elsevierStyleCrossRef" href="#bib0265">53</a> has provided further development in this research area and has led to the introduction of the so-called “microbial culturomics”. This approach introduces an array of novel culturing methods, coupled with matrix-assisted laser desorption/ionization–time of flight mass spectrometry (MS), to detect a range of previously uncultivated microbiota from the gut. Interestingly, this technique has overcome many of the aforementioned limitations and has led to the recognition of 174 new species in the human gut.Despite these recent developments, it remains clear that culture-independent are more effective in providing a rapid overview of the gut microbiota. One of the most revolutionary modalities was the development and application of fast and low-cost DNA sequencing methods. High throughput sequencing (HTS) technologies have been widely used to investigate the gut microbiome, due to their speed, scale and precision. The 16S rRNA gene has been most commonly targeted for compositional analysis, as it is present in all prokaryotes. Moreover, the existence of variable domains enable the distinction of different taxa. Although, most of HTS reports have relied on the Roche 454 pyrosequencing platforms, other sequencing technologies, are becoming more preferred [e.g. as those provided by Illumina (San Diego, CA, USA)].<a class="elsevierStyleCrossRef" href="#bib0270">54</a>16S rRNA studies provide information regarding the microbial status of an ecosystem, they do not offer direct data in relation with the microbial viability or the potential functions. This issue is addressed by metagenomic (or shotgun sequencing) studies, which can define the full genetic content of a microbial population and therefore its functional capacity. It must be noted though, that detailed bio-informatic analyses to cope with the large volumes of data generated are required in theses sequencing technologies.<a class="elsevierStyleCrossRefs" href="#bib0275">55–58</a>Moreover, analysis gene expression (metatranscriptomics), protein products (metaproteomics) and metabolic profiles (metabolomics) is necessary for furtherly recognizing specific microbial activity. However, apart from being complex, these techniques are still at early stages of their development.<a class="elsevierStyleCrossRef" href="#bib0295">59</a>Alterations of the gut microbiome in extra-intestinal systemic immune-mediated disordersPatterns deriving from the intestinal microbiota have been correlated to extra-intestinal immune-mediated diseases such as MS, RA and AS. Characteristically, it was shown that in new-onset treatment-naive RA patients, which often present with scleritis (inflammation of the sclera), Prevotella copri is substantially elevated in the intestinal tract, while beneficial bacteria, such as Bacteroides species, are conversely lessened.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> This profusion of intestinal P. copri is inversely associated with the existence of RA-associated genetic risk factors (the ‘shared-epitope’ genes), indicating that non-genetic RA (most cases of RA), is notably more possible to be associated with this specific pattern of intestinal dysbiosis than genetic RA.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Similarly, in MS that can be associated with anterior or intermediate uveitis with retinal vasculitis, an intestinal dysbiosis has been found. In that case, a crucial depletion in essential Clostridia clusters IV and XIVa (known to promote Tregs differentiation) has been demonstrated.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> In a study that facilitated the relapsing-remitting mouse model of spontaneously developing experimental autoimmune encephalomyelitis, two groups have shown how changes in the intestinal microbiome affect disease severity. The first group revealed that mice raised in a germ-free environment presented almost no CNS inflammation,<a class="elsevierStyleCrossRef" href="#bib0300">60</a> while the other group showed a notable decrease in CNS inflammation when mice were administered with broad-spectrum oral antibiotics.<a class="elsevierStyleCrossRef" href="#bib0305">61</a> These observations suggest that in the absence of pathogenic agents gut flora is critical in triggering immune processes, leading to a relapsing-remitting autoimmune disorder driven by myelin-specific CD4 (+) T cells.<a class="elsevierStyleCrossRef" href="#bib0300">60</a> The latter study reported that broad-spectrum oral antibiotics suppressed CNS inflammation by increasing the number Tregs in specific lymphoid tissues.<a class="elsevierStyleCrossRef" href="#bib0300">60</a> Another study by Berer et al.<a class="elsevierStyleCrossRef" href="#bib0310">62</a> highlighted that CNS inflammation was enabled when microbiota from MS patients were transplanted into mice.Alterations of the gut microbiome in immune-mediated uveitisIn gut-associated lymphoid tissue (GALT), under normal conditions, potential pathogens are presented by antigen-presenting cells to Th cells (especially Th17 cells), to promote inflammatory response by stimulating the proliferation and secretion of inflammatory cytokines (e.g. IL-17). On the contrary, Tregs suspend the hyperbolic immune response and impede persistent inflammation. As can be inferred, there is a dynamic balance among Th17 and Tregs in order to preserve the gut homeostasis. Interestingly, commensal bacteria of the gut can modify the mucosal immunity of the intestinal tract, including the equilibrium between Th17 and Tregs.<a class="elsevierStyleCrossRef" href="#bib0315">63</a> The dysbiosis of gut microbiome may cause significant homeostatic disorders, affect the balance of Th17/Tregs (a rise in Th17 generation and a drop in Tregs production), degrade the threshold of immune activation, and eventually lead to a wide spectrum of intestinal and extra-intestinal inflammatory pathologies, such as autoimmune uveitis.<a class="elsevierStyleCrossRefs" href="#bib0320">64,65</a>In contrast with other extra-intestinal immune-mediated disorders, the number of studies about the correlation of the gut microbiome in the pathogenesis of autoimmune uveitis (and other ophthalmologic pathologies) remains limited. Nakamura et al.<a class="elsevierStyleCrossRef" href="#bib0330">66</a> investigated the contribution of the gut microbiota to the pathogenesis of uveitis by facilitating the method of experimental autoimmune uveitis (EAU) in B10.RIII mice. Their study showed that the severity of uveitis seems to be correlated with specific commensal bacteria, whereas the state of uveitis is associated with particular strains of bacteria. More specifically, they found that oral, but not intraperitoneal antibiotics, reduced mean uveitis clinical scores substantially compared with water-treated animals. Oral metronidazole and vancomycin alone suppressed inflammatory activity, while ampicillin and neomycin did not affect mean uveitis scores. The administration of oral broad-spectrum antibiotics lead to elevated Tregs in the gastrointestinal lamina propria after 1 week, and later in extra-intestinal lymphoid tissues, whereas inflammatory cytokines and Teff were reduced. 16S sequencing of gastrointestinal contents changes the microbiome of immunized mice in comparison with non-immunized mice. EAU mice also revealed intestinal microbial diversity clustering associated with clinical score severity. These results suggest that oral antibiotics can regulate the severity of inducible EAU and that there may be protective, and conversely intestinal microbiota that can be potentially uveitogenic.Similarly, Heissigerova et al.<a class="elsevierStyleCrossRef" href="#bib0335">67</a> reported that the presence of microbiota during autoantigen recognition regulates the inflammatory response by influencing the adaptive immune response in the murine model of EAU, as either germ-free rearing or treatment with oral antibiotics (metronidazole and ciprofloxacin) led to significant reduction of uveitis severity. Another study that utilized a novel mouse model of spontaneous uveitis exhibited that activation of retina-specific T cells is dependent on gut commensal microbiota. This involved signaling via the autoreactive T cell receptor (TCR) in response to non-cognate antigen in the intestine and was independent of the endogenous retinal autoantigen. These results indicate that the activation of TCRs by commensal microbes can trigger the pathogenesis of autoimmune diseases.<a class="elsevierStyleCrossRef" href="#bib0340">68</a>A more recent study by Nakamura et al.<a class="elsevierStyleCrossRef" href="#bib0345">69</a> highlighted that even during the priming uveitic phase (before ocular inflammation, 1 week after immunization), alterations of the gut bacteria may occur. Some of these changes are associated with uveitis, whereas others are due to the mycobacterial adjuvant. Furthermore, there are morphological alterations in the intestinal crypts and submucosa, a change in the intestinal mucosal immunity (defined by enhanced expression of intestinal zonulin, which is a marker for intestinal permeability) and increased production of antimicrobial peptides lipocalin and S100A8 in the gut.<a class="elsevierStyleCrossRef" href="#bib0350">70</a> It has also been highlighted that 2 weeks after immunization mycobacterial antigen (MTB) and retinal peptide a peak in inflammatory process was observed. At the same period, apart from increased abundance of several gut bacteria, an increased trafficking of Th1 and Th17 effector T cells between the gut and the spleen was noted. Interestingly, the amount of leukocytes deriving from the intestines detected in the eye was associated with the degree of uveitic activity.<a class="elsevierStyleCrossRef" href="#bib0345">69</a> Finally, taking into consideration all the above, it has been suggested that re-establishing immune homeostatic mechanisms by strengthening the function of Tregs can play a key role in the treatment of uveitis, either by manipulating commensal bacterial dietary metabolites or by direct alteration of intestinal bacteria.<a class="elsevierStyleCrossRefs" href="#bib0345">69,70</a>Observations in specific clinical entities associated with uveitisBehcet’s diseaseBehçet's disease is a multisystem immune-related disorder of unknown etiology characterized by recurrent oro-genital ulcers, mucocutaneous lesions, and serious organ involvement. It has been proposed that various environmental and other triggering factors are implicated with the onset and the clinical relapses of Behçet's disease. Stress appears to be a common self-triggering factor for most of these patients. Stimuli such as some food substances can activate oral ulcers, and may be relevant to the histamine content of the food. Oral/skin trauma and menstruation related to hormonal factors aggravate, whereas allergy/atopy seem to alleviate the disorder’s symptoms. Infections have been associated with Behçet's disease, as microbial stimuli can activate inflammation in mucosal surfaces with increased Th1/Th17 responses. Interestingly, alterations in the diversity and composition of fecal and oral microbiome patterns have also been reported.<a class="elsevierStyleCrossRef" href="#bib0355">71</a> The association of microbiota with Behçet’s disease has not fully clarified yet.Consolandi et al.<a class="elsevierStyleCrossRef" href="#bib0360">72</a> compared the fecal microbiota of 22 Behçet patients with that of 16 healthy co-habiting controls, by facilitating pyrosequencing of the V3-V4 hypervariable regions of the 16 rDNA gene and biochemical analyses. Their results highlighted significant differences in gut microbiota between the two groups. More specifically, it was demonstrated that patients with Behçet's disease were significantly depleted in the genera Roseburia and Subdoligranulum, compared to the controls. Another important finding of this study is the decreased production of butyrate in Behçet's patients. As butyrate promotes the differentiation of Tregs, a disorder in its production could cause reduced Treg responses and also activation of immuno-pathological T-effector responses.Another study by Seoudi et al.<a class="elsevierStyleCrossRef" href="#bib0365">73</a> reported differences in the microbial composition of the saliva of 54 Behçet's patients, eight subjects affected by recurrent aphthous stomatitis, and 25 controls. In Behçet's individuals non-ulcerous oral cavities were mostly colonised by Rothia denticariosa, whereas ulcerous oral cavities showed a higher prevalence of Streptococcus salivarius and Streptococcus sanguinis in comparison with those of the subjects in the two control groupsBased on the theory that the class Clostridia includes short-chain fatty acid-producing bacteria, which are important for the equilibrium the balance between Tregs and helper Th17 cells, it has been suggested that the bacterial compositional changes may lead to low intestinal short-chain fatty acid concentrations and therefore to immune disorders in Behçet's patients. To explore this hypothesis Shimizu et al.<a class="elsevierStyleCrossRef" href="#bib0370">74</a> investigated species composition and gene functions from the 16S rRNA data by utilizing PICRUSt software. It was found that these individuals have a relative abundance of Eggerthella lenta, Acidaminococcus species, Lactobacillus mucosae, Bifidobacterium bifidum, Lactobacillus iners, Streptococcus species, and Lactobacillus salivarius. On the other hand relative abundance of Megamonas hypermegale, Butyrivibrio species, Streptococcus infantis, and Filifactor species increased notably in controls in comparison with Behçet's patients. It was highlighted that prevalent gene functions of the pentose phosphate pathway and the inosine monophosphate biosynthesis were recorded in patients with Behçet's disease, indicating that gut microbes affected nucleic acid and fatty acid synthesis. The same team conducted a fecal metagenomics analysis in Behçet's patients.<a class="elsevierStyleCrossRef" href="#bib0375">75</a> In these patients, direct comparison of the relative abundance of bacterial taxa showed that the genera Bifidobacterium and Eggerthella increased remarkably and the genera Megamonas and Prevotella decreased substantially. Moreover, it was shown that the phylum Actinobacteria, including Bifidobacterium, and the family Lactobacillaceae presented larger positive effect sizes than other bacteria in patients with Behçet's. These data come in agreement with another metagenomics study conducted by Ye et al.<a class="elsevierStyleCrossRef" href="#bib0380">76</a> who reported that fecal samples from active Behçet's patients were found to be enriched in Bilophila spp., a sulfate-reducing bacteria (SRB) and various opportunistic pathogens (e.g., Parabacteroides spp. and Paraprevotella spp.) together with a lower level of butyrate-producing bacteria (BPB) Clostridium spp. and methanogens (Methanoculleus spp. Methanomethylophilus spp.). Remarkably, capsular polysaccharide transport system, oxidation-reduction process, type III, and type IV secretion systems were also aggravated in individuals with active disease. Additionally, transplantation of fecal microbiota from human patients to experimental animals caused exacerbation of EAU activity and elevated production of inflammatory cytokines (IL-17, IFN-γ).Another interesting potential association has been noted regarding the pathogenetic role of Helicobacter pylori in this disease. Interestingly, there is a high prevalence of this infection in areas where Behçet's disease is more frequent.<a class="elsevierStyleCrossRefs" href="#bib0385">77–79</a> There are implications that the geographic distribution of gastric cancer, which is the most severe complication of this infection, may have various similarities to Behçet's disease.<a class="elsevierStyleCrossRefs" href="#bib0400">80,81</a> Results from recent studies<a class="elsevierStyleCrossRefs" href="#bib0410">82,83</a> indicated that H. pylori may indeed have a role in the pathogenesis of this multisystem disease and clinical features (e.g. oral and genital ulcers, or cutaneous lesions) can be improved after H. pylori eradication.<a class="elsevierStyleCrossRef" href="#bib0415">83</a>Consequently, unfavorable compositional and functional changes in the gut microbiota (dysbiosis) may have an association with the immune aberrations and the pathophysiology of Behçet's disease.HLA-B27-associated acute anterior uveitisAcute anterior uveitis (AAU) and associated spondyloarthropathies (i.e. ankylosing spondylitis, enthesitis related arthritis in children, reactive arthritis, arthritis associated with inflammatory bowel disease, and psoriatic arthritis) have been incorporated in the broad spectrum of immune-mediated inflammatory diseases which have been linked with the biology of the intestinal microbiome.<a class="elsevierStyleCrossRef" href="#bib0420">84</a>Spondyloarthropathies are clearly connected to bowel inflammation, which may often be asymptomatic in a disease such as ankylosing spondylitis.<a class="elsevierStyleCrossRefs" href="#bib0425">85,86</a> Patients with ankylosing spondylitis, appear to have an intestinal dysbiosis too, as well as increased bowel permeability,<a class="elsevierStyleCrossRef" href="#bib0435">87</a> whereas a variety of enteric infections including Salmonella, Yersinia, Shigella, and Campylobacter can trigger reactive arthritis.<a class="elsevierStyleCrossRefs" href="#bib0440">88,89</a>HLA molecules regulate the immune response in more than 100 diseases. However, the exact pathogenetic mechanisms remain unknown.<a class="elsevierStyleCrossRef" href="#bib0450">90</a> Interestingly, the association between HLA B27 and spondyloarthritis is considered to be among the strongest. It has been hypothesized that HLA molecules affect the intestinal bacterial composition. More specifically, these individuals are often defined by the HLA-B27 genotype and acute anterior uveitis can occur in up to 30-40% of cases. A positive HLA-B27 itself has also a remarkable correlation with the development of acute anterior uveitis. Notably, a significant proportion of patients with AS or other spondyloarthropathies present with subclinical features of gastrointestinal inflammation. Lin et al.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> reported the use of a culture-independent method of sequencing a small fragment of the bacterial 16S rRNA gene. This study showed that transgenic rats expressing human HLA-B27 had a dysbiosis leading to increased amounts of Paraprevotella (a bacterial genus within the same family as Prevotella), and decreased amounts of Rikenellaceae family of bacteria. Interestingly, in patients with AS, terminal ileum is enriched with five families of bacteria including Lachnospiraceae and Prevotellaceae.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> It has also been suggested that HLA-B27 changes intestinal microbial components, disrupts intestinal permeability and causes subclinical intestinal inflammation, which may lead to leakage of bacterial constituents that advocate inflammation in other anatomical sites.<a class="elsevierStyleCrossRef" href="#bib0455">91</a> This hypothesis could probably explain how AS patients develop uveitis, joint inflammation or other HLA-B27 related disorders.Further data, deriving from experiments on HLA B27 transgenic rats<a class="elsevierStyleCrossRef" href="#bib0460">92</a> were used to test this hypothesis. This animal model express multiple copies of HLA B27 along with the invariant Major histocompatibility complex (MHC) light chain, beta 2 microglobulin. More than two decades ago, Taurog et al.<a class="elsevierStyleCrossRef" href="#bib0465">93</a> described the spondyloarthropathy affecting these rats. The animals develop diarrhea around two to four months of age and subsequently many of them will develop spondylitis, peripheral arthritis, and psoriasiform rashes. The bowel and joint disease is significantly reduced if the rats are raised in a germ free environment, showing that microbiome plays a crucial role in the pathophysiology of this disease.<a class="elsevierStyleCrossRef" href="#bib0470">94</a> Some bacteria (e.g. Lactobacillus rhamnosus GG) contribute in a way that the remission is maintained, whereas other lead to recurrence of the disease.<a class="elsevierStyleCrossRef" href="#bib0475">95</a> HLA B27 clearly affects the gut microbiome of these rats. One of the first immunological alterations is the upregulation of antimicrobial peptides [e.g. RegIIIγ and S100A8 (calprotectin)] in the colon of these animals<a class="elsevierStyleCrossRef" href="#bib0480">96</a> may precede the development of dysbiosis. Therefore it has been proposed that alterations in the gut microbiome may be a primary event in the pathogenesis of spondyloarthropathy rather than an epiphenomenon.<a class="elsevierStyleCrossRef" href="#bib0420">84</a> Serum calprotectin has been suggested as a biomarker for juvenile idiopathic arthritis with uveitis,<a class="elsevierStyleCrossRef" href="#bib0485">97</a> posterior uveitis,<a class="elsevierStyleCrossRef" href="#bib0490">98</a> and Behçet's disease.<a class="elsevierStyleCrossRef" href="#bib0495">99</a> There is evidence that MHC can modify the microbiota and therefore predispose to various immune-diseases.<a class="elsevierStyleCrossRefs" href="#bib0500">100,101</a>Regarding the potential role of H. pylori in the pathogenesis of inflammatory disorders, the studies of Bae et al.<a class="elsevierStyleCrossRef" href="#bib0510">102</a> and Otasevic et al.<a class="elsevierStyleCrossRef" href="#bib0515">103</a> have investigated the association between H. pylori seropositivity and HLA-B27-positive acute anterior uveitis, with the first study<a class="elsevierStyleCrossRef" href="#bib0480">96</a> suggesting an inverse association.Several mechanisms have been proposed for how HLA B27 may lead to the loss of ocular tolerance and uveitogenesis, many of which may be also relevant with for the loss of intestinal tolerance that accompanies several forms of spondyloarthropathies. However, these mechanisms are not mutually exclusive. B27-dependent mechanisms may impact the gut and/or the eye itself, where loss of tolerance could contribute to the manifestation of uveitis.<a class="elsevierStyleCrossRef" href="#bib0405">81</a> Some of the models where the gut microbiome is a key component of AAU pathogenesis include self-antigen dependent or self-antigen independent model of uveitis. However, these mechanisms and models cannot be thoroughly discussed in the context of this review and therefore readers are referred to the studies of Rosenbaum et al.<a class="elsevierStyleCrossRefs" href="#bib0420">84,104,105</a>Vogt-Koyanagi-Harada (VKH) diseaseVKH disease is a multisystem autoimmune pathology associated with granulomatous panuveitis. It has been proposed that gut microbiome plays a substantial role in the pathogenesis of this disease. Ye et al.<a class="elsevierStyleCrossRef" href="#bib0530">106</a> reported detecting depleted butyrate-producing bacteria, lactate-producing bacteria and methanogens and enriched Gram-negative bacteria in patients with active VKH disease. Interestingly, gut microbiome alterations were partially restored in these patients after administrating immunosuppressive treatment. Furthermore, the disease susceptibility genotype HLA-DRA was correlated to Bacteroides sp.2.1.33B, Paraprevotella clara, Alistipes finegoldii and Eubacterium eligens. Based on an experimental animal model, it was shown that transfer of gut microbiome from VKH patients could lead to significant exacerbation (clinically and pathologically) of the disease activity in the recipient mice. The results from this study also indicate that developing microbial marker profiles could be helpful in distinguishing VKH patients from healthy controls as well as predicting the effectiveness of treatment.Potential therapeutic targets of the gut microbiome for ocular inflammationFirstly, targeting specific causative bacteria could be facilitated by intelligent techniques defined by high specificity. For instance, this could be achieved by designing immunoglobulins that target specific bacteria or bacterial components/ metabolites that have been linked to the inflammatory condition, but without affecting the status of other beneficial bacteria. Okai et al.<a class="elsevierStyleCrossRef" href="#bib0535">107</a> reported a beneficial effect on colitis models in mice.Another approach for targeting the intestinal microbiome could be by oral administration of live bacterial strains that are proven to promote immune homeostasis (e.g. by enhancing differentiation of regulatory T cells). Although this method appears to have great potential, it is critical to design probiotics so that they will be able to maximize colonization in the human gut.<a class="elsevierStyleCrossRefs" href="#bib0540">108,109</a>A third strategy could employ what are widely considered as chemical drugs. For example, utilizing antibiotics that may not be broad-spectrum but instead are chemicals targeting specific metabolic pathways of only one community of bacteria. This could partially contribute to a therapeutic approach which is based on the administration of beneficial bacteria in the form of colonization-ready probiotics after antibiotics so as to re-establish the immune balance and intestinal homeostasis. Targeting of intestinal bacteria has been used for the treatment of systemic rheumatic diseases over the last decades. Designing agonists to short chain fatty acid cell surface receptors or analogues of the components of beneficial bacteria, could be another drug therapy method. It has been demonstrated that oral administration of Bacteroides fragilis (polysaccharide from the human commensal) had a protective action against an MS-like CNS demyelinating disease in rodents,<a class="elsevierStyleCrossRef" href="#bib0545">109</a> whereas oral short chain fatty acids can ameliorate uveitis.<a class="elsevierStyleCrossRef" href="#bib0345">69</a>A fourth approach involves dietary modifications, such as exposure to a diet high in non-digestible fibres in order to boost the production of endogenous short chain fatty acids by the intestinal microbiota.<a class="elsevierStyleCrossRef" href="#bib0350">70</a>A final therapeutic strategy is to replace an entire community of intestinal bacteria with a normal community using a fecal microbial transplant. This method has been found to have favorable outcomes in antibiotic-resistant Clostridium difficile colitis in large clinical trials.<a class="elsevierStyleCrossRef" href="#bib0550">110</a> However, this approach may have to overcome various challenges, such as defining healthy or appropriate donors or establishing regulations for donor material testing to avoid transplant complications.Future trendsThe microbiome research is expected to shed light in several pathologies within ophthalmology and beyond. The refinement of laboratory and experimental techniques over the last decade has enabled researchers to define important parameters regarding the composition and function of microbiotas. More specifically, new assays and bioinformatics has allowed a more detailed analysis of host-microbiota interactions, whereas large-scale longitudinal studies have indicated new insights regarding the effect of microbiotas on various pathogenetic mechanisms. Furthermore, clinical trials have been essential for investigating microbiotas as potential biomarkers and their potential role in the prevention or treatment of disease.<a class="elsevierStyleCrossRefs" href="#bib0555">111,112</a>Despite the existence of provisional findings about the links between microbiome and ocular pathologies, it consists a new field of research for investigators in Ophthalmology. Therefore, it is yet to be defined how this apprehension will be gradually translated to interventions with clinical significance.<a class="elsevierStyleCrossRefs" href="#bib0565">113–115</a> Implementation of methods from the wider field of microbiome research (e.g. protein expression, transcriptional activity profile or microbiotas’ metabolic by-products) would be extremely useful in investigating ophthalmological diseases.Moreover, understanding the host biology through functional measures is also essential. These methods can contribute in comprehending whether microorganisms are temporary present and rapidly inactivated or whether they are more persistent forming more permanent, active communities. Another important parameter is to find ways of implicating gnotobiotic animal models in ophthalmological research, considering their significance in microbiome research.<a class="elsevierStyleCrossRef" href="#bib0580">116</a> The juncture between basic science and observational research is substantial and calls for new experimental techniques, so that new larger scale clinical trials can be designed.A continuous experimental elaboration toward this direction will not only provide answers to the current questions, but may also indicate further associations between extraocular microbiome and ocular diseases, or even ophthalmic interventions that potentially affect ocular microbiota.ConclusionThere is growing evidence that intestinal dysbiosis has an immense impact on extra-intestinal immune-mediated pathologies, which are associated with uveitis. The gut microbiota may be a significant link between genetic background and environmental factors that contribute to the pathogenesis of the disease. Larger studies are needed to define the exact interplay of intestinal microbiota and at which stage of the disease are these alterations more crucial. Shedding more light to these perplex pathophysiological mechanisms will enable us to design targeted therapeutic strategies in order to re-establish the intestinal and immune homeostasis, and prevent the progression of the disease.FundingAll authors declare that they received no funding for this study.Conflict of interestAll authors declare that there is no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:19 [ 0 => array:3 [ "identificador" => "xres1704072" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1508573" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1704073" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Materiales y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1508574" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Materials and Methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Understanding Uveitis" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Understanding the microbiome" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Gut microbiota and immune system development" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Tools for investigating the intestinal microbiome" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Alterations of the gut microbiome in extra-intestinal systemic immune-mediated disorders" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Alterations of the gut microbiome in immune-mediated uveitis" ] 12 => array:3 [ "identificador" => "sec0045" "titulo" => "Observations in specific clinical entities associated with uveitis" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Behcet’s disease" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "HLA-B27-associated acute anterior uveitis" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Vogt-Koyanagi-Harada (VKH) disease" ] ] ] 13 => array:2 [ "identificador" => "sec0065" "titulo" => "Potential therapeutic targets of the gut microbiome for ocular inflammation" ] 14 => array:2 [ "identificador" => "sec0070" "titulo" => "Future trends" ] 15 => array:2 [ "identificador" => "sec0075" "titulo" => "Conclusion" ] 16 => array:2 [ "identificador" => "sec0080" "titulo" => "Funding" ] 17 => array:2 [ "identificador" => "sec0085" "titulo" => "Conflict of interest" ] 18 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-09-07" "fechaAceptado" => "2021-01-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1508573" "palabras" => array:5 [ 0 => "Microbiome" 1 => "Uveitis" 2 => "Autoimmune diseases" 3 => "Homeostasis" 4 => "Antibiotics" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1508574" "palabras" => array:5 [ 0 => "Microbioma" 1 => "Uveítis" 2 => "Enfermedades autoinmunes" 3 => "Homeostasis" 4 => "Antibióticos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and objectivesThe microbiome is strongly implicated in a wide spectrum of immune-mediated diseases, whereas gut commensal microbiota plays a pivotal role in immune and intestinal homeostasis. Materials and methodsA thorough literature search was performed in PubMed database. An additional search was made in Google Scholar to complete the collected items. ResultsDue to complex interactions with the host genetics and other factors, intestinal dysbiosis has been linked to various immune-mediated disorders. In particular, the role of intestinal microbiota in the pathogenesis of uveitis has been demonstrated by several studies, indicating that changes in the microbiome can trigger autoimmune ocular inflammatory processes or affect their severity. ConclusionsThis review summarizes how alterations in the intestinal microbiota can conduce to immune-mediated ocular pathologies and how microbiome can be targeted in order to form novel therapeutic approaches to treat these severe and potentially blinding conditions." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "Introducción y objetivosEl microbioma está fuertemente implicado en un amplio espectro de enfermedades inmunomediadas, mientras que la microbiota comensal intestinal juega un papel fundamental en la homeostasis inmunológica e intestinal. Materiales y métodosSe realizó una búsqueda exhaustiva de la literatura en la base de datos PubMed. Se realizó una búsqueda adicional en Google Scholar para completar los elementos recopilados. ResultadosDebido a las complejas interacciones con la genética del huésped y otros factores, la disbiosis intestinal se ha relacionado con varios trastornos inmunomediados. En particular, el papel de la microbiota intestinal en la patogenia de la uveítis ha sido demostrado por varios estudios, lo que indica que los cambios en el microbioma pueden desencadenar procesos inflamatorios oculares autoinmunes o afectar su gravedad. ConclusionesEsta revisión resume cómo las alteraciones en la microbiota intestinal pueden conducir a patologías oculares inmunomediadas y cómo el microbioma puede ser dirigido para formar nuevos enfoques terapéuticos para tratar estas condiciones severas y potencialmente cegadoras." 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The association between intestinal microbiome and autoimmune uveitis

La asociación entre microbioma intestinal y uveítis autoinmune

D. Kalogeropoulosa,

Corresponding author

dkalog1990@gmail.com

Corresponding author.

, R. Barryb,c, C. Kalogeropoulosa

a Department of Ophthalmology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece

b Institute of Clinical Sciences, University of Birmingham, College of Medical and Dental Sciences, Birmingham, United Kingdom

c Department of Ophthalmology, Birmingham & Midland Eye Centre, Sandwell & West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Microbiome is an umbrella term that encompasses a community of microorganisms and their genetic material&#46; The target of the Human Microbiome Project&#44; originally launched by the National Institutes of Health in 2007&#44; was to recognize the microorganisms that normally populate the human body in healthy individuals&#44; as well as to identify alterations related to specific pathologies&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Some of the cardinal roles of the gut bacteria include the breakdown of food remnants&#44; immunomodulation&#44; biosynthesis of vitamins and amino acids&#44; drug metabolism etc&#46; These bacteria are affiliated to the affiliated to the phyla Bacteroidetes and Firmicutes&#44; which together with Actinobacteria and Proteobacteria constitute 90&#37; of intestinal microbiota&#46; Fluctuations in the core microbiome in abundance&#44; diversity and functionality with reference to the healthy-control microbiome is referred to as &#8216;dysbiosis&#8217; &#40;i&#46;e&#46; imbalance of commensal organisms&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In particular&#44; intestinal dysbiosis has been linked with immune system disorders that eventually lead to various diseases&#44; such as spondyloarthropathies&#44; rheumatoid arthritis &#40;RA&#41;&#44; ankylosing spondylitis &#40;AS&#41; and multiple sclerosis &#40;MS&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;6</span></a> Many of these clinical entities are also associated with uveitis&#44; but the pathogenesis of non-infectious &#40;or immune-mediated&#41; uveitis remains obscure&#46; Actually&#44; most cases of uveitis not attributed to surgical or accidental trauma consist manifestations of infectious or immune mediated clinical entities&#46; Approximately 30&#37; to 45&#37; cases with uveitis are associated with an underlying systemic disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;8</span></a> In particular&#44; autoimmune uveitis is a group of intraocular inflammatory pathologies that occur without known infectious etiology&#46; Inflammation of the uveal tract can occur in the context of a systemic autoimmune syndrome such as Beh&#231;et&#8217;s disease&#44; systemic sarcoidosis and Vogt-Koyanagi-Harada disease&#46; However&#44; in other conditions&#44; such as idiopathic uveitis&#44; sympathetic ophthalmia and birdshot retinochoroidopathy&#44; the eye may be the only target&#46; Individuals with autoimmune uveitis often present recognizable memory responses to specific retinal proteins &#40;e&#46;g&#46; retinal arrestin and interphotoreceptor retinoid binding protein - IRBP&#41;&#44; which are expressed in photoreceptor cells and take part in the visual process&#46; Various types of uveitis have been correlated with particular HLA haplotypes &#40;e&#46;g&#46;&#44; A29&#44; B27&#44; B51&#44; DR4&#44; DQ4&#41;&#44; enhancing the concept of the autoimmune pathogenetic mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Although it has been suggested that some types of uveitis may be related with systemic microbial infections&#44; our knowledge remains limited&#46; Previous studies with data deriving from humans and animal models proposed a causative role of gut microbiota in the pathogenesis of autoimmune diseases and uveitis&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The scope of this report is to review the evidence that gut microbiome can trigger immune-mediated mechanisms leading to the development of non-infectious &#40;or autoimmune&#41; uveitis and how it can be potentially targeted for developing therapeutic approaches&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and Methods</span><p id="par0010" class="elsevierStylePara elsevierViewall">A thorough literature search was performed in the PubMed database&#46; An additional search was made in Google Scholar to complete the collected items&#46; The following keywords were used&#58; &#8220;microbiome&#47;microbiota and autoimmunity&#8221;&#44; &#8220;microbiome&#47;microbiota and autoimmune uveitis&#8221;&#44; &#8220;microbiome&#47;microbiota and autoimmune disease&#8221;&#44; &#8220;gut&#47;intestinal microbiome&#47;microbiota and uveitis&#47;autoimmune uveitis&#8221;&#46; Studies that were written in any other language than English were excluded&#46; We also excluded irrelevant studies and those that the full article could not be found&#46; Overall we included 118 references dated from 1989 to 2020&#59; the vast majority of them were published after 2004 &#40;109 out of 118&#41;&#46; An increasing interest in the correlation between the gut microbiome and autoimmune uveitis is noted after 2016&#46; Special emphasis was given to those studies that focus on autoimmune uveitis&#46; However&#44; other studies that approach the role of intestinal microbiota in the pathogenesis of autoimmune disorders&#44; as well as data from experimental studies&#44; were also analyzed and included in our review to support our study&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Understanding Uveitis</span><p id="par0015" class="elsevierStylePara elsevierViewall">Uveitis is associated with around 10&#8211;15&#37; of all cases of blindness in the United States&#44; and consists the fifth cause of visual loss in the developed world&#44; accounting for up to 20&#37; of legal blindness&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Impairment of vision has a crucial impact on the quality of life and productivity of individuals suffering from uveitis worldwide&#46; Therefore&#44; there is an immediate need of improvement in the understanding of uveitis&#44; so as to develop more efficient and sophisticated diagnostic and therapeutic approaches&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The uveal tract is defined as a pigmented&#44; highly vascular loose fibrous tissue that can be divided into three distinct anatomical regions&#58; the iris &#40;anteriorly&#41;&#44; the ciliary body &#40;in the middle&#41; &#40;subdivided into pars plicata anteriorly and pars plana posteriorly&#41;&#44; and the choroid &#40;posteriorly&#41;&#46; Uveitis is a general term describing a group of inflammatory disorders affecting any of these structures&#44; and may also involve other surrounding tissues such as sclera&#44; retina&#44; and optic nerve&#46; Classifying uveitis according to the predominant site of inflammation can contribute in narrowing the differential diagnosis&#46; As established by the SUN &#40;Standardization of uveitis nomenclature&#41; Working group&#44; the anatomic division of the uveal tract facilitates the classification of uveitis into anterior uveitis &#40;iritis&#44; anterior cyclitis&#44; iridocyclitis&#41;&#44; intermediate uveitis&#44; posterior uveitis &#40;focal&#44; multifocal&#44; or diffuse choroiditis&#44; retinochoroiditis&#44; or neuro-uveitis with optic nerve inflammation&#41;&#44; and panuveitis &#40;generalized intraocular inflammation&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The unique anatomical and physiological features of the human eye makes the management of uveitis even more complicated&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Currently&#44; despite the available diagnostic resources&#44; more than 30&#37; of cases do not have a definitive etiologic diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The clinical manifestations of uveitis can provide crucial clues into setting diagnosis and detecting the infectious&#44; inflammatory&#44; or neoplastic etiologies&#46; Thus&#44; uveitis calls for a thorough ophthalmologic assessment&#46; Slit-lamp biomicroscopy remains the cornerstone of clinical evaluation&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> but retinal imaging &#40;e&#46;g&#46; Optical Coherence Tomography &#8211; OCT&#44; Fluorescein Angiography &#8211; FA&#44; or Fundus Photography&#41; can provide significant information not only during the first assessment but also for patient&#8217;s follow-up&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Understanding the microbiome</span><p id="par0030" class="elsevierStylePara elsevierViewall">Born devoid of microorganisms&#44; human gut becomes gradually heavily colonized by a complex spectrum of bacteria&#44; archaea&#44; eukaryotes and viruses that form communities&#44; which are collectively mentioned as the intestinal microbiota&#46; Its presence is crucial in several aspects of host physiology&#44; including the acquisition and provision of nutrients&#44; resistance to invading pathogens and education of the immune system&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> Although there has been a climax of interest in the microbes that colonize our body&#44; it appears that this field has gained scientific attention for more than a century&#46; Indeed&#44; Elie Metchnikoff was fascinated by the potential effect of this complex ecosystem on physiological and pathological states of our immune system&#46; This notion is correlated with how health-promoting bacteria &#40;probiotics&#41; have been implemented in therapeutic approaches in the early twentieth century&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The concept of microbiome is very important&#44; especially if we take into account that commensal microorganisms colonize all exposed surfaces of the human body and outnumber human cells by at least 10 to 1&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> If we translate this in terms of genetic information&#44; it means that there is a greater than 100-fold difference&#44; since a single human comprises 23&#46;000 host genes&#44; whereas the microbes residing in our body encompass more than 3&#46;000&#46;000 genes&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> A significant amount of the human microbiome is found in the gastrointestinal tract&#44; where a substantial proportion of the human body&#8217;s immune system is also settled&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The immune system of the human body is significantly influenced by the development of the early microbiota&#44; whereas the insufficient normal colonization of the gastrointestinal tract in infants &#40;as occurs in C-section delivery in comparison to vaginal delivery&#41; can predispose to immune-mediated diseases at later stages of life&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">As mentioned above&#44; the pathogenesis of non-infectious &#40;or immune-mediated&#41; uveitis is not completely understood&#46; Many uveitic entities are associated with specific inflammatory cytokine pathways&#46; Data deriving from the study of the serum or ocular fluids of immune-mediated uveitis individuals of various causes have shown increased levels of interleukin-6 &#40;IL- 6&#41;&#44; IL-17&#44; IL-23 or tumor necrosis factor-alpha&#46; Interestingly&#44; over the last decade&#44; the vast majority of therapeutic targets have involved these pathways with various degrees of success but still calling for further investigation of their efficacy&#46; The triggering factors of uveitis and pathogenetic mechanisms that lead to the elevation of cytokine levels are not always obvious&#46; Moreover&#44; treatments targeting at the restoration of immune homeostasis remain inadequately explored&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Commensal microbiota has been found to play a pivotal role in immune-mediated disorders either by promoting or by inhibiting inflammatory process&#46; Thus&#44; an improved understanding and manipulating of the microbiome may contribute in recognizing novel pathogenetic mechanisms and consequently new therapeutic approaches&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The complex interactions between the human immune system and the microbiome of the gastrointestinal tract can occur even at the level of strain-specific changes of immune cell repository&#46; For example&#44; the differentiation of T helper 17 cells &#40;Th17&#41; in the gut can be promoted by certain bacterial strains&#44; segmented filamentous bacteria f detected in rodents<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> and analogous bacterial strains detected in humans&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> When Th17 become pathogenic&#44; they are significantly associated with autoimmune diseases including uveitis&#46; On the other hand&#44; other bacteria &#40;e&#46;g&#46; certain types of <span class="elsevierStyleItalic">Clostridia</span>&#44; and the bacterial species&#44; <span class="elsevierStyleItalic">Bacteroides fragilis</span>&#41; can augment the differentiation of colonic Tregs therefore contribute to immune homeostasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;25</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Although the equilibrium of microbiota can conduce to the pathogenesis of immune disorders&#44; it has been found that host genetics&#44; such as HLA-type&#44; can affect the microbial framework of the gut&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> Other aspects of the human microbiome &#40;e&#46;g&#46; oral&#44; skin&#44; pulmonary or ocular microbiome&#41; may indeed be substantial for the pathogenesis of disease but will not be analyzed in the context of this review&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Gut microbiota and immune system development</span><p id="par0065" class="elsevierStylePara elsevierViewall">The mucosal immune system is defined by high-specialization and many of its functions are quite independent of the systemic immune system&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> whereas it goes through significant alterations after bacterial colonization of the intestinal tract&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Commensal microorganisms contribute to the maturation of the immune system&#44; which is &#8220;trained&#8221; to distinguish commensal bacteria from pathogenic bacteria&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;31</span></a> This differential recognition is mediated by Toll-like receptors &#40;TLRs&#41;&#44; which are detected in the membrane of the epithelial and lymphoid cells of the small intestine and play a pivotal role in the development of the normal intestinal mucosal immune system&#46; TLRs suppress the inflammatory responses and promote immunological tolerance to normal microbiota components&#46; TLRs identify different general microbe-associated molecular patterns &#40;MAMPs&#41; that contain several bacterial antigens &#40;such as capsular polysaccharides and lipopolysaccharides&#44; peptidoglycan components-muramic acid&#44; flagellin and unmethylated bacterial DNA CpG motifs&#41; and trigger the innate intestinal immunity&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> After stimulation&#44; a complex surge of signals leads to the release of nuclear factor kappa-light-chain-enhancer of activated B cells &#40;NF-kB&#41;&#44; activating a wide spectrum of genes coding acute phase proteins&#44; cytokines&#44; chemokines and other components of the humoral immune response&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;35</span></a> TLR activity declines gradually during the first weeks of life&#44; allowing the formation of a constant gut bacterial community&#46; Moreover&#44; activation of TLRs by antigens of the normal gut microbiota is signaling the repression of inflammatory responses&#44; and is therefore necessary for maintaining intestinal homeostasis&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> Furthermore&#44; NOD-like receptors &#40;NLRs&#41; detect microbial specific molecules and trigger the group of inflammasomes&#44; which can recognize damage-associated patterns&#46; In particular&#44; the deficiency of NLPRP6 has been correlated to alterations of immune response&#44; dysbiosis&#44; and intestinal hyperplasia&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a> Microbiota of the gastrointestinal tract has been found to regulate neutrophil migration and function&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> as well as the differentiation of T cell populations into different types of helper cells &#40;Th&#41; &#40;Th1&#44; Th2&#44; and Th17&#41; or into regulatory T cells &#40;Tregs&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> The Th17 cells constitute a subset of TCD4&#43; cells that release various cytokines &#40;IL-22&#44; IL-17A&#44; and IL-17F&#41;&#44; with a tremendous effect on immune homeostasis and inflammation&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a> Th1 and Th2 cells maintain a stable secretory profile after differentiation&#44; whereas Th17 cells are defined by a divergent cytokine expression profiles and functions&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> Interestingly&#44; the administration of the purified capsular polysaccharide from the commensal bacterium B&#46; fragilis reduces IL-17 production and stimulates TCD4&#43; lymphocytes to produce IL-10 in order to protect the colonic mucosa against inflammatory processes triggered by bacterial antigens&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> On the other side&#44; the colonic milieu also regulates the de novo differentiation and outspread of peripherally derived Tregs from na&#239;ve CD4&#43; T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> Tregs are essential for immune tolerance&#59; they can suppress an inappropriately high inflammatory reaction&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> whereas their dysregulation can lead to autoimmune diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> Secretory immunoglobulin A &#40;sIgA&#41; is an important component of the local immune response&#44; shaping a first line of defense against toxins and pathogens&#46; Production of sIgA specific to different mucosal antigens occurs after the captivation of these antigens by Peyer&#8217;s patches M cells&#44; transformation by dendritic cells &#40;DCs&#41;&#44; T cells activation&#44; and finally B cell class switching in gut-associated lymphoid tissue and mesenteric lymph nodes &#40;MLNs&#41;&#46; Production of small amounts of sIgA is induced by the commensal antigens via the configuration of their immune-dominant epitopes&#44; providing a supremacy for the gut colonization&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> IgA production is stimulated by a cascade of cytokines&#44; including IL-4&#44; IL-5&#44; IL-6&#44; IL-10 and TGF-&#946;&#46; Particularly IL-10 and TGF-&#946;&#44; are important for the mucosal tolerance&#44; indicating the strong link between sIgA secretion&#44; immunity&#44; and intestinal homeostasis&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> Immune reactivity could be upregulated to enhance the establishment of a more favorable status in individuals with intestinal dysbiosis&#46; This could be achieved through specific effects of sIgA&#44; or less specific effects of innate immunity effectors &#40;e&#46;g&#46; defensins&#41; or local milieu alterations &#40;i&#46;e&#46;&#44; diarrhea&#41;&#46; In diarrhea&#44; undesirable microbial communities are eliminated so as to reform intestinal niches for a re-colonization process with optimal microbial populations in order to promote healing&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Additionally&#44; the commensal microbiota of the host initiates several responses from the epithelium&#44; such as the production of various antibacterial lectins &#40;e&#46;g&#46; RegIIIc&#44; &#945;-defensins&#44; and angiogenins&#41;&#46; These effectors restrict the volume of potential pathogens&#44; providing protection against pathological immune responses&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;50</span></a> In overall&#44; microbial products can lead to continuous immune responses and thus to chronic non-resolving inflammation and tissue destruction&#44; especially after mucosal injury&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Tools for investigating the intestinal microbiome</span><p id="par0070" class="elsevierStylePara elsevierViewall">Shedding more light in aspects regarding the composition and functional capacity of the gut microbiome is a great challenge&#46; The research in this field is continuously developing and currently a number of approaches are being facilitated in order to determine the genetic background&#44; the composition and function of intestinal microbiota&#46; Culture-based techniques were traditionally used for defining the composition of the gut microbiome&#46; However&#44; this methods focused mainly on the &#8220;easy-to-culture&#8221; pathogens and gradually became less popular considering that approximately 10&#8211;50&#37; of the gut bacteria are culturable&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> These techniques have obviously limitations and cannot provide a pragmatic overview regarding the microbial composition of the gut&#46; Despite these restrictions&#44; some of the progress in this field can be attributed to the increased availability of specialized media for cultivating fastidious organisms&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">A study by Lagier et al&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> has provided further development in this research area and has led to the introduction of the so-called &#8220;microbial culturomics&#8221;&#46; This approach introduces an array of novel culturing methods&#44; coupled with matrix-assisted laser desorption&#47;ionization&#8211;time of flight mass spectrometry &#40;MS&#41;&#44; to detect a range of previously uncultivated microbiota from the gut&#46; Interestingly&#44; this technique has overcome many of the aforementioned limitations and has led to the recognition of 174 new species in the human gut&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Despite these recent developments&#44; it remains clear that culture-independent are more effective in providing a rapid overview of the gut microbiota&#46; One of the most revolutionary modalities was the development and application of fast and low-cost DNA sequencing methods&#46; High throughput sequencing &#40;HTS&#41; technologies have been widely used to investigate the gut microbiome&#44; due to their speed&#44; scale and precision&#46; The 16S rRNA gene has been most commonly targeted for compositional analysis&#44; as it is present in all prokaryotes&#46; Moreover&#44; the existence of variable domains enable the distinction of different taxa&#46; Although&#44; most of HTS reports have relied on the Roche 454 pyrosequencing platforms&#44; other sequencing technologies&#44; are becoming more preferred &#91;e&#46;g&#46; as those provided by Illumina &#40;San Diego&#44; CA&#44; USA&#41;&#93;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">16S rRNA studies provide information regarding the microbial status of an ecosystem&#44; they do not offer direct data in relation with the microbial viability or the potential functions&#46; This issue is addressed by metagenomic &#40;or shotgun sequencing&#41; studies&#44; which can define the full genetic content of a microbial population and therefore its functional capacity&#46; It must be noted though&#44; that detailed bio-informatic analyses to cope with the large volumes of data generated are required in theses sequencing technologies&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">55&#8211;58</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Moreover&#44; analysis gene expression &#40;metatranscriptomics&#41;&#44; protein products &#40;metaproteomics&#41; and metabolic profiles &#40;metabolomics&#41; is necessary for furtherly recognizing specific microbial activity&#46; However&#44; apart from being complex&#44; these techniques are still at early stages of their development&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Alterations of the gut microbiome in extra-intestinal systemic immune-mediated disorders</span><p id="par0095" class="elsevierStylePara elsevierViewall">Patterns deriving from the intestinal microbiota have been correlated to extra-intestinal immune-mediated diseases such as MS&#44; RA and AS&#46; Characteristically&#44; it was shown that in new-onset treatment-naive RA patients&#44; which often present with scleritis &#40;inflammation of the sclera&#41;&#44; <span class="elsevierStyleItalic">Prevotella copri</span> is substantially elevated in the intestinal tract&#44; while beneficial bacteria&#44; such as <span class="elsevierStyleItalic">Bacteroides</span> species&#44; are conversely lessened&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> This profusion of intestinal <span class="elsevierStyleItalic">P&#46; copri</span> is inversely associated with the existence of RA-associated genetic risk factors &#40;the &#8216;shared-epitope&#8217; genes&#41;&#44; indicating that non-genetic RA &#40;most cases of RA&#41;&#44; is notably more possible to be associated with this specific pattern of intestinal dysbiosis than genetic RA&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Similarly&#44; in MS that can be associated with anterior or intermediate uveitis with retinal vasculitis&#44; an intestinal dysbiosis has been found&#46; In that case&#44; a crucial depletion in essential <span class="elsevierStyleItalic">Clostridia</span> clusters IV and XIVa &#40;known to promote Tregs differentiation&#41; has been demonstrated&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In a study that facilitated the relapsing-remitting mouse model of spontaneously developing experimental autoimmune encephalomyelitis&#44; two groups have shown how changes in the intestinal microbiome affect disease severity&#46; The first group revealed that mice raised in a germ-free environment presented almost no CNS inflammation&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> while the other group showed a notable decrease in CNS inflammation when mice were administered with broad-spectrum oral antibiotics&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> These observations suggest that in the absence of pathogenic agents gut flora is critical in triggering immune processes&#44; leading to a relapsing-remitting autoimmune disorder driven by myelin-specific CD4 &#40;&#43;&#41; T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> The latter study reported that broad-spectrum oral antibiotics suppressed CNS inflammation by increasing the number Tregs in specific lymphoid tissues&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> Another study by Berer et al&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> highlighted that CNS inflammation was enabled when microbiota from MS patients were transplanted into mice&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Alterations of the gut microbiome in immune-mediated uveitis</span><p id="par0105" class="elsevierStylePara elsevierViewall">In gut-associated lymphoid tissue &#40;GALT&#41;&#44; under normal conditions&#44; potential pathogens are presented by antigen-presenting cells to Th cells &#40;especially Th17 cells&#41;&#44; to promote inflammatory response by stimulating the proliferation and secretion of inflammatory cytokines &#40;e&#46;g&#46; IL-17&#41;&#46; On the contrary&#44; Tregs suspend the hyperbolic immune response and impede persistent inflammation&#46; As can be inferred&#44; there is a dynamic balance among Th17 and Tregs in order to preserve the gut homeostasis&#46; Interestingly&#44; commensal bacteria of the gut can modify the mucosal immunity of the intestinal tract&#44; including the equilibrium between Th17 and Tregs&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> The dysbiosis of gut microbiome may cause significant homeostatic disorders&#44; affect the balance of Th17&#47;Tregs &#40;a rise in Th17 generation and a drop in Tregs production&#41;&#44; degrade the threshold of immune activation&#44; and eventually lead to a wide spectrum of intestinal and extra-intestinal inflammatory pathologies&#44; such as autoimmune uveitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">64&#44;65</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In contrast with other extra-intestinal immune-mediated disorders&#44; the number of studies about the correlation of the gut microbiome in the pathogenesis of autoimmune uveitis &#40;and other ophthalmologic pathologies&#41; remains limited&#46; Nakamura et al&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> investigated the contribution of the gut microbiota to the pathogenesis of uveitis by facilitating the method of experimental autoimmune uveitis &#40;EAU&#41; in B10&#46;RIII mice&#46; Their study showed that the severity of uveitis seems to be correlated with specific commensal bacteria&#44; whereas the state of uveitis is associated with particular strains of bacteria&#46; More specifically&#44; they found that oral&#44; but not intraperitoneal antibiotics&#44; reduced mean uveitis clinical scores substantially compared with water-treated animals&#46; Oral metronidazole and vancomycin alone suppressed inflammatory activity&#44; while ampicillin and neomycin did not affect mean uveitis scores&#46; The administration of oral broad-spectrum antibiotics lead to elevated Tregs in the gastrointestinal lamina propria after 1 week&#44; and later in extra-intestinal lymphoid tissues&#44; whereas inflammatory cytokines and Teff were reduced&#46; 16S sequencing of gastrointestinal contents changes the microbiome of immunized mice in comparison with non-immunized mice&#46; EAU mice also revealed intestinal microbial diversity clustering associated with clinical score severity&#46; These results suggest that oral antibiotics can regulate the severity of inducible EAU and that there may be protective&#44; and conversely intestinal microbiota that can be potentially uveitogenic&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Similarly&#44; Heissigerova et al&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> reported that the presence of microbiota during autoantigen recognition regulates the inflammatory response by influencing the adaptive immune response in the murine model of EAU&#44; as either germ-free rearing or treatment with oral antibiotics &#40;metronidazole and ciprofloxacin&#41; led to significant reduction of uveitis severity&#46; Another study that utilized a novel mouse model of spontaneous uveitis exhibited that activation of retina-specific T cells is dependent on gut commensal microbiota&#46; This involved signaling via the autoreactive T cell receptor &#40;TCR&#41; in response to non-cognate antigen in the intestine and was independent of the endogenous retinal autoantigen&#46; These results indicate that the activation of TCRs by commensal microbes can trigger the pathogenesis of autoimmune diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">A more recent study by Nakamura et al&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> highlighted that even during the priming uveitic phase &#40;before ocular inflammation&#44; 1 week after immunization&#41;&#44; alterations of the gut bacteria may occur&#46; Some of these changes are associated with uveitis&#44; whereas others are due to the mycobacterial adjuvant&#46; Furthermore&#44; there are morphological alterations in the intestinal crypts and submucosa&#44; a change in the intestinal mucosal immunity &#40;defined by enhanced expression of intestinal zonulin&#44; which is a marker for intestinal permeability&#41; and increased production of antimicrobial peptides lipocalin and S100A8 in the gut&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> It has also been highlighted that 2 weeks after immunization mycobacterial antigen &#40;MTB&#41; and retinal peptide a peak in inflammatory process was observed&#46; At the same period&#44; apart from increased abundance of several gut bacteria&#44; an increased trafficking of Th1 and Th17 effector T cells between the gut and the spleen was noted&#46; Interestingly&#44; the amount of leukocytes deriving from the intestines detected in the eye was associated with the degree of uveitic activity&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> Finally&#44; taking into consideration all the above&#44; it has been suggested that re-establishing immune homeostatic mechanisms by strengthening the function of Tregs can play a key role in the treatment of uveitis&#44; either by manipulating commensal bacterial dietary metabolites or by direct alteration of intestinal bacteria&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">69&#44;70</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Observations in specific clinical entities associated with uveitis</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Behcet&#8217;s disease</span><p id="par0125" class="elsevierStylePara elsevierViewall">Beh&#231;et&#39;s disease is a multisystem immune-related disorder of unknown etiology characterized by recurrent oro-genital ulcers&#44; mucocutaneous lesions&#44; and serious organ involvement&#46; It has been proposed that various environmental and other triggering factors are implicated with the onset and the clinical relapses of Beh&#231;et&#39;s disease&#46; Stress appears to be a common self-triggering factor for most of these patients&#46; Stimuli such as some food substances can activate oral ulcers&#44; and may be relevant to the histamine content of the food&#46; Oral&#47;skin trauma and menstruation related to hormonal factors aggravate&#44; whereas allergy&#47;atopy seem to alleviate the disorder&#8217;s symptoms&#46; Infections have been associated with Beh&#231;et&#39;s disease&#44; as microbial stimuli can activate inflammation in mucosal surfaces with increased Th1&#47;Th17 responses&#46; Interestingly&#44; alterations in the diversity and composition of fecal and oral microbiome patterns have also been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> The association of microbiota with Beh&#231;et&#8217;s disease has not fully clarified yet&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Consolandi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> compared the fecal microbiota of 22 Beh&#231;et patients with that of 16 healthy co-habiting controls&#44; by facilitating pyrosequencing of the V3-V4 hypervariable regions of the 16 rDNA gene and biochemical analyses&#46; Their results highlighted significant differences in gut microbiota between the two groups&#46; More specifically&#44; it was demonstrated that patients with Beh&#231;et&#39;s disease were significantly depleted in the genera <span class="elsevierStyleItalic">Roseburia</span> and <span class="elsevierStyleItalic">Subdoligranulum</span>&#44; compared to the controls&#46; Another important finding of this study is the decreased production of butyrate in Beh&#231;et&#39;s patients&#46; As butyrate promotes the differentiation of Tregs&#44; a disorder in its production could cause reduced Treg responses and also activation of immuno-pathological T-effector responses&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Another study by Seoudi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> reported differences in the microbial composition of the saliva of 54 Beh&#231;et&#39;s patients&#44; eight subjects affected by recurrent aphthous stomatitis&#44; and 25 controls&#46; In Beh&#231;et&#39;s individuals non-ulcerous oral cavities were mostly colonised by <span class="elsevierStyleItalic">Rothia denticariosa</span>&#44; whereas ulcerous oral cavities showed a higher prevalence of <span class="elsevierStyleItalic">Streptococcus salivarius</span> and <span class="elsevierStyleItalic">Streptococcus sanguinis</span> in comparison with those of the subjects in the two control groups</p><p id="par0140" class="elsevierStylePara elsevierViewall">Based on the theory that the class <span class="elsevierStyleItalic">Clostridia</span> includes short-chain fatty acid-producing bacteria&#44; which are important for the equilibrium the balance between Tregs and helper Th17 cells&#44; it has been suggested that the bacterial compositional changes may lead to low intestinal short-chain fatty acid concentrations and therefore to immune disorders in Beh&#231;et&#39;s patients&#46; To explore this hypothesis Shimizu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> investigated species composition and gene functions from the 16S rRNA data by utilizing PICRUSt software&#46; It was found that these individuals have a relative abundance of <span class="elsevierStyleItalic">Eggerthella lenta</span>&#44; <span class="elsevierStyleItalic">Acidaminococcus species</span>&#44; <span class="elsevierStyleItalic">Lactobacillus mucosae</span>&#44; <span class="elsevierStyleItalic">Bifidobacterium bifidum</span>&#44; <span class="elsevierStyleItalic">Lactobacillus iners</span>&#44; <span class="elsevierStyleItalic">Streptococcus species</span>&#44; and <span class="elsevierStyleItalic">Lactobacillus salivarius</span>&#46; On the other hand relative abundance of <span class="elsevierStyleItalic">Megamonas hypermegale</span>&#44; <span class="elsevierStyleItalic">Butyrivibrio</span> species&#44; <span class="elsevierStyleItalic">Streptococcus infantis</span>&#44; and <span class="elsevierStyleItalic">Filifactor</span> species increased notably in controls in comparison with Beh&#231;et&#39;s patients&#46; It was highlighted that prevalent gene functions of the pentose phosphate pathway and the inosine monophosphate biosynthesis were recorded in patients with Beh&#231;et&#39;s disease&#44; indicating that gut microbes affected nucleic acid and fatty acid synthesis&#46; The same team conducted a fecal metagenomics analysis in Beh&#231;et&#39;s patients&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> In these patients&#44; direct comparison of the relative abundance of bacterial taxa showed that the genera <span class="elsevierStyleItalic">Bifidobacterium</span> and <span class="elsevierStyleItalic">Eggerthella</span> increased remarkably and the genera <span class="elsevierStyleItalic">Megamonas</span> and <span class="elsevierStyleItalic">Prevotella</span> decreased substantially&#46; Moreover&#44; it was shown that the phylum <span class="elsevierStyleItalic">Actinobacteria</span>&#44; including <span class="elsevierStyleItalic">Bifidobacterium</span>&#44; and the family <span class="elsevierStyleItalic">Lactobacillaceae</span> presented larger positive effect sizes than other bacteria in patients with Beh&#231;et&#39;s&#46; These data come in agreement with another metagenomics study conducted by Ye et al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> who reported that fecal samples from active Beh&#231;et&#39;s patients were found to be enriched in <span class="elsevierStyleItalic">Bilophila</span> spp&#46;&#44; a sulfate-reducing bacteria &#40;SRB&#41; and various opportunistic pathogens &#40;e&#46;g&#46;&#44; <span class="elsevierStyleItalic">Parabacteroides</span> spp&#46; and <span class="elsevierStyleItalic">Paraprevotella</span> spp&#46;&#41; together with a lower level of butyrate-producing bacteria &#40;BPB&#41; <span class="elsevierStyleItalic">Clostridium</span> spp&#46; and methanogens &#40;<span class="elsevierStyleItalic">Methanoculleus</span> spp&#46; <span class="elsevierStyleItalic">Methanomethylophilus</span> spp&#46;&#41;&#46; Remarkably&#44; capsular polysaccharide transport system&#44; oxidation-reduction process&#44; type III&#44; and type IV secretion systems were also aggravated in individuals with active disease&#46; Additionally&#44; transplantation of fecal microbiota from human patients to experimental animals caused exacerbation of EAU activity and elevated production of inflammatory cytokines &#40;IL-17&#44; IFN-&#947;&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Another interesting potential association has been noted regarding the pathogenetic role of <span class="elsevierStyleItalic">Helicobacter pylori</span> in this disease&#46; Interestingly&#44; there is a high prevalence of this infection in areas where Beh&#231;et&#39;s disease is more frequent&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">77&#8211;79</span></a> There are implications that the geographic distribution of gastric cancer&#44; which is the most severe complication of this infection&#44; may have various similarities to Beh&#231;et&#39;s disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">80&#44;81</span></a> Results from recent studies<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">82&#44;83</span></a> indicated that <span class="elsevierStyleItalic">H&#46; pylori</span> may indeed have a role in the pathogenesis of this multisystem disease and clinical features &#40;e&#46;g&#46; oral and genital ulcers&#44; or cutaneous lesions&#41; can be improved after <span class="elsevierStyleItalic">H&#46; pylori</span> eradication&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Consequently&#44; unfavorable compositional and functional changes in the gut microbiota &#40;dysbiosis&#41; may have an association with the immune aberrations and the pathophysiology of Beh&#231;et&#39;s disease&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">HLA-B27-associated acute anterior uveitis</span><p id="par0155" class="elsevierStylePara elsevierViewall">Acute anterior uveitis &#40;AAU&#41; and associated spondyloarthropathies &#40;i&#46;e&#46; ankylosing spondylitis&#44; enthesitis related arthritis in children&#44; reactive arthritis&#44; arthritis associated with inflammatory bowel disease&#44; and psoriatic arthritis&#41; have been incorporated in the broad spectrum of immune-mediated inflammatory diseases which have been linked with the biology of the intestinal microbiome&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Spondyloarthropathies are clearly connected to bowel inflammation&#44; which may often be asymptomatic in a disease such as ankylosing spondylitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">85&#44;86</span></a> Patients with ankylosing spondylitis&#44; appear to have an intestinal dysbiosis too&#44; as well as increased bowel permeability&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> whereas a variety of enteric infections including <span class="elsevierStyleItalic">Salmonella&#44; Yersinia&#44; Shigella&#44;</span> and <span class="elsevierStyleItalic">Campylobacter</span> can trigger reactive arthritis&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">88&#44;89</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">HLA molecules regulate the immune response in more than 100 diseases&#46; However&#44; the exact pathogenetic mechanisms remain unknown&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a> Interestingly&#44; the association between HLA B27 and spondyloarthritis is considered to be among the strongest&#46; It has been hypothesized that HLA molecules affect the intestinal bacterial composition&#46; More specifically&#44; these individuals are often defined by the HLA-B27 genotype and acute anterior uveitis can occur in up to 30-40&#37; of cases&#46; A positive HLA-B27 itself has also a remarkable correlation with the development of acute anterior uveitis&#46; Notably&#44; a significant proportion of patients with AS or other spondyloarthropathies present with subclinical features of gastrointestinal inflammation&#46; Lin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> reported the use of a culture-independent method of sequencing a small fragment of the bacterial 16S rRNA gene&#46; This study showed that transgenic rats expressing human HLA-B27 had a dysbiosis leading to increased amounts of <span class="elsevierStyleItalic">Paraprevotella</span> &#40;a bacterial genus within the same family as <span class="elsevierStyleItalic">Prevotella</span>&#41;&#44; and decreased amounts of <span class="elsevierStyleItalic">Rikenellaceae</span> family of bacteria&#46; Interestingly&#44; in patients with AS&#44; terminal ileum is enriched with five families of bacteria including <span class="elsevierStyleItalic">Lachnospiraceae</span> and <span class="elsevierStyleItalic">Prevotellaceae</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> It has also been suggested that HLA-B27 changes intestinal microbial components&#44; disrupts intestinal permeability and causes subclinical intestinal inflammation&#44; which may lead to leakage of bacterial constituents that advocate inflammation in other anatomical sites&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> This hypothesis could probably explain how AS patients develop uveitis&#44; joint inflammation or other HLA-B27 related disorders&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Further data&#44; deriving from experiments on HLA B27 transgenic rats<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a> were used to test this hypothesis&#46; This animal model express multiple copies of HLA B27 along with the invariant Major histocompatibility complex &#40;MHC&#41; light chain&#44; beta 2 microglobulin&#46; More than two decades ago&#44; Taurog et al&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a> described the spondyloarthropathy affecting these rats&#46; The animals develop diarrhea around two to four months of age and subsequently many of them will develop spondylitis&#44; peripheral arthritis&#44; and psoriasiform rashes&#46; The bowel and joint disease is significantly reduced if the rats are raised in a germ free environment&#44; showing that microbiome plays a crucial role in the pathophysiology of this disease&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a> Some bacteria &#40;e&#46;g&#46; <span class="elsevierStyleItalic">Lactobacillus rhamnosus GG</span>&#41; contribute in a way that the remission is maintained&#44; whereas other lead to recurrence of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a> HLA B27 clearly affects the gut microbiome of these rats&#46; One of the first immunological alterations is the upregulation of antimicrobial peptides &#91;e&#46;g&#46; RegIII&#947; and S100A8 &#40;calprotectin&#41;&#93; in the colon of these animals<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">96</span></a> may precede the development of dysbiosis&#46; Therefore it has been proposed that alterations in the gut microbiome may be a primary event in the pathogenesis of spondyloarthropathy rather than an epiphenomenon&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> Serum calprotectin has been suggested as a biomarker for juvenile idiopathic arthritis with uveitis&#44;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">97</span></a> posterior uveitis&#44;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">98</span></a> and Beh&#231;et&#39;s disease&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a> There is evidence that MHC can modify the microbiota and therefore predispose to various immune-diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">100&#44;101</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Regarding the potential role of <span class="elsevierStyleItalic">H&#46; pylori</span> in the pathogenesis of inflammatory disorders&#44; the studies of Bae et al&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">102</span></a> and Otasevic et al&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">103</span></a> have investigated the association between <span class="elsevierStyleItalic">H&#46; pylori</span> seropositivity and HLA-B27-positive acute anterior uveitis&#44; with the first study<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">96</span></a> suggesting an inverse association&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Several mechanisms have been proposed for how HLA B27 may lead to the loss of ocular tolerance and uveitogenesis&#44; many of which may be also relevant with for the loss of intestinal tolerance that accompanies several forms of spondyloarthropathies&#46; However&#44; these mechanisms are not mutually exclusive&#46; B27-dependent mechanisms may impact the gut and&#47;or the eye itself&#44; where loss of tolerance could contribute to the manifestation of uveitis&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> Some of the models where the gut microbiome is a key component of AAU pathogenesis include self-antigen dependent or self-antigen independent model of uveitis&#46; However&#44; these mechanisms and models cannot be thoroughly discussed in the context of this review and therefore readers are referred to the studies of Rosenbaum et al&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">84&#44;104&#44;105</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Vogt-Koyanagi-Harada &#40;VKH&#41; disease</span><p id="par0185" class="elsevierStylePara elsevierViewall">VKH disease is a multisystem autoimmune pathology associated with granulomatous panuveitis&#46; It has been proposed that gut microbiome plays a substantial role in the pathogenesis of this disease&#46; Ye et al&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">106</span></a> reported detecting depleted butyrate-producing bacteria&#44; lactate-producing bacteria and methanogens and enriched Gram-negative bacteria in patients with active VKH disease&#46; Interestingly&#44; gut microbiome alterations were partially restored in these patients after administrating immunosuppressive treatment&#46; Furthermore&#44; the disease susceptibility genotype HLA-DRA was correlated to <span class="elsevierStyleItalic">Bacteroides</span> sp&#46;2&#46;1&#46;33B&#44; <span class="elsevierStyleItalic">Paraprevotella clara</span>&#44; <span class="elsevierStyleItalic">Alistipes finegoldii</span> and <span class="elsevierStyleItalic">Eubacterium eligens</span>&#46; Based on an experimental animal model&#44; it was shown that transfer of gut microbiome from VKH patients could lead to significant exacerbation &#40;clinically and pathologically&#41; of the disease activity in the recipient mice&#46; The results from this study also indicate that developing microbial marker profiles could be helpful in distinguishing VKH patients from healthy controls as well as predicting the effectiveness of treatment&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Potential therapeutic targets of the gut microbiome for ocular inflammation</span><p id="par0190" class="elsevierStylePara elsevierViewall">Firstly&#44; targeting specific causative bacteria could be facilitated by intelligent techniques defined by high specificity&#46; For instance&#44; this could be achieved by designing immunoglobulins that target specific bacteria or bacterial components&#47; metabolites that have been linked to the inflammatory condition&#44; but without affecting the status of other beneficial bacteria&#46; Okai et al&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">107</span></a> reported a beneficial effect on colitis models in mice&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Another approach for targeting the intestinal microbiome could be by oral administration of live bacterial strains that are proven to promote immune homeostasis &#40;e&#46;g&#46; by enhancing differentiation of regulatory T cells&#41;&#46; Although this method appears to have great potential&#44; it is critical to design probiotics so that they will be able to maximize colonization in the human gut&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">108&#44;109</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">A third strategy could employ what are widely considered as chemical drugs&#46; For example&#44; utilizing antibiotics that may not be broad-spectrum but instead are chemicals targeting specific metabolic pathways of only one community of bacteria&#46; This could partially contribute to a therapeutic approach which is based on the administration of beneficial bacteria in the form of colonization-ready probiotics after antibiotics so as to re-establish the immune balance and intestinal homeostasis&#46; Targeting of intestinal bacteria has been used for the treatment of systemic rheumatic diseases over the last decades&#46; Designing agonists to short chain fatty acid cell surface receptors or analogues of the components of beneficial bacteria&#44; could be another drug therapy method&#46; It has been demonstrated that oral administration of <span class="elsevierStyleItalic">Bacteroides fragilis</span> &#40;polysaccharide from the human commensal&#41; had a protective action against an MS-like CNS demyelinating disease in rodents&#44;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">109</span></a> whereas oral short chain fatty acids can ameliorate uveitis&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">A fourth approach involves dietary modifications&#44; such as exposure to a diet high in non-digestible fibres in order to boost the production of endogenous short chain fatty acids by the intestinal microbiota&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">A final therapeutic strategy is to replace an entire community of intestinal bacteria with a normal community using a fecal microbial transplant&#46; This method has been found to have favorable outcomes in antibiotic-resistant Clostridium difficile colitis in large clinical trials&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">110</span></a> However&#44; this approach may have to overcome various challenges&#44; such as defining healthy or appropriate donors or establishing regulations for donor material testing to avoid transplant complications&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Future trends</span><p id="par0215" class="elsevierStylePara elsevierViewall">The microbiome research is expected to shed light in several pathologies within ophthalmology and beyond&#46; The refinement of laboratory and experimental techniques over the last decade has enabled researchers to define important parameters regarding the composition and function of microbiotas&#46; More specifically&#44; new assays and bioinformatics has allowed a more detailed analysis of host-microbiota interactions&#44; whereas large-scale longitudinal studies have indicated new insights regarding the effect of microbiotas on various pathogenetic mechanisms&#46; Furthermore&#44; clinical trials have been essential for investigating microbiotas as potential biomarkers and their potential role in the prevention or treatment of disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">111&#44;112</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Despite the existence of provisional findings about the links between microbiome and ocular pathologies&#44; it consists a new field of research for investigators in Ophthalmology&#46; Therefore&#44; it is yet to be defined how this apprehension will be gradually translated to interventions with clinical significance&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">113&#8211;115</span></a> Implementation of methods from the wider field of microbiome research &#40;e&#46;g&#46; protein expression&#44; transcriptional activity profile or microbiotas&#8217; metabolic by-products&#41; would be extremely useful in investigating ophthalmological diseases&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Moreover&#44; understanding the host biology through functional measures is also essential&#46; These methods can contribute in comprehending whether microorganisms are temporary present and rapidly inactivated or whether they are more persistent forming more permanent&#44; active communities&#46; Another important parameter is to find ways of implicating gnotobiotic animal models in ophthalmological research&#44; considering their significance in microbiome research&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">116</span></a> The juncture between basic science and observational research is substantial and calls for new experimental techniques&#44; so that new larger scale clinical trials can be designed&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">A continuous experimental elaboration toward this direction will not only provide answers to the current questions&#44; but may also indicate further associations between extraocular microbiome and ocular diseases&#44; or even ophthalmic interventions that potentially affect ocular microbiota&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conclusion</span><p id="par0235" class="elsevierStylePara elsevierViewall">There is growing evidence that intestinal dysbiosis has an immense impact on extra-intestinal immune-mediated pathologies&#44; which are associated with uveitis&#46; The gut microbiota may be a significant link between genetic background and environmental factors that contribute to the pathogenesis of the disease&#46; Larger studies are needed to define the exact interplay of intestinal microbiota and at which stage of the disease are these alterations more crucial&#46; Shedding more light to these perplex pathophysiological mechanisms will enable us to design targeted therapeutic strategies in order to re-establish the intestinal and immune homeostasis&#44; and prevent the progression of the disease&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Funding</span><p id="par0240" class="elsevierStylePara elsevierViewall">All authors declare that they received no funding for this study&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflict of interest</span><p id="par0245" class="elsevierStylePara elsevierViewall">All authors declare that there is no conflict of interest&#46;</p></span></span>"
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              "titulo" => "Behcet&#8217;s disease"
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              "titulo" => "HLA-B27-associated acute anterior uveitis"
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              "titulo" => "Vogt-Koyanagi-Harada &#40;VKH&#41; disease"
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          "titulo" => "Potential therapeutic targets of the gut microbiome for ocular inflammation"
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Article information

ISSN: 21735794
Original language: English

DOI:10.1016/j.oftale.2021.01.012

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