OP-1 GUT METATRANSCRIPTOMICS AND METABOLOMICS REVEAL ASSOCIATION OF CYSTEINE AND PURINE METABOLISMS WITH METABOLIC ASSOCIATED FATTY LIVER DISEASE (MAFLD)

Background

The gut microbiome represents a niche for biomarkers discovery to risk-stratify MAFLD patients. However, each population may have unique microbiome signatures and studies are needed in Latin America where MAFLD prevalence and severity are high.

Aims

To identify gut metatranscriptome and metabolome signatures associated with MAFLD and steatohepatitis (SH) in Argentina.

Methods

Stool samples, diet, demographic and clinical data were obtained from 33 biopsy-proven patients (12 simple steatosis -SS- and 21 SH) and 19 healthy volunteers (HV). PNPLA3 rs738409 SNP was genotyped. HPLC, flow injection analysis with MS/MS in tandem and MetaboAnalyst-v4.0 were used for metabolomics. RNA-seq was performed in NovaSeq6000®. bioBakery-v1.8 and Maaslin2-v1.2.0 were used for data analysis.

Results

BMI was higher in MAFLD patients, particularly in SH (q=4.49e-06). After adjusting for BMI, 89 and 53 gene family clusters were differentially expressed between HV and MAFLD and between SS and SH, respectively (q<0.1). Pathways related to sulfur oxidation, short-chain fatty acid metabolism, purine metabolism and lipopolysaccharide synthesis were enriched in MAFLD patients when compared with HV and in SH when compared with SS, whereas folate synthesis was enriched in SS patients (q<0.1). Gene expression associated with Desulfobacteraceae bacteria harbored most of the functional features of MAFLD patients when compared with HV, and of SH patients within the case group (Figure). The PNPLA3 GG genotype was related to decreased hydrolysis of glycerolipids, high expression of Clostridium cadaveris and low expression of Desulfobacteraceae bacteria associated genes (q<0.1).

Higher concentrations of xanthine, implicated in purine metabolism, and of the sulfur amino acid cysteine were detected in the stool of MAFLD patients when compared with HV, and of SH patients within the case group (BMI-adjusted q<0.1).

Conclusion

Cysteine and purine metabolisms are strongly related to MAFLD and SH in Argentinian patients. Cysteine and xanthine could be useful as potential biomarkers.