Purine starvation driven by host-microbiota maladaptation contributes to the pathogenesis of irritable bowel syndrome

Irritable bowel syndrome (IBS) is a prominent functional gastrointestinal disorder globally. Gut microbiota has been suggested to mediate IBS pathogenesis, but evidence is limited. Metagenomics and 16s rRNA sequencing were performed and functional prediction analysis showed that purine ribonucleosides degradation was significantly upregulated. Faecal hypoxanthine and xanthine concentrations were obviously lower and negatively correlated with disease severity in IBS patients. Further, faecal microbiota transplantation from diarrhea-predominant IBS (IBS-D) patients was conducted. Low faecal purine concentrations and damaged mucosal barrier function were observed in mouse recipients. Both bulk RNA-seq and enzyme assays confirmed impaired ATP biosynthesis in epithelia cells. The gut microbiota-driven purine degradation could be rescued by Bacillus subtilis (B. subtilis) monocolonization. B. subtilis also improved symptoms of IBS-D patients. Collectively, our study provides pathogenetic insights into how gut microbiota affect mucosal barrier function in a purine nucleotides-dependent way, and suggests B. subtilis supplement as an alternative for IBS-D patients.