Clinical and Mechanistic Association Between Intestinal Permeability and the Gut Microbiome in Cirrhosis: Role of Phascolarctobacterium.

BACKGROUND

In patients with liver cirrhosis, intestinal permeability and the composition of the gut microbiome are altered. Thus, the microbiome might be a therapeutic target for the treatment of both liver diseases and intestinal permeability. We aimed to investigate the relationship between the intestinal barrier and microbiome composition in cirrhosis and elucidate potential mechanisms for how bacteria influence permeability.

METHODS

We analyzed the fecal permeability biomarker zonulin by ELISA and microbiome composition by 16s rDNA sequencing in a discovery (n = 78) and a validation cohort (n = 90) of patients with liver cirrhosis. In the validation cohort, we analyzed the composition of the fecal metabolome by NMR spectroscopy. For mechanistic exploration, an intestinal barrier cell culture model using T84 cells was used.

RESULTS

In the discovery cohort (n = 78, 77% Child-Pugh Grade A, 21% Child-Pugh Grade B, 3% Child-Pugh Grade C), decreasing zonulin levels in stool over 6 months were associated with higher Phascolarctobacterium abundance in the microbiome. Phascolarctobacterium was associated with better liver function (lower bilirubin, p = 0.04, INR p = 0.04, MELD Score, p = 0.02). Lower Phascolarctobacterium levels were observed in decompensated cirrhosis and were associated with 36-month mortality in two cohorts. Metabolomics analysis showed an association between Phascolarctobacterium and lower succinate levels. Succinate increased gut permeability in vitro, and Phascolarctobacterium succinatutens strains improved the intestinal permeability, potentially by alleviating the effect of succinate.

CONCLUSION

Phascolarctobacterium may represent a candidate biomarker of adverse outcomes in cirrhosis and a promising target for further investigation as a next-generation probiotic involved in gut barrier function and succinate homeostasis.

TRIAL REGISTRATION: NCT01607528, NCT03080129.