Changes in intestinal permeability and gut microbiota following diet-induced weight loss in patients with metabolic dysfunction-associated steatohepatitis and liver fibrosis

Weight loss improves metabolic dysfunction-associated steatohepatitis (MASH). We investigated whether there were associated changes in intestinal permeability, short-chain fatty acids (SCFAs), and gut microbiota, which are implicated in the pathophysiology of MASH. Sixteen adults with MASH, moderate fibrosis, and obesity received a low-energy total diet replacement program for 12 weeks and stepped food re-introduction over the following 12 weeks (ISRCTN12900952). Intestinal permeability, fecal SCFAs, and fecal microbiota were assessed at 0, 12, and 24 weeks. Data were analyzed using mixed-effects linear regression and sparse partial least-squares regression. Fourteen participants completed the trial, lost 15% (95% CI: 11.2-18.6%) of their weight, and 93% had clinically relevant reductions in liver disease severity markers. Serum zonulin concentrations were reduced at both 12 and 24 weeks (152.0 ng/ml, 95% CI: 88.0-217.4, <i>p</i> < 0.001). Each percentage point of weight loss was associated with a 13.2 ng/mL (95% CI: 3.8-22.5, <i>p</i> < 0.001) reduction in zonulin. For every 10 ng/mL reduction in zonulin, there was a 6.8% (95% CI: 3.5%-10.2, <i>p</i> < 0.001) reduction in liver fat. There were reductions in SCFA and alpha diversity evenness as well as increases in beta diversity of the gut microbiota at 12 weeks, but the changes did not persist at 24 weeks. In conclusion, substantial dietary energy restriction is associated with significant improvement in MASH markers alongside reduction in intestinal permeability. Changes in gut microbiota and SCFA were not maintained with sustained reductions in weight and liver fat, suggesting that microbiome modulation may not explain the relationship between weight loss and improvements in MASH.