Gut microbiota and microbial factors regulate the pathogenesis of nonalcoholic fatty liver disease (NAFLD) in patients with obesity and metabolic abnormalities, but little is known about their roles in nonobese NAFLD. Expansion of Escherichia is associated with NAFLD pathogenesis. We aimed to investigate the pathogenic role of Escherichia fergusonii and its products in the development of nonobese NAFLD. We characterized the intestinal microbiome signature in a cohort of NAFLD patients and healthy controls by 16S ribosomal RNA sequencing. The role of E fergusonii was estimated in rats after 16 weeks of administration, and features of NAFLD were assessed. E fergusonii–derived microRNA-sized, small RNAs (msRNAs) were analyzed by deep sequencing. We detected an expansion of Escherichia_Shigella in NAFLD patients compared with healthy controls, and its increase was associated with disease severity independent of obesity. E fergusonii, a member of the genus Escherichia, induced the development of nonobese NAFLD characterized by hepatic steatosis and hepatocyte ballooning in rats without obesity. It disturbed host lipid metabolism by inhibiting hepatic lipid β-oxidation and promoting de novo lipogenesis. We also showed that E fergusonii caused the development of hepatic inflammation and fibrosis in a sizable fraction of animals at an advanced stage of NAFLD. Mechanistically, E fergusonii–derived msRNA 23487 down-regulated host hepatic peroxisome proliferator-activated receptor α expression, which could contribute to lipid accumulation in the liver. These results suggest that E fergusonii promotes the pathogenesis of steatohepatitis and fibrosis in nonobese rats by secreting msRNA 23487, and it might be a potential biomarker for predicting steatohepatitis in nonobese NAFLD.

The development and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in children are closely related to alterations of gut microbiota. This study aims to investigate changes in the gut microbiota signature and microbial metabolites in children with MASLD. We collected fecal samples from children and adolescents aged 6–16 years, and the presence of MASLD was diagnosed by ultrasound. We performed 16S ribosomal DNA sequencing and targeted metabolomics in 36 and 25 subjects, consisting of healthy controls, children with obesity, and children with MASLD. The α-diversity was significantly lower in children with obesity and MASLD compared with healthy controls. Linear discriminant analysis of effect size analysis identified Anaerostipes and A. hadrus as the top biomarkers differentiating the obesity group from the MASLD group. In MASLD patients with high alanine aminotransferase values (≥50 U/L for boys and 44 U/L for girls), we observed a decrease in the gut microbiota health index. MASLD patients with high shear wave elastography ( E ) values (≥6.2 kPa) showed an increased abundance of Ruminococcus torques , which was positively correlated with the levels of deoxycholic acid (DCA) and E values. Importantly, the mediation analysis identified positive associations between R. torques and clinical indicators of MASLD that were mediated by DCA. Overall, our study suggests that gut microbiota and metabolites are significantly altered in children with MASLD, and targeting R. torques may offer potential benefits for disease management. IMPORTANCE: This study investigated alterations in the gut microbiota signature and microbial metabolites in children with metabolic dysfunction-associated steatotic liver disease (MASLD). We found that an increased abundance of Ruminococcus torques was associated with increased levels of deoxycholic acid and the progression of MASLD, suggesting that R. torques may serve as a novel clinical target in pediatric MASLD.

Alcoholic hepatitis is a major health care burden in the United States due to significant morbidity and mortality. Early identification of patients with alcoholic hepatitis at greatest risk of death is extremely important for proper treatments and interventions to be instituted. In this study, we used gradient boosting, random forest, support vector machine and logistic regression analysis of laboratory parameters, fecal bacterial microbiota, fecal mycobiota, fecal virome, serum metabolome and serum lipidome to predict mortality in patients with alcoholic hepatitis. Gradient boosting achieved the highest AUC of 0.87 for both 30-day mortality prediction using the bacteria and metabolic pathways dataset and 90-day mortality prediction using the fungi dataset, which showed better performance than the currently used model for end-stage liver disease (MELD) score.

Parenteral nutrition–associated liver disease (PNALD) refers to a spectrum of conditions that can develop cholestasis, steatosis, fibrosis, and cirrhosis in the setting of parenteral nutrition (PN) use. Patient risk factors include short bowel syndrome, bacterial overgrowth and translocation, disturbance of hepatobiliary circulation, and lack of enteral feeding. A growing body of evidence suggests an intricate linkage between the gut microbiota and the pathogenesis of PNALD. In this review, we highlight current knowledge on the taxonomic and functional changes in the gut microbiota that might serve as noninvasive biomarkers. We also discuss the function of microbial metabolites and associated signaling pathways in the pathogenesis of PNALD. By providing the perspectives of microbiota-host interactions in PNALD for basic and translational research and summarizing current limitations of microbiota-based approaches, this review paves the path for developing novel and precise microbiota-based therapies in PNALD.

Parenteral nutrition (PN), a vital therapy for patients with intestinal failure, can lead to the development of parenteral nutrition-associated liver disease (PNALD). In this study, we aimed to investigate the role of Lactobacillus johnsonii (L. johnsonii) in a rat model of PNALD. Total parenteral nutrition (TPN)-fed rats were used to assess the role of L. johnsonii in liver steatosis, bile acid metabolism, gut microbiota, and hepatocyte apoptosis. We observed a depletion of L. johnsonii that was negatively correlated with the accumulation of glycochenodeoxycholic acid (GCDCA), a known apoptosis inducer, in rats subjected to TPN. L. johnsonii attenuated TPN-induced liver steatosis by inhibiting fatty acid synthesis and promoting fatty acid oxidation. TPN resulted in a decrease in bile acid synthesis and biliary bile secretion, which were partially restored by L. johnsonii treatment. The gut microbial profile revealed depletion of pathogenic bacteria in L. johnsonii-treated rats. L. johnsonii treatment reduced both hepatic GCDCA levels and hepatocyte apoptosis compared with the TPN group. In vitro, L. johnsonii treatment inhibited GCDCA-induced hepatocyte apoptosis via its bile salt hydrolase (BSH) activity. Our findings suggest that L. johnsonii protects against liver steatosis, bile acid dysregulation, and hepatocyte apoptosis in TPN-fed rats.