Pathogenic effects of Desulfovibrio in the gut on fatty liver in diet-induced obese mice and children with obesity.

BACKGROUND: Although we know the key role of gut dysbiosis in nonalcoholic fatty liver disease (NAFLD), it remains unclear what microbe(s) are responsible. This study aims to identify the microbes that cause NAFLD. METHODS: C57BL/6JNarl male mice fed a high-fat diet (HFD) were orally administered Lactobacillus reuteri (L. reuteri) or Lactobacillus rhamnosus GG plus Bifidobacterium animalis subsp. lactis BB12 (LGG plus BB12). Their fecal microbiomes identified by 16S rRNA sequencing were correlated with the severity of fatty liver. We then used a human cohort to confirm the role of the microbe(s). The HFD-fed mice were administrated with the identified bacterium, Desulfovibrio. The histopathological changes in the liver and ileum were analyzed. RESULTS: Lactobacillus and Bifidobacterium improved hepatic steatosis and fibrosis in HFD-fed mice, which was related to the decreased abundance of Desulfovibrio in feces. Further human study confirmed the amount of D. piger in the fecal microbiota of obese children with NAFLD was increased. We then administered D. piger and found aggravated hepatic steatosis and fibrosis in HFD-fed mice. Hepatic expression of CD36 was significantly increased in HFD-fed mice gavaged with D. piger. In HepG2 cells, overexpression of CD36 increased lipid droplets, whereas knockdown of CD36 decreased lipid droplets. HFD-fed mice gavaged with D. piger had a decrease in the villus length, crypt depth, and zonula occludens-1 density in the ileum tissue. CONCLUSIONS: Our findings provide novel insights into the role of Desulfovibrio dysregulation in NAFLD. Modulation of Desulfovibrio may be a potential target for the treatment of NAFLD.

Variants in the autophagy-related gene IRGM confer susceptibility to non-alcoholic fatty liver disease by modulating lipophagy.

BACKGROUND & AIMS: Autophagy has been shown to be crucial in the regulation of the intracellular lipid stores in hepatocytes. We hypothesize that immunity-related GTPase family M (IRGM) gene (an autophagy-related gene) variants confer the susceptibility to non-alcoholic fatty liver disease (NAFLD) development. METHODS: 832 obese children and adolescents aged 6-18years were recruited. NAFLD was determined by liver ultrasonography. We genotyped PNPLA3 rs738409, GCKR rs780094, TM6SF2 rs58542926, six IRGM single nucleotide polymorphisms (rs13361189, rs9637876, rs72553867, rs10065172, rs1000113, and rs11747270). To understand the molecular mechanism, we examined the effects of IRGM knockdown and overexpression on autophagic flux and lipid droplet metabolism in human hepatoma cells. RESULTS: 22.8% of recruited obese children and adolescents had NAFLD. Multiple logistic regression analysis revealed that after controlling for the effects of age- and gender-adjusted body mass index, gender, PNPLA3, GCKR, and TM6SF2 polymorphisms, variant IRGM rs10065172 TT genotype independently increased the odds ratio of NAFLD by 2.04 (95% confidence interval 1.22-3.42; p=0.007), as compared to the CC genotype. The predictive model was validated by means of 10-fold cross validation. Functional assay revealed that IRGM knockdown inhibited autophagic flux and increased lipid droplet content in HepG2 and PLC/PRF/5 cells, which were reversed by the autophagy inducer rapamycin administration. Similarly, wortmannin (an autophagy inhibitor) increased intracellular lipid droplet content. In contrast, overexpression of IRGM caused decreased lipid droplet content in HepG2 cells. CONCLUSIONS: Our findings suggest that IRGM may contribute to the development of human NAFLD by altering hepatic lipid metabolism through the autophagy pathway. LAY SUMMARY: Autophagy is involved in the process of lipid metabolism in hepatocytes. The mechanism of autophagy regulation by IRGM has just been unveiled. This study demonstrates that genetic variants in IRGM confer risk of human non-alcoholic fatty liver disease. The functional studies reveal how IRGM regulates hepatic lipid droplet content.