Gut microbiota and butyrate contribute to nonalcoholic fatty liver disease in premenopause due to estrogen deficiency

Abstract

The incidence of nonalcoholic fatty liver disease (NAFLD) in postmenopausal women has increased significantly. Estrogen plays a very important role in NAFLD, but whether NAFLD in premenopausal women was caused by estrogen deficiency was unknown. Thus, it is of great clinical significance to explore the mechanism of NAFLD in premenopausal women. Gut microbiota and its metabolites short chain fatty acids (SCFA) have been shown to play important roles in the development of NAFLD. In this study, we investigated the impact of gut microbiota and SCFA in NAFLD patients and mice caused by estrogen deficiency. We showed that premenopause NAFLD patients had much lower estrogen levels. Estrogen deficient mice, due to ovariectomy (OVX), suffered more severe liver steatosis with an elevated body weight, abdominal fat weight, serum triglycerides and deterioration in hepatic steatosis. Altered gut microbiota composition and decreased butyrate content were found in NAFLD patients and in OVX mice. Furthermore, fecal microbiota transplantation (FMT) or supplementing with butyrate alleviated NAFLD in OVX mice. The production of antimicrobial peptides (AMP) Reg3ɣ, β-defensins and the expression of intestinal epithelial tight junction, including ZO-1 and Occluding-5, were decreased in the OVX mice compared to control mice. Upregulation of PPAR-ɣ and VLDLR, downregulation of PPAR-ɑ indicated that OVX mice suffered from abnormal lipid metabolism. These data indicate that changes in the gut microbiota and SCFA caused by estrogen reduction, together with a disorder in AMP production and lipid metabolism, promote NAFLD, thus provide SCFAs derived from microbiota as new therapeutic targets for the clinical prevention and treatment of NAFLD.

Gut microbiota–mitochondrial inter-talk in non-alcoholic fatty liver disease

“…Lipid accumulation in the liver is partly responsible for the uptake of circulating FA and decreases in the rate of FA oxidation and secretion ( 60 ). Indeed, butyrate can reverse PPAR-α activation to enhance FA β-oxidation, inhibit lipid synthesis, and deplete the level of nuclear factor-kappa B ( 61 , 62 ), which was also observed in NAFLD-OVX mice ( 50 ).…”

“…Short-chain fatty acids are a primary type of bacterial metabolite produced by bacterial fermentation of otherwise indigestible fibers in the colon (46). Many previous studies have illustrated the role of aberrant levels of SCFAs in NAFLD progression (39,40,(47)(48)(49)(50). SCFAs can disrupt the functioning of the intestinal barrier impairing the translocation of LPS and increasing the level of liver endotoxemia to promote the pathogenesis of NAFLD (50).…”

“…Many previous studies have illustrated the role of aberrant levels of SCFAs in NAFLD progression (39,40,(47)(48)(49)(50). SCFAs can disrupt the functioning of the intestinal barrier impairing the translocation of LPS and increasing the level of liver endotoxemia to promote the pathogenesis of NAFLD (50). Butyrate and propionate are the main components of SCFAs, which can decrease gut inflammation and improve gut barrier integrity to limit LPS translocation (51).…”

“…Butyrate and propionate are the main components of SCFAs, which can decrease gut inflammation and improve gut barrier integrity to limit LPS translocation (51). Liu et al (50) confirmed that butyrate was significantly reduced in female patients with NAFLD and in ovariectomized (OVX) mice. Butyrate was also positively correlated with Tregs and effector IL-10 and negatively correlated with cytotoxic CD8 T-cells in participants with NAFLD-HCC (39).…”

Spotlight on the Gut Microbiome in Menopause: Current Insights

“…(4) Finally, are menopause-related health sequelae mediated by the gut microbiome? Animal models suggest a causal role of the gut microbiome in potentiating disease states induced by ovariectomy, including metabolic syndrome, 73 non-alcoholic fatty liver disease, 85 osteoporosis, 86 , 87 and atherosclerosis. 74 For example, enhanced microbial translocation due to ovariectomy has been shown to induce bone loss in mice, and a less diverse and altered gut microbiome 88 , 89 and higher gut permeability 62 have been associated with lower bone mineral density in studies of post-menopausal women.…”