Fructo-oligosaccharides ameliorate steatohepatitis, visceral adiposity, and associated chronic inflammation via increased production of short-chain fatty acids in a mouse model of non-alcoholic steatohepatitis

Abstract

Background Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Within the spectrum of NAFLD, non-alcoholic steatohepatitis (NASH) in combination with hepatic inflammation and fibrosis can lead to liver cirrhosis and hepatocellular carcinoma. Dysbiosis was reported to contribute to NASH pathogenesis. This study aimed to determine the effects of fructo-oligosaccharides (FOS) on steatohepatitis and visceral adiposity in an obese mouse model of NASH. Methods Twelve newborn C57BL/6 J male mice were subcutaneously injected with monosodium glutamate (MSG) to induce obesity on a conventional diet. Six mice were also administered 5% FOS via drinking water from 10 weeks of age. At 18 weeks, histological characteristics of the liver and epididymal fat were compared between the groups. Hepatic mRNA expression of lipid metabolism enzymes and SCFA in feces and sera were measured. Results Hepatic steatosis, inflammatory cell infiltration, and hepatocyte ballooning in the liver and increased hepatic mRNA expression of fatty acid synthase and glycerol-3-phosphate acyltransferase were observed in the MSG-treated mice. FOS treatment improved the liver pathology and blunted the increases in the mRNA expression levels of lipid metabolism enzymes. In addition, FOS inhibited adipocyte enlargement and formation of crown-like structures and reduced the M1 macrophage frequency in the epididymal fat of the MSG mice (39.4% ± 3.0% vs. 22.8% ± 0.7%; P = 0.001). FOS increased not only the fecal concentrations of n-butyric acid (0.04 ± 0.01 vs. 0.38 ± 0.14 mg/g, P = 0.02), propionic acid (0.09 ± 0.03 vs. 0.42 ± 0.16 mg/g, P = 0.02), and acetic acid (0.65 ± 0.16 vs. 1.48 ± 0.29 mg/g, P = 0.03) but also the serum concentration of propionic acid (3.9 ± 0.5 vs. 8.2 ± 0.5 μmol/L, P = 0.001). Conclusions FOS ameliorates steatohepatitis, visceral adiposity, and chronic inflammation by increasing SCFA production.

A metagenome-wide association study of gut microbiome and visceral fat accumulation

“…Propionate inhibited adipocytes formation from mesenchymal stem cells via GPR43 [58] . Fructo-oligosaccharides, a soluble dietary fiber, ameliorated visceral adiposity by increasing SCFAs production [59] . Moreover, dietary SCFAs were reported to induce a peroxisome proliferator-activated receptor-γ-dependent switch from lipid synthesis to utilization [60] .…”

Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications

“…FOS have been tested in animal models of NAFLD established by administration of monosodium glutamate, methionine-choline deficiency or with feeding of a high-fat diet. FOS have been reported to ameliorate NAFLD parameters such as steatosis and inflammation in animal models of NAFLD [ 94 , 95 ].…”

“…In monosodium glutamate-injected mice, Takai et al (2020) showed that supplementation with FOS reduced hepatic steatosis, inflammatory cell infiltration and hepatocyte ballooning as well as decreased expression of fatty acid synthase and glycerol-3-phosphate acyltransferase [ 94 ]. This has been associated with increased faecal SCFAs including butyrate, propionate and acetate.…”

Sodium Acetate Inhibit TGF-β1-Induced Activation of Hepatic Stellate Cells by Restoring AMPK or c-Jun Signaling

“…Importantly SCFAs are not only metabolic substrates but also signaling molecules that regulate liver metabolism ( 18 ). A previous study indicated that fructo-oligosaccharide treatment increased intestinal SCFAs and improved hepatic steatosis, inflammatory cell infiltration, and hepatocyte ballooning of NASH mice ( 19 ). Takayama et al ( 20 ) showed that feeding partially hydrolyzed guar gum increases butyrate, acetate, and propionate in the gut and attenuates liver inflammatory markers (TNF-α and MCP-1) and fibrogenic markers (Col1a1 and α-SMA) in mice.…”