Hepatic Adenosine Triphosphate Reduction Through the Short‐Chain Fatty Acids–Peroxisome Proliferator‐Activated Receptor γ–Uncoupling Protein 2 Axis Alleviates Immune‐Mediated Acute Hepatitis in Inulin‐Supplemented Mice

Abstract

How liver tolerance is disrupted in immune-mediated liver injury is currently unclear. There is also insufficient information available regarding susceptibility, precipitation, escalation, and perpetuation of autoimmune hepatitis. To explore how dietary fiber influences hepatic damage, we applied the concanavalin A (ConA)-induced acute immune-mediated liver injury model in mice fed a diet supplemented with 6.8% inulin, a water-soluble fermentable fiber. Twelve hours after ConA administration, inulin-supplemented diet-fed mice demonstrated significantly alleviated hepatic damage histologically and serologically, with down-regulation of hepatic interferonγ and tumor necrosis factor and reduced myeloperoxidase (MPO)-producing neutrophil infiltration. Preconditioning with an inulin-supplemented diet for 2 weeks significantly reduced hepatic adenosine triphosphate (ATP) content; suramin, a purinergic P2 receptor antagonist, abolished the protective effect. Of note, the portal plasma derived from mice fed the inulin-supplemented diet significantly alleviated ConA-induced immune-mediated liver injury. Mechanistically, increased portal short-chain fatty acid (SCFA) levels, such as those of acetate and butyrate, by inulin supplementation leads to up-regulation of hepatic γtype peroxisome proliferator-activated receptor (Pparg) and uncoupling protein 2 (Ucp2), which uncouples mitochondrial ATP synthesis downstream of PPARγ. Pparg down-regulating small interfering RNA cancelled the protective effect of inulin supplementation against MPO-producing neutrophil infiltration and the subsequent immune-mediated liver injury, suggesting that the SCFA-PPARγ-UCP2 axis plays a key role in the protective effect by inulin supplementation. Moreover, significant changes in the gut microbiota, including increased operational taxonomic units in genera Akkermansia and Allobaculum, also characterized the protective effect of the inulin-supplemented diet. Conclusion: There is a possible unraveled etiopathophysiological link between the maintenance of liver tolerance and dietary fiber. The SCFA-PPARγ-UCP2 axis may provide therapeutic targets for immune-mediated liver injury in the future. (Hepatology Communications 2021;0:1-16).L iver tolerance, the physiological predisposition toward immune unresponsiveness, is an important adaptive response that limits exaggerated tissue damage. (1) However, immune tolerance in the liver can be disturbed, resulting in robust, hepatic, immunologic reactions against pathogens

T-Fiber, A Highland Barley Fiber-Rich Powder, Alleviates Hyperglycemia and Improves Kidney Pathology in Db/db Mice

“…Researches showed that whole-grain dietary fber could improve the hepatic pathology and ameliorate the symptoms of diabetes by activating the IRS1/PI3K/AKT pathway in Db/ db mice [33]. Meanwhile, supplementing inulin rich in dietary fber could improve liver damage in mice with liver damage [34]. Whole grain dietary fber could reduce blood sugar by regulating the insulin signaling pathway.…”

Intestinal homeostasis in autoimmune liver diseases

“…Other modulating approaches include prebiotics that can support the growth of certain beneficial taxa. Dietary fiber and inulin, both indigestible polysaccharides and fermented by the intestinal microbiota, ameliorated liver lesions in experimental AIH mice [71,72] …”

“…Dietary fiber and inulin, both indigestible polysaccharides and fermented by the intestinal microbiota, ameliorated liver lesions in experimental AIH mice. [ 71 , 72 ]…”

“…Dietary fiber and inulin, both indigestible polysaccharides and fermented by the intestinal microbiota, ameliorated liver lesions in experimental AIH mice. [71,72] Probiotics Given that AILD is characterized by a reduced abundance of beneficial taxa, administration of commensal bacteria, also termed probiotics, can be of therapeutic value.…”

The Role of Gut Microbiota in Some Liver Diseases: From an Immunological Perspective

“…Inulin is an indigestible, biodegradable natural functional dietary fiber and a natural prebiotic. Yamaguchi et al found that liver damage was significantly reduced histologically and serologically in mice fed inulin for 12h after ConA administration (66). In addition, antibiotics or specific vaccines can effectively inhibit the growth of enterococci and control the disease progression (59).…”