Concomitant Improvement of Synaptic Decline and NASH using Fermentable Fiber Inulin

Introduction A Western diet with enriched sugar and fat is implicated in cognitive impairment and the development of non‐alcoholic steatohepatitis (NASH). This study examines the impact of fermentable fiber inulin in shifting gut microbiota and metabolites to affect liver and brain health in Western diet‐fed mice. Methods C57BL/6 mice were fed a healthy rodent control diet (CD) or a fructose, palmitate, and cholesterol (FPC)‐enriched diet after weaning until they were 3‐months old. Then, FPC diet‐fed mice were supplemented with or without 6% inulin for 5 months. All the mice were euthanized when they were 8 months of age. Results Long‐term consumption of the FPC diet induced NASH with elevated IL‐17A signaling. In addition, FPC diet reduced hippocampal long‐term potentiation (LTP) and induced microglia activation. Similarly, FPC diet induced Th17 pathway driven hepatic IL17A production along with increased IL17A inducers including Il1 β , Il6 , and Tgf β . In contrast, inulin supplementation reduced these changes. Furthermore, FPC diet intake induced gut dysbiosis by increasing Proteobacteria whereas inulin supplementation prevented such changes. In the microbiota families Coriobacteriaceae and Erysipelotrichaceae , which are implicated in cholesterol metabolism, and the genus of Erysipelotrichaceae and Allobaculum also shifted in the same direction in response to FPC intake and inulin supplementation. Accordingly, cecum cholesterol and zymosterol, a precursor of cholesterol, were increased in FPC diet‐fed mice but reduced in inulin‐supplemented mice. In addition, FPC diet‐fed mice had reduced bile acid receptors TGR5 and FXR signaling, and inulin supplementation reversed such changes. Conclusion The data suggest that inulin via gut fermentation shifts gut microbes, alters IL‐17A signaling, as well as activates bile acid receptor‐regulated pathways to coordinately ameliorate impaired neuroplasticity and neuroinflammation as well as NASH found in Western diet‐fed mice. Together, diet simultaneously affects brain and liver health. Support or Funding Information This study is supported by grants funded by National Institutes of Health U01CA179582 and R01CA222490 and Mouse Metabolic Phenotyping Center (MMPC) Microbiome Program (30835‐60), Subaward A19‐2654.