The term gut liver axis describes how the intestine affects the function of the liver and vice versa, how the liver guides the functioning of the intestine. Bile acid dysregulation with deletion of the farnesoid X receptor (FXR, bile acid receptor) leads to inflammation and spontaneous liver cancer. The intestinal microbiota is a vital part of the gut liver axis such that altered gut microbiota is a common etiology for liver dysfunctions, including cirrhosis. Compelling evidence for the role of the gut microbiota in liver injury is the effects of direct intervention with probiotics. Extensive research at UC Davis has le to a detailed description of the natural colonization of anti-inflammatory bifidobacteria in breastfed infants and the role of milk in delivering complex milk oligosaccharides (MO), which specifically enrich their growth and function. The intestinal microbiota is important in protecting and nourishing the host, however the interactions between microbes and bile acid metabolism and inflammation are not understood. This proposal brings together an interdisciplinary team of investigators from the UC Davis Comprehensive Cancer Center and the UC Davis Foods for Health Institute. This project will leverage from the fields of liver pathophysiology, microbiology analytical chemistry, biochemistry, molecular biology and medicine to determine if reducing inflammation by shifting gut microbiota toward bifidobacteria prevents the liver cancer. In this proposal, we will examine the overall hypothesis that selective enrichment of intestinal B. infantis using a synbiotic treatment of B. infantis and MO (Bi+MO) reduces inflammation induced by dysregulated bile acid homeostasis and prevent carcinogenesis in FXR knockout (KO) mice.. To test our hypothesis in this model, which forms spontaneous cancer in 100% of animals when they are 14 months old, in Aim 1, we will establish the relationships linking gut microbiota, microbial metabolome, bile acid metabolism, inflammation, and carcinogenesis in FXR KO mice.
In Aim 2, we will treat animals with the strategic synbiotic treatment to determine whether the effects of the FXR KO, including cancer development, can be reversed. These findings will lead to the development of novel analytical platforms necessary to interrogate the relationships between gut microbiota and bile acid metabolism in relation to cancer and demonstrate the proof of concept that a shift toward dominance in anti-inflammatory bifidobacteria influences the progression of cancer.
Genetic disruption of bile acid receptors in murine models causes bile acid dysregulation and invariably leads to spontaneous liver cancer and increased colon cancer. We hypothesize that selective enrichment of bifidobacterial species using a synbiotic treatment of milk oligosaccharides of bifidobacterial strains protects the gut and liver from inflammation and bile acid toxicity and prevents carcinogenesis. If positive, these microbiota strategies could be translated into an intervention that uses diet to prevent inflammation and cancer.
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