Butyrate’s Maintenance of Colonic Homeostasis via PPARγ Activation

Abstract

The human colon is colonized by trillions of bacteria, characterized by a dominance of obligate anaerobic bacteria that require hypoxic conditions for survival (Silva et al. 2020, Rinninella et al. 2019, Litvak et al. 2018). Disruption of hypoxic conditions provides a competitive advantage for facultative anaerobic bacteria, which can grow both in the presence and absence of oxygen (André et al. 2021). Most life-threatening pathogenic bacteria are facultative anaerobes, and their abundance is a hallmark of dysbiosis in the colon (André et al. 2021). Their adaptability to variable oxygen concentrations creates a selective advantage for bacterial translocation and infection, whereby persistent disruption of the mucosal barrier is a predominant underlying cause of inflammatory bowel diseases (IBDs), such as Crohn’s disease (CD) and ulcerative colitis (UC) (André et al. 2021, Litvak et al. 2018, Nagpal et al. 2017, Kotas et al. 2015). Diagnosis of these diseases continues to increase in prevalence across the United States. Therefore, identifying molecules that protect against facultative anaerobes and support obligate anaerobic bacteria in the colon serves great importance in alleviating disease burden (Ye et al. 2020). Obligate anaerobes obtain energy through fermentation of undigested dietary carbohydrates, specifically resistant starches and dietary fibers not absorbed by the small intestine (Silva et al. 2020, Rinninella et al. 2019, Litvak et al. 2018). Butyrate, a four-carbon short-chain fatty acid (SCFA), is a byproduct of this fermentation process, serving as both the primary energy source for colon epithelial cells (colonocytes), and a key facilitator of the mutualistic relationship between a human host and the gut microbiome. Butyrate supports intestinal homeostasis through modulation of the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway. Downstream PPARγ signaling from butyrate provides maintenance of colonic hypoxic conditions, thereby promoting growth of obligate anaerobic bacteria, supporting intestinal barrier integrity, and downregulating inflammation through T cell differentiation. Butyrate drives a multilayer system of host defense mechanisms; therefore, its administration is at the forefront of treating chronic inflammatory diseases in the human colon