Modifying microbially derived short chain fatty acids to promote health

The intestinal mucosa has evolved to facilitate interactions between the host and the constellation of intestinal microbes, collectively termed the microbiota. A well-orchestrated balance exists in the healthy mucosa where microbes and microbial products first encounter a barrier formed by a single layer of intestinal epithelial cells (IECs). This homeostasis exists at a harsh interface between the highly vascularized mucosa and the anaerobic intestinal lumen. This steep oxygen gradient establishes 'physiological hypoxia' as a central metabolic characteristic of the mucosa. Recently, interest in understanding the dynamic host-microbe interplay has identified microbial metabolites that support host functions at several different levels. Of singular relevance are short-chain fatty acids, particularly butyric acid. Studies have demonstrated that IECs have evolved to benefit from butyrate through a plethora of functions, including energy procurement, metabolism, barrier and wound healing regulation, production of antimicrobial peptides, etc. Butyrate is consumed by differentiated colonic epithelial cells preferentially for energy, creating a distinct butyrate gradient along the intestinal cryp-tvillus axis. The depletion of butyrate and butyrate-producing microbes during active inflammation, termed dysbiosis, promotes disease and attenuates tissue healing responses. Furthermore, in a disease state, the butyrate gradient is disrupted leading to reduced utilization of butyrate and inhibition of proliferation of colonic stem cells. Emerging studies suggest that chemical modifications to butyrate could be useful in targeting select IEC functions for particular benefits to the host. In this review, we consider how butyrate molecular mimicry may play out in the setting of mucosal health and disease and discuss current discoveries on endogenous and synthetic butyrate-like compounds and their pathways.