Metabolic engineering of commensal bacteria for gut butyrate delivery and dissection of host-microbe interaction.

An overwhelming number of studies have reported the correlation of decreased abundance of butyrate-producing commensals with a wide range of diseases. However, the molecular-level mechanisms whereby gut butyrate causally affects the host mucosal immunity and pathogenesis were poorly understood, hindered by the lack of efficient tools to control intestinal butyrate. Here we engineered a facultative anaerobic commensal bacterium to delivery butyrate at the intestinal mucosal surface, and implemented it to dissect the causal role of gut butyrate in regulating host intestinal homeostasis in a model of murine chronic colitis. Mechanistically, we show that gut butyrate protected against colitis and preserved intestinal mucosal homeostasis through its inhibiting effect on the key pyroptosis executioner gasdermin D (GSDMD) of colonic epithelium, via functioning as an HDAC3 inhibitor. Overall, our work presents a new avenue to build synthetic living delivery bacteria to decode causal molecules at the host-microbe interface with molecular-level insights.

Butyrate Suppresses Glucose Metabolism of Colorectal Cancer Cells via GPR109a-AKT Signaling Pathway and Enhances Chemotherapy.

Glycolysis inhibitors are promising therapeutic drugs for tumor treatment, which target the uniquely elevated glucose metabolism of cancer cells. Butyrate is a critical product of beneficial microbes in the colon, which exerts extraordinary anti-cancer activities. In particular, butyrate shows biased inhibitory effects on the cell growth of cancerous colonocytes, whereas it is the major energy source for normal colonocytes. Besides its roles as the histone deacetylases (HDACs) inhibitor and the ligand for G-protein coupled receptor (GPR) 109a, the influence of butyrate on the glucose metabolism of cancerous colonocytes and the underlying molecular mechanism are not fully understood. Here, we show that butyrate markedly inhibited glucose transport and glycolysis of colorectal cancer cells, through reducing the abundance of membrane GLUT1 and cytoplasmic G6PD, which was regulated by the GPR109a-AKT signaling pathway. Moreover, butyrate significantly promoted the chemotherapeutical efficacy of 5-fluorouracil (5-FU) on cancerous colonocytes, with exacerbated impairment of DNA synthesis efficiency. Our findings provide useful information to better understand the molecular basis for the impact of butyrate on the glucose metabolism of colorectal cancer cells, which would promote the development of beneficial metabolites of gut microbiota as therapeutical or adjuvant anti-cancer drugs.