Messengers From the Gut: Gut Microbiota-Derived Metabolites on Host Regulation

Abstract

The human gut is the natural habitat for trillions of microorganisms, known as the gut microbiota, which play indispensable roles in maintaining host health. Defining the underlying mechanistic basis of the gut microbiota-host interactions has important implications for treating microbiota-associated diseases. At the fundamental level, the gut microbiota encodes a myriad of microbial enzymes that can modify various dietary precursors and host metabolites and synthesize, de novo, unique microbiota-derived metabolites that traverse from the host gut into the blood circulation. These gut microbiota-derived metabolites serve as key effector molecules to elicit host responses. In this review, we summarize recent studies in the understanding of the major classes of gut microbiota-derived metabolites, including short-chain fatty acids (SCFAs), bile acids (BAs) and peptidoglycan fragments (PGNs) on their regulatory effects on host functions. Elucidation of the structures and biological activities of such gut microbiota-derived metabolites in the host represents an exciting and critical area of research.

Keywords: adaptive and innate immunity; bile acids; gut microbiota-derived metabolites; host homeostasis; peptidoglycan fragments; short-chain fatty acids.

Figure 1

Gut microbiota-derived short-chain fatty acids such as acetate, propionate, butyrate regulate host intestinal immune homeostasis, epithelial repair and restoration, and facilitate pathogen clearance in the host gut niche.

Figure 2

Bile acids synthesized in the host liver undergo bile salt hydrolases (BSHs) reaction followed by diverse biotransformation by the gut microbiota to become a variety of secondary bile acid metabolites that play key functions in host homeostasis. (A) The co-metabolism of bile acid in host and gut microbiota. (B) The distinct effects of specific secondary bile acids to T-cell differentiation.

Figure 3

Gut microbiota-derived peptidoglycan fragments (PGNs) in the host gut niche as well as in systemic circulation act to modulate host homeostasis in multiple aspects.

Figure 4

Peptidoglycan fragment agonists of NOD1 and NOD2 pathways manifest opposing effects on insulin resistance in high-fat diet mice. While MDP, a NOD2 ligand that triggers overexpression of IRF4 via PIPK2 in non-hematopoietic cells, ameliorates insulin resistance induced by high-fat diet in mice, the iE-DAP agonist of NOD1 pathways induces Cxcl1 expression via RIPK2 in hematopoietic cells that contributes to insulin resistance in high-fat diet mice.

Figure 5

l-tryptophan from dietary proteins is metabolized by gut microbiota into a variety of indole derivatives, which are potent AhR agonists in the host.

Figure 6

The gut microbiota is involved in converting dietary phosphatidylcholine into TMA, which is transported to the host liver and converted to TMAO that is strongly associated with cardiovascular disease in the host.