Pathways and functions of gut microbiota metabolism impacting host physiology

Abstract

The bacterial populations in the human intestine impact host physiological functions through their metabolic activity. In addition to performing essential catabolic and biotransformation functions, the gut microbiota produces bioactive small molecules that mediate interactions with the host and contribute to the neurohumoral axes connecting the intestine with other parts of the body. This review discusses recent progress in characterizing the metabolic products of the gut microbiota and their biological functions, focusing on studies that investigate the responsible bacterial pathways and cognate host receptors. Several key areas are highlighted for future development: context-based analysis targeting pathways; integration of analytical approaches; metabolic modeling; and synthetic systems for in vivo manipulation of microbiota functions. Prospectively, these developments could further our mechanistic understanding of host-microbiota interactions.

Figure 1

Representative dietary inputs and metabolic functions of intestinal microbiota. Metabolic functions are indicated in italics. Closed and open arrows indicate flow of specific metabolites and dietary residues, respectively. Dotted lines illustrate negative feedback of hepatic bile acid synthesis under the regulation of intestinal farnesoid X receptor (FXR), which is antagonized by conjugated bile acids.

Figure 2

Major pathways of propionate (green arrows) and butyrate (blue arrows) metabolism in gut bacteria. For clarity, only a subset of the intermediates and reactions are shown. Enzyme name abbreviations are shown in bold italics. Dotted and solid arrows indicate multiple and single reaction steps, respectively. PDU: propionaldehyde dehydrogenase; MMD: methylmalonyl-CoA decarboxylase; GCD: glutaconyl-CoA decarboxylase; CRO: crotonase; 4HBT: 4-hydroxybutyrate CoA-transferase; KAL: 3-aminobutyryl-CoA ammonia-lyase; BCD: butyryl-CoA dehydrogenase.

Figure 3

(a) Tryptophan (TRP) co-metabolism by host and microbiota. Enzyme name abbreviations are shown in bold italics. Blue and red fonts indicate strictly bacterial and host enzymes, respectively. ARAT: aromatic amino acid transferase; IPD: indolepyruvate decarboxylase; TRD: tryptophan decarboxylase; MAO: monoamine oxidase; ALDH: IAAld dehydrogenase; AMI: amidase; TMO: tryptophan 2-monooxygenase. See text for additional definitions of abbreviations. (b) TRP catabolism in gut bacteria produces TrA and IAA, which can translocate across intestinal epithelial cells (IECs) to activate the arylhydrocarbon receptor (AhR) expressed in innate lymphoid cells. This in turn induces secretion of interleukin-22 (IL-22), which triggers an immune response against pathogens, e.g. resulting in production of antimicrobial peptides by Paneth cells.

Figure 4

(a) Key steps in host-microbiota co-metabolism of bile acids. Enzymatic steps are shown in bold italics. Blue font indicates bacterial reactions taking place in the intestine. Note that deoxycholate, a secondary bile acid formed by the microbiota, can enter the liver through the enteroheaptic circulation and then conjugated with glycine or taurine to a bile salt. See text for definitions of abbreviations. (b) Choline co-metabolism by the host and microbiota. Dietary choline is metabolized in the intestine by bacterial trimethylamine (TMA)-lyase to yield TMA, ethanol, and acetate. Blue font indicates bacterial enzyme. In the liver, TMA is further metabolized into trimethylamine N-oxide (TMAO) by a flavin-containing monooxygenase (FMO). Additional metabolic products of TMA include dimethylamine (DMA); however, the responsible enzyme remains to be elucidated. Choline can also enter the liver, phosphorylated by choline kinase (CKI), and activated to form a substrate for phosphatidylcholine synthesis.