Essential Amino Acid Metabolites as Chemical Mediators of Host-Microbe Interaction in the Gut

Abstract

Amino acids are indispensable substrates for protein synthesis in all organisms and incorporated into diverse aspects of metabolic physiology and signaling. However, animals lack the ability to synthesize several of them and must acquire these essential amino acids from their diet or perhaps their associated microbial communities. The essential amino acids therefore occupy a unique position in the health of animals and their relationships with microbes. Here we review recent work connecting microbial production and metabolism of essential amino acids to host biology, and the reciprocal impacts of host metabolism of essential amino acids on their associated microbes. We focus on the roles of the branched-chain amino acids (valine, leucine, and isoleucine) and tryptophan on host-microbe communication in the intestine of humans and other vertebrates. We then conclude by highlighting research questions surrounding the less-understood aspects of microbial essential amino acid synthesis in animal hosts.

Keywords: isoleucine; leucine; microbiome; serotonin; tryptophan; valine.

Figure 1.. Microbial branched chain amino acid (BCAA) metabolism in the gut affects vertebrate host physiology.

A. The BCAA synthesis pathway is conserved among most eubacteria. Glucose is hydrolyzed into 2 pyruvate which is then condensed into 2 acetolactate by the IlvBN enzyme complex. IlvBN is regulated by negative feedback via transcriptional inhibition upstream of the ilvBN operon and by BCAA binding to the small subunit IlvN. The ketoacids KIV, KMV and KIC are transaminated by the branched chain amino transferase enzyme IlvE to their respective BCAA. B. Gut microbes Phocaeicola vulgatus and Prevotella copri and their ability to synthesize BCAA have been linked to higher levels of insulin resistance in both mice and humans, higher circulating levels of BCAA in mice and humans, higher fat mass in mice, and polycystic ovary syndrome in humans. Alternatively, the presence of gut microbes Faecalibacterium prausnitzii, Butyrivibrio crossotus, Eubacterium siraeum and Ruminoccocus gnavus have been linked to increased BCAA uptake as well as lower levels of circulating BCAA in mice, rats, and humans, and lower insulin resistance in humans. C. Increased levels of dietary protein have been linked to levels of the microbial fermentation products of BCAA, the branched chain fatty acids (BCFA). These metabolites have been associated with increased cholesterol and lipidemia in humans as well as increased glucose release from hepatocytes in vitro and increased intestinal inflammation. Created with Biorender.com.

Figure 2.. Host and microbial pathways for metabolism of tryptophan.

Tryptophan that is not used for protein synthesis can enter three major pathways: the kynurenine pathway, the serotonin pathway, and the indole-related pathways. Metabolites known to act as ligands for host receptors are indicated with asterisks. Created with Biorender.com.