A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites

Abstract

The human gut microbiota produces dozens of metabolites that accumulate in the bloodstream1,2, where they can have systemic effects on the host. Although these small molecules commonly reach concentrations similar to those achieved by pharmaceutical agents, remarkably little is known about the microbial metabolic pathways that produce them. Here we use a combination of genetics and metabolic profiling to characterize a pathway from the gut symbiont Clostridium sporogenes that generates aromatic amino acid metabolites. Our results reveal that this pathway produces twelve compounds, nine of which are known to accumulate in host serum. All three aromatic amino acids (tryptophan, phenylalanine and tyrosine) serve as substrates for the pathway, and it involves branching and alternative reductases for specific intermediates. By genetically manipulating C. sporogenes, we modulate serum levels of these metabolites in gnotobiotic mice, and show that in turn this affects intestinal permeability and systemic immunity. This work has the potential to provide the basis of a systematic effort to engineer the molecular output of the gut bacterial community.

Metabolism at the centre of the host–microbe relationship

“…Tryptophan is an essential amino acid important for the generation of a range of bioactive molecules, including serotonin and melatonin [51]. The host utilizes the majority of diet-derived tryptophan, but the gut microbiota also metabolize a portion resulting in indolecontaining molecules [52,53]. Several of these are aryl hydrocarbon receptor ligands and regulate mucosal immunity, which will be discussed in later sections, and is also discussed in detail in a review by Roager and Licht [54].…”

“…Analysis of the metabolic pathway involved revealed that there are 12 resulting metabolites, nine of which accumulate in host serum, including indolepropionic acid (IPA) [52]. Analysis of the metabolic pathway involved revealed that there are 12 resulting metabolites, nine of which accumulate in host serum, including indolepropionic acid (IPA) [52].…”

“…IPA was found to be important for maintaining barrier integrity, and lack of IPA and the other AAA metabolites increased intestinal permeability [52,55]. Systemic immunity was affected by diminished IPA production, with increased percentage of neutrophils and CD8 T cells and increased anti-C. sporogenes immunoglobulin (Ig)A [52]. Systemic immunity was affected by diminished IPA production, with increased percentage of neutrophils and CD8 T cells and increased anti-C. sporogenes immunoglobulin (Ig)A [52].…”

Effects of yeast cultures with different fermentation times on the growth performance, caecal microbial community and metabolite profile of broilers

“…Amino acids play an important role in regulating the nutritional metabolism of the host. It can be inferred that lysine catabolism in the intestinal tract may be related to intestinal micro-organisms Dodd et al (2017). Proteins are absorbed in the form of amino acids in the animals' body(Dai, Zhang, Wu, & Zhu, 2010).…”

Role of Microbiota and Tryptophan Metabolites in the Remote Effect of Intestinal Inflammation on Brain and Depression

“…These gut bacteria has coevolved with the human body to perform numerous beneficial functions ranging from being simple fermenters of food to having profound effects on the host immune development, metabolism and food preferences, brain development, stress responses, pain and behavior [1][2][3][4][5]. Consequently, disruptions or alterations in this resilient relationship is a significant factor in many diseases such as inflammatory gastrointestinal diseases, and neuropsychiatric disorders, including depression [1,[6][7][8].…”