Microbial-Derived Tryptophan Metabolites and Their Role in Neurological Disease: Anthranilic Acid and Anthranilic Acid Derivatives

Abstract

The gut microbiome provides the host access to otherwise indigestible nutrients, which are often further metabolized by the microbiome into bioactive components. The gut microbiome can also shift the balance of host-produced compounds, which may alter host health. One precursor to bioactive metabolites is the essential aromatic amino acid tryptophan. Tryptophan is mostly shunted into the kynurenine pathway but is also the primary metabolite for serotonin production and the bacterial indole pathway. Balance between tryptophan-derived bioactive metabolites is crucial for neurological homeostasis and metabolic imbalance can trigger or exacerbate neurological diseases. Alzheimer's, depression, and schizophrenia have been linked to diverging levels of tryptophan-derived anthranilic, kynurenic, and quinolinic acid. Anthranilic acid from collective microbiome metabolism plays a complex but important role in systemic host health. Although anthranilic acid and its metabolic products are of great importance for host-microbe interaction in neurological health, literature examining the mechanistic relationships between microbial production, host regulation, and neurological diseases is scarce and at times conflicting. This narrative review provides an overview of the current understanding of anthranilic acid's role in neurological health and disease, with particular focus on the contribution of the gut microbiome, the gut-brain axis, and the involvement of the three major tryptophan pathways.

Keywords: anthranilic acid; gut–brain axis; kynurenine; metabolites; microbiome; neuroactive compounds; tryptophan.

Figure 1

Tryptophan is a central amino acid and is channeled into three pathways: indole, kynurenine, and serotonin. Serotonin and kynurenine are produced by both microbes and mammals via multiple enzymes, listed in teal above. Indole is a tryptophan derivative produced solely by microbes. The majority of tryptophan is moved into the production of kynurenine and related metabolites, with the remaining portion split between indoles and serotonin. Examples of microbial producers of these small molecules are in green while examples of microbes affected by these metabolites are in orange. The broader host effects are graphically represented above.

Figure 2

The three major routes of tryptophan after ingestion, metabolism, and absorption in the human gut. Tryptophan can be absorbed into the blood stream and metabolized via the kynurenine pathway in the liver or via the serotonin or kynurenine pathway in the brain. Within the gut, tryptophan can also be funneled towards the kynurenine, indole, or serotonin pathway. These three metabolic pathways contain neuroactive metabolites that affect host physiology and neurology. Fading lines represent metabolism to a primary compound, dotted lines represent metabolism to secondary or downstream metabolites, green text ovals represent positive effects, red ovals represent negative effects, and orange ovals represent neutral outcomes.

Figure 3

Orthologous and paralogous genes encoding enzymes for the microbial metabolism of tryptophan towards the kynurenine and indole pathways. The number of phyla containing orthologs of the microbial enzyme responsible for each reaction was determined through a search using the OrthoDB database. Enzymes or non-specific reaction types are indicated by rectangular shapes above each phyla list. White circles indicate the number of species in the taxa containing orthologs and gray circles represent the number of species containing paralogs in that phyla. Six chosen phyla are shown, and all other phyla with hits are grouped into “other”. Indole is derived from tryptophan digestion by tryptophanase (TnaA). Down an alternate route from indole, kynurenine can be produced from tryptophan with a two-step process involving tyrptophan 2,3-dioxygenase (TDO) and kynurenine formamidase (KFA). The breakdown of the resulting kynurenine to anthranilic acid by microbes is catalyzed by kynureninase (KNYU). KYNU also catalyzes the reaction of 3-hydroxykynurenine to 3-hydroxyanthranilic acid; this overlap in activity is denoted by an asterisk (*). Anthranilic acid is converted to 3-hydroxyanthranilic acid via non-specific hydroxylation. 3-hydroxyanthranilic acid can then be converted to multiple downstream metabolites, such as picolinic acid (not shown) or quinolinic acid (shown here). The production of quinolinic acid from 3-hydroxyanthranilic acid is catalyzed by 3-hydroxyanthranilate 3,4-dioxygenase (HAAO).

Figure 4

STRING database output from the search for Escherichia coli K12 MG1655 indole amine 2,3-dioxygenase 1 (IDO1), one enzyme responsible for the gut conversion of tryptophan to kynurenine. Full protein names are tryptophan 2,3-dioxygenase (TDO2), kynureninase (KYNU), tryptophan hydroxylase (TPH1), kynurenine formamidase (AFMID), human cytochromes P450 1A1 (CYP1A1) P450 1B1 (CYP1B1), tryptophan hydroxylase 2 (TPH2), monoamine oxidase A (MAOA), IL4-induced gene 1 (IL4I1), and acetylserotonin O-methyltransferase (ASMT). (A) Protein interaction network with IDO1 as the central node. Light blue connections indicate known interaction from curated databases; pink lines indicate the interaction has been experimentally validated. Light green connections indicate the encoding genes are in the same gene neighborhood; red-orange lines indicate gene fusions, and dark blue indicate gene co-occurrence. Black lines indicate co-expression and light blue indicate protein homology. (B) Gene co-occurrence across Bacteria, Eukarya, and Archaea of IDO1- encoding genes and related protein-encoding genes. Color indicates highest sequence similarity within the taxa, with darker reds and black indicating higher similarity.