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Emerging effects of tryptophan pathway metabolites and intestinal microbiota on metabolism and intestinal function

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Abstract

The metabolism of dietary tryptophan occurs locally in the gut primarily via host enzymes, with ~ 5% metabolized by gut microbes. Three major tryptophan metabolic pathways are serotonin (beyond the scope of this review), indole, kynurenine and related derivatives. We introduce the gut microbiome, dietary tryptophan and the potential interplay of host and bacterial enzymes in tryptophan metabolism. Examples of bacterial transformation to indole and its derivative indole-3 propionic acid demonstrate associations with human metabolic disease and gut permeability, although causality remains to be determined. This review will focus on less well-known data, suggestive of local generation and functional significance in the gut, where kynurenine is converted to kynurenic acid and xanthurenic acid via enzymatic action present in both host and bacteria. Our functional data demonstrate a limited effect on intestinal epithelial cell monolayer permeability and on healthy mouse ileum. Other data suggest a modulatory effect on the microbiome, potentially in pathophysiology. Supportive of this, we found that the expression of mRNA for three kynurenine pathway enzymes were increased in colon from high-fat-fed mice, suggesting that this host pathway is perturbed in metabolic disease. These data, along with that from bacterial genomic analysis and germ-free mice, confirms expression and functional machinery of enzymes in this pathway. Therefore, the host and microbiota may play a significant dual role in either the production or regulation of these kynurenine metabolites which, in turn, can influence both host and microbiome, especially in the context of obesity and intestinal permeability.

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Abbreviations

3-HK:

3-Hydroxykynurenine

AADAT:

Aminoadipate aminotransferase

ACMSD:

Aminocarboxymuconate semialdehyde decarboxylase

AhR:

Aryl hydrocarbon receptor

DDC:

DOPA decarboxylase

FITC:

Fluorescein isothiocyanate

GF:

Germ-Free

HFD:

High fat diet

I3AA:

Indole-3-acetic acid

IDO:

Indoleamine 2,3-dioxygenase

IFN-γ:

Interferon g

IPA:

Indole-3 propionic acid

ISA:

Indoxyl-3-sulfuric acid

KA:

Kynurenic acid

KAT:

Kynurenine aminotransferase/cysteine conjugate beta-lyase (CCBL)

KMO:

Kynurenine 3-monooxygenase

KYN:

Kynurenine

kynA:

Tryptophan 2,3-dioxygenase (bacterial)

KYNU:

Kynureninase

NAD:

Nicotinamide

RFU:

Relative fluorescence units

T2DM:

Type 2 diabetes

tam1:

Tryptophan amino transferase 1 (bacterial)

TDO:

Tryptophan 2,3-dioxygenase

tnAa:

Tryptophanase (bacterial)

TNF-α:

Tumor necrosis factor-α

TPH1:

Tryptophan hydroxylase 1

TTX:

Tetrodotoxin

XA:

Xanthurenic acid

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Acknowledgements

The authors would like to thank John Mabus and Dr. Matthew Jennis (CVM, Janssen R&D, PA, USA) for their excellent analysis of metabolite effects in vitro, and Dr. James Lenhard (CVM, Janssen R&D, PA, USA) for discussions on the gut microbiome and protein metabolism. We thank Dr Harriët Schellekens (Department of Anatomy and Neuroscience, University College Cork, Ireland) for the high-fat-fed mice colons used for mRNA expression. The research was supported in part by a Science Foundation Ireland (SFI) Industry Fellowship Award (15/IFB/3578) to N. Hyland for C. Cavanaugh to conduct the experiments at APC Microbiome Ireland, a research center funded by SFI (12/RC/2273).

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  1. Niall P. Hyland, Cassandre R. Cavanaugh and Pamela J. Hornby: senior co-authors.

Authors and Affiliations

  1. Department of Physiology and APC Microbiome Ireland, University College Cork, Cork, Ireland

    Niall P. Hyland

  2. Cardiovascular and Metabolic Disease Discovery, Janssen R&D, LLC, 1400 McKean Road, Spring House, PA, 19477, USA

    Cassandre R. Cavanaugh & Pamela J. Hornby

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  1. Niall P. Hyland
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  2. Cassandre R. Cavanaugh
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  3. Pamela J. Hornby
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Correspondence to Pamela J. Hornby.

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None of the authors have a conflict of interest; CC and PH are fulltime employees of Janssen R&D, LLC.

Research involving animals

All experiments were performed in accordance with European guidelines following approval by University College Cork Animal Ethics Experimentation.

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N/A, no human subjects participated in the original research reported here.

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Hyland, N.P., Cavanaugh, C.R. & Hornby, P.J. Emerging effects of tryptophan pathway metabolites and intestinal microbiota on metabolism and intestinal function. Amino Acids 54, 57–70 (2022). https://doi.org/10.1007/s00726-022-03123-x

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