The Role of the Microbial Metabolites Including Tryptophan Catabolites and Short Chain Fatty Acids in the Pathophysiology of Immune-Inflammatory and Neuroimmune Disease

Abstract

There is a growing awareness that gut commensal metabolites play a major role in host physiology and indeed the pathophysiology of several illnesses. The composition of the microbiota largely determines the levels of tryptophan in the systemic circulation and hence, indirectly, the levels of serotonin in the brain. Some microbiota synthesize neurotransmitters directly, e.g., gamma-amino butyric acid, while modulating the synthesis of neurotransmitters, such as dopamine and norepinephrine, and brain-derived neurotropic factor (BDNF). The composition of the microbiota determines the levels and nature of tryptophan catabolites (TRYCATs) which in turn has profound effects on aryl hydrocarbon receptors, thereby influencing epithelial barrier integrity and the presence of an inflammatory or tolerogenic environment in the intestine and beyond. The composition of the microbiota also determines the levels and ratios of short chain fatty acids (SCFAs) such as butyrate and propionate. Butyrate is a key energy source for colonocytes. Dysbiosis leading to reduced levels of SCFAs, notably butyrate, therefore may have adverse effects on epithelial barrier integrity, energy homeostasis, and the T helper 17/regulatory/T cell balance. Moreover, dysbiosis leading to reduced butyrate levels may increase bacterial translocation into the systemic circulation. As examples, we describe the role of microbial metabolites in the pathophysiology of diabetes type 2 and autism.

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Acknowledgments

MB is supported by a NHMRC Senior Principal Research Fellowship 1059660.

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Correspondence to Michael Maes.

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Conflict of Interest

MB has received grants from the NIH, Simons Autism Foundation, Stanley Medical Research Foundation, NHMRC, and CRC for Mental Health; he has been a paid consultant for Astra Zeneca, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, and Pfizer and a paid speaker for Astra Zeneca, Eli Lilly, Glaxo SmithKline, Lundbeck, and Merck. FNJ has received grants from the Brain and Behaviour Research Institute, NHMRC, Australian Rotary Health, and the Meat and Livestock Board and has been a paid speaker for Sanofi-Synthelabo, Janssen Cilag, Servier, and Health Ed. The other authors have no conflicts to declare.

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Morris, G., Berk, M., Carvalho, A. et al. The Role of the Microbial Metabolites Including Tryptophan Catabolites and Short Chain Fatty Acids in the Pathophysiology of Immune-Inflammatory and Neuroimmune Disease. Mol Neurobiol 54, 4432–4451 (2017). https://doi.org/10.1007/s12035-016-0004-2

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Keywords

  • Leaky gut
  • Bacterial translocation
  • Diabetes type 2
  • Autism
  • Immune inflammation
  • Oxidative stress