Control and dysregulation of redox signalling in the gastrointestinal tract

Abstract

Redox signalling in the gastrointestinal mucosa is held in an intricate balance. Potent microbicidal mechanisms can be used by infiltrating immune cells, such as neutrophils, to protect compromised mucosae from microbial infection through the generation of reactive oxygen species. Unchecked, collateral damage to the surrounding tissue from neutrophil-derived reactive oxygen species can be detrimental; thus, maintenance and restitution of a breached intestinal mucosal barrier are paramount to host survival. Redox reactions and redox signalling have been studied for decades with a primary focus on contributions to disease processes. Within the past decade, an upsurge of exciting findings have implicated subtoxic levels of oxidative stress in processes such as maintenance of mucosal homeostasis, the control of protective inflammation and even regulation of tissue wound healing. Resident gut microbial communities have been shown to trigger redox signalling within the mucosa, which expresses similar but distinct enzymes to phagocytes. At the fulcrum of this delicate balance is the colonic mucosal epithelium, and emerging evidence suggests that precise control of redox signalling by these barrier-forming cells may dictate the outcome of an inflammatory event. This Review will address both the spectrum and intensity of redox activity pertaining to host–immune and host–microbiota crosstalk during homeostasis and disease processes in the gastrointestinal tract.

Key points

  • Immune cells, microorganisms and the epithelium all generate and respond to redox signals in the colonic mucosa during homeostasis and in disease.

  • Redox signals, particularly H2O2, are generated by the host and the gut microbiota to impede overgrowth of opportunistic pathogens; similarly, certain pathogens utilize these systems to subvert host defences.

  • Host responses to reactive oxygen species (ROS) produced in situ and hypoxia act in concert and opposition to regulate homeostasis in the gut.

  • Host–immune and host–microbiota crosstalk can both contribute to excessive ROS production, participating in collateral damage at the tissue level.

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Fig. 1: Host–microbial redox signalling during hypoxia.
Fig. 2: Host redox–hypoxia crosstalk in the gastrointestinal mucosa.
Fig. 3: ROS collateral damage and gastrointestinal disease.

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Acknowledgements

E.L.C. is supported by NIH grant DK103639, and S.P.C. is supported by NIH grants DK50189, DK104713, DK095491, DK103712 and a Merit Award from the Veterans Administration.

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PubMed was searched from 1999 to 2017 for articles using the terms: “reactive oxygen species”, “hydrogen peroxide”, “hypoxia”, “microbiota”, “mucosa” and “epithelium” alone or in combination. Articles in English were considered on the basis of their relevance to this article’s topic. The reference lists of articles were crosschecked for additional references.

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E.L.C. researched data for the article. E.L.C. and S.P.C. made substantial contributions to discussion of content, wrote the article and reviewed/edited the manuscript before submission.

Correspondence to Eric L. Campbell.

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