Redox signaling mediated by the gut microbiota

Abstract

The microbiota that occupies the mammalian intestine can modulate a range of physiological functions, including control over immune responses, epithelial barrier function, and cellular proliferation. While commensal prokaryotic organisms are well known to stimulate inflammatory signaling networks, less is known about control over homeostatic pathways. Recent work has shown that gut epithelia contacted by enteric commensal bacteria rapidly generate reactive oxygen species (ROS). While the induced production of ROS in professional phagocytes via stimulation of formyl peptide receptors (FPRs) and activation of NADPH oxidase 2 (Nox2) is a well-studied process, ROS are also similarly elicited in other cell types, including intestinal epithelia, in response to microbial signals via FPRs and the epithelial NADPH oxidase 1 (Nox1). ROS generated by Nox enzymes have been shown to function as critical second messengers in multiple signal transduction pathways via the rapid and transient oxidative inactivation of a distinct class of sensor proteins bearing oxidant-sensitive thiol groups. These redox-sensitive proteins include tyrosine phosphatases that serve as regulators of MAP kinase pathways, focal adhesion kinase, as well as components involved in NF-κB activation. As microbe-elicited ROS has been shown to stimulate cellular proliferation and motility, and to modulate innate immune signaling, we hypothesize that many of the established effects of the normal microbiota on intestinal physiology may be at least partially mediated by this ROS-dependent mechanism.

Figure 1

Host signaling events controlled by symbiotic bacterial-induced cellular ROS generation. Symbiotic bacteria residing in the gut lumen stimulate intestinal tissue homeostatic events via the reversible activation of cellular redox signaling processes. The gut microbiota generate formylated peptides that are sensed by formyl peptide receptors (FPRs) situated on the apical surface of epithelial cells. Receptor binding initiates a singling cascade that trigger the NADPH oxidase Nox1 to catalyze localized ROS generation, which then oxidizes critical cysteine residues and the regulatory influence of redox sensor proteins including the Nedd8 ligase, Ubc12, DUSP3, and LMW-PTPase. Ensuing signaling processes influence gut physiology by including stem cell proliferation, epithelial cell motility, and dampening of innate immune responses.

Figure 2

Activation of the redox-sensitive Nrf2 cytoprotective pathway by lactobacilli-induced generation of cellular ROS. Under homeostatic conditions, Keap1 binds to Nrf2 and inhibits its nuclear translocation. Generation of lactobacilli-induced ROS catalyzed by Nox1 oxidizes cysteine residues within Keap1, resulting in conformation change and release of binding from Nrf2, allowing it to translocate into the nucleus. Nrf2 then binds to an anti-oxidant response DNA promoter element and induces the transcription of a battery of Nrf2-responsive genes including a plethora of cytoprotective factors. The Nrf2 responsive gene products protect macromolecules from oxidative damage thereby promoting cell survival and preserving tissue physiological integrity.