Reactive Oxygen Production Induced by the Gut Microbiota: Pharmacotherapeutic Implications

R. M. Jones, J. W. Mercante, A. S. Neish

Abstract

The resident prokaryotic microbiota of the mammalian intestine influences diverse homeostatic functions, including regulation of cellular growth, maintenance of barrier function, and modulation of immune responses. However, it is unknown how commensal prokaryotic organisms mechanistically influence eukaryotic signaling networks. Recent data has demonstrated that gut epithelia contacted by enteric commensal bacteria rapidly generate reactive oxygen species (ROS). While the induced generation of ROS via stimulation of formyl peptide receptors is a cardinal feature of the cellular response of phagocytes to pathogenic or commensal bacteria, evidence is accumulating that ROS are also similarly elicited in other cell types, including intestinal epithelia, in response to microbial signals. Additionally, ROS have been shown to serve as critical second messengers in multiple signal transduction pathways stimulated by proinflammatory cytokines and growth factors. This physiologically-generated ROS is known to participate in cellular signaling via the rapid and transient oxidative inactivation of a defined class of sensor proteins bearing oxidant-sensitive thiol groups. These proteins include tyrosine phosphatases that serve as regulators of MAP kinase pathways, cytoskeletal dynamics, as well as components involved in control of ubiquitination-mediated NF-κB activation. Consistently, microbial-elicited ROS has been shown to mediate increased cellular proliferation and motility and to modulate innate immune signaling. These results demonstrate how enteric microbiota influence regulatory networks of the mammalian intestinal epithelia. We hypothesize that many of the known effects of the normal microbiota on intestinal physiology, and potential beneficial effects of candidate probiotic bacteria, may be at least partially mediated by this ROSdependent mechanism.

Keywords: Formyl peptide receptors, Inflammatory bowel disease, Nox enzymes, Probiotics, Lactobacillus, Wound healing, Hormesis, Crohn's disease, proinflammatory cytokines, microbial signals