Host-Microbiota Interactions in the Gut
Andrew S. Neish
The resident prokaryotic microbiota of the mammalian intestine is a numerically vast and taxonomically
complex symbiotic community that influences diverse homeostatic functions including maintenance of the
epithelial barrier, modulation of immune responses, and control over cellular growth/differentiation and
restitutive pathways. Specifically, recent advances have implicated the commensal microbiota in regulating
epithelial cell cycle and stem cell dynamics in wide variety of organisms, thus indicating a role in normal gut
growth and development and suggesting that “dysbiosis” of the bacterial community may influence initiation
and progression of GI cancers. However, there is a gap in the knowledge concerning a mechanistic
understanding of how the commensal microbiota influences regulation of cellular growth signaling networks in
health and disease. Insight has come from studies of lower organisms, which have revealed a common
paradigm wherein contact of prokaryotic organisms stimulate the enzymatic generation of reactive oxygen
species (ROS) in the host, as an anti-microbial effector, or more significantly, as a cellular signaling
intermediate. In mammals, while the induced generation of ROS via stimulation of formyl peptide receptors
(FPRs) is a cardinal feature of the cellular response of phagocytes to all bacteria, evidence is accumulating
that ROS are also similarly elicited in other cell types, including intestinal epithelia, also in response to
microbial signals and FPRs.
Physiological ROS generation occurs via the action of highly conserved NADPH oxidase (Nox)
enzymes, including Nox2 in phagocytes and Nox1 in intestinal epithelia. Interestingly, a subset of highly
conserved bacteria, predominately lactobacilli and bifidobacteria, potently stimulates Nox dependent ROS
generation in the guts of animals as disparate as mammals and invertebrates. This physiologically-generated
ROS is known to function in cellular signaling via the rapid and transient oxidative inactivation of an expanding
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-kB activation.
Germ free flies and mice are known to exhibit suppressed epithelial proliferation and sensitivity to
injury. We have demonstrated aberrant crypt dynamics in epithelial-specific Nox1 and Fpr1 null mice, and
impaired gut stem cell proliferation in Drosophila when the orthologous dNox is genetically suppressed in
discrete stem cell microenvironments. We hypothesize that ROS generated by NADPH oxidases function as
signaling molecules during normal development and proliferation of intestinal enterocytes. In addition, specific
commensal bacteria (and fMLP) accelerate epithelial cell movement in a redox dependent fashion. Similarly,
mucosal wound closure in vivo is enhanced by certain members of the microbiota, and these effects are
abolished in Nox1 and Fpr1 (but not MyD88) null animals. These results demonstrate how enteric microbiota
influence highly conserved regulatory networks of the intestinal epithelia.
Additionally, a well-studied and evolutionarily highly conserved system for transducing exogenous
stimuli into eukaryotic host tissues is Nrf2 signaling. Nrf2 pathway activation upregulates a regulon of genes
including those involved in xenobiotic and ROS detoxification, as well as pro-restitutive function. This pathway
has attracted considerable attention because small molecule inducers of Nrf2 have cytoprotective and growth
modulatory effects. We show cellular ROS generated in response to contact with lactobacilli have
cytoprotective effects in the intestinal epithelium through the activation of Nrf2 responsive cytoprotective
genes. These data suggest that the Nrf2 pathway, and perhaps other highly conserved pathways that respond
to environmental alterations, have been adapted as signaling conduits between eukaryotic host and
prokaryotic symbiont, and highlight the role the microbiota plays in eukaryotic cytoprotective pathways.
Characterization of these pathways may have significant implications in the delineation of a eubiotic
microbiota, and in the identification of probiotic microbes with potential to influence epithelial growth and
survival.
Future challenges include the characterization of novel redox sensitive pathways that are influenced by
microbially induced ROS. Additionally, delineation of members of the microbiota that potently stimulate ROS,
and the microbiological determinants in these organisms responsible for ROS induction, will enable a
mechanistic description of an important host-microbial relationship.
Other important gaps include
characterizing the temporal acquisition of pro-proliferative members of the microbiota, their role in the
development of the neonatal intestine and their activities in modulating proliferation/homeostasis in normal
conditions, restitution post injury or during oncogenesis.