Scientific Premise: Inflammatory bowel diseases cause significant morbidity and mortality (2, 3); likewise, geriatric infirmity (frailty) accounts for 23% of the total global burden of disease in people aged 60 years and older and will only increase over the next 20 years. Both conditions are associated with dysbiosis, but it is unclear how changes in the microbiota contribute. We have identified indole and its derivatives (e.g. indole-3- carboxaldehyde (ICA)) as molecules secreted by benevolent commensal bacteria that act across diverse phyla (C. elegans, Drosophila and mice) to augment health and allow animals to live better for longer (called healthspan(1)). Dysbiosis dysregulates indole levels in colitis and indole levels predict disease susceptibility. Hypothesis: Indoles increase integrity of the intestinal epithelial barrier and thereby mitigate damage in response to various stressors, including environmental stressors (e.g. radiation), inflammatory immune responses, and pathogens(5, 6). During establishment of intestinal homeostasis, indoles organize the cellular composition of the intestinal tract, which regulates tissue function as well as the microbiota, and promotes healthy aging. Augmenting intestinal barrier integrity may provide protection from various diseases or conditions associated with bacterial factors crossing the intestinal epithelia and causing localized or systemic deleterious inflammation, called inflammaging. Background: The Aryl hydrocarbon receptor (Ahr) mediates indole effects in diverse phyla. Our work shows that in response to acute stressors, indoles act via Type I Interferon (IFN1) to detect, preserve, and repair the intestinal epithelia, thereby promoting barrier integrity; without indoles, animals are hypersusceptible to stressors. Also, indoles act via IL-10 signaling to regulate both the cellular composition of the intestine, and limit deleterious inflammation; with aging, levels of indoles and IL-10 decline, the cellular composition of the colon is altered, and animals become frail, all of which are reversed by indoles. Research Plan:
Aim 1 will determine the molecular mechanisms by which indole and related metabolites regulate IL-10 during establishment of healthy homeostasis to control the cellular composition of the epithelia, increase barrier integrity, limit deleterious inflammation (inflammaging), and promote healthspan.
Aim 2 will assess how indoles regulate Type I IFN signaling in response to acute stressors, such as radiation, to facilitate intestinal barrier resilience and repair. Significance: These experiments will provide mechanistic information on how indoles, derived from commensal bacteria or from functional foods, regulate innate immune function and establish tissue homeostasis so as to limit morbidity associated with diverse stressors or with aging. Innovation: This proposal explores how indoles secreted by the commensal microbiota promote integrity of the epithelial and the mucus barriers both during homeostasis, and following stressors. These data will provide the basis for developing indoles as biomarkers for frailty and health, and as drugs for chronic inflammatory diseases (e.g. Crohn?s, frailty).
The goal of this proposal is to determine how indole derivatives derived from the microbiota orchestrate resilience and repair responses in the intestinal tract, thereby mitigating disease severity and extending periods of health (healthspan). The concepts and mechanisms developed here are applicable to diverse stressors including environmental stressors, pathogens, and hyper-inflammatory immune responses, and to cumulative responses to damage (i.e. frailty), which is evident in geriatric individuals. In this regard, indoles may serve as the basis for novel classes of drugs that mimic the effects of protective microbiota and promote healthspan.
|Bhatt, Shantanu; Romeo, Tony; Kalman, Daniel (2011) Honing the message: post-transcriptional and post-translational control in attaching and effacing pathogens. Trends Microbiol 19:217-24|