Excessive Psychological Stress Disrupts the Colon's Mucosal Layer.
Did you know that excessive psychological stress disrupts the colon's mucosal layer?
Description: Peer reviewed study “Psychological stress disrupts intestinal epithelial cell function and mucosal integrity through microbe and host-directed processes” abstract.
“Psychological stress alters the gut microbiota and predisposes individuals to increased risk for enteric infections and chronic bowel conditions. Intestinal epithelial cells (IECs) are responsible for maintaining homeostatic interactions between the gut microbiota and its host. In this study, we hypothesized that disruption to colonic IECs is a key factor underlying stress-induced disturbances to intestinal homeostasis. Conventionally raised (CONV-R) and germ-free (GF) mice were exposed to a social disruption stressor (Str) to ascertain how stress modifies colonic IECs, the mucosal layer, and the gut microbiota. RNA sequencing of IECs isolated from CONV-R mice revealed a robust pro-inflammatory (Saa1, Il18), pro-oxidative (Duox2, Nos2), and antimicrobial (Reg3b/g) transcriptional profile as a result of Str. This response occurred concomitant to mucus layer thinning and signs of microbial translocation. In contrast to their CONV-R counterparts, IECs from GF mice or mice treated with broad spectrum antibiotics exhibited no detectable transcriptional changes in response to Str. Nevertheless, IECs from Str-exposed GF mice exhibited an altered response to ex vivo bacterial challenge (increased dual Oxidase-2 [Duox2] and nitric oxide synthase-2 (Nos2)), indicating that STR primes host IEC pro-oxidative responses. In CONV-R mice stress-induced increases in colonic Duox2 and Nos2 (ROS generating enzymes) strongly paralleled changes to microbiome composition and function, evidencing Str-mediated ROS production as a primary factor mediating gut-microbiota dysbiosis. In conclusion, a mouse model of social stress disrupts colonic epithelial and mucosal integrity, a response dependent on an intact microbiota and host stress signals. Together these preclinical findings may provide new insight into mechanisms of stress-associated bowel pathologies in humans.”…
Discussion
“Exposure to psychological stress alters the microbiota and predisposes individuals to increased risk of enteric infections and bowel diseases and conditions.1–3,9,20,31,32 However, stressor-induced modifications to the gut microbiota and gastrointestinal health have not been surveyed in context of intestinal epithelial cells (IECs), which have a unique role in: 1) maintaining a physical barrier between microbe and host, 2) relaying microbial signals to the immune system, and 3) producing bioactive molecules that subsequently modify the gut microbiota.33–35 In this study, we provide evidence that a mouse model of social defeat stress (Str) results in broad and physiologically relevant shifts to IEC physiology, underscored by an upregulation in antimicrobial, pro-inflammatory, and ROS-generating pathways that occur concomitantly to mucosal disruption, signs of systemic bacterial translocation, and functional changes to the gut microbiota.
Evidence of coordinated antimicrobial and immune signaling was present in Str-exposed IECs. This was apparent by transcriptional network analysis, which revealed an IEC gene signature supporting heightened innate immune signaling downstream of toll-like receptor (TLR) and nucleotide-binding oligomerization domain-like receptor (NLR) pathways. Constitutively expressed bacterial components such as LPS, FLG, and muramyl dipeptides bind TLRs and NLRs to activate the NFκB pathway, which ultimately enhances the expression of genes involved in innate immune signaling and ROS generation, such as Saa1, Nos2 and Duox2.36 This enhancement in IEC TLR/NLR-to-NFκB signaling likely has important implications for understanding how stress predisposes to enteric infection and inflammatory bowel disease. Indeed, studies have demonstrated that hyperactivation of the NFκB pathway contributes to aberrant inflammatory responses to enteric infection and colitis.37,38 In addition, recent data from our laboratory showed that ablation of the classical NFκB pathway in IECs conferred increased host protection against a colonic Citrobacter rodentium infection challenge.19 This is in contrast to stress, which exacerbates C. rodentiuminfection.3,20,21 Further studies are needed to unravel the mechanistic underpinnings of IEC NFκB signaling in response to stress and its potential role in mediating gastrointestinal infection and/or inflammatory bowel disease.
Under homeostatic conditions, the colon relies on two mucus layers to provide biochemical and physical protection against aberrant microbial signaling.23 We found that stress reduced the thickness and disrupted the integrity of these mucus layers. Morphological changes to the mucus coincided with altered transcription of genes involved in glycoprotein biosynthesis (e.g. Muc1, Muc13) and mucin glycosylation (e.g. Fut2, St8sia1) in IECs. While mechanisms underlying stress-induced mucus disruption remain unknown, it is important to note these transcriptional and morphological changes did not occur in GF mice, highlighting a key role of an intact microbiota in modifying the mucus layer during Str. Indeed, other research has identified specific members of the microbiota, such as Bacteroides thetaiotamicron, that are directly responsible for modifying mucus integrity and barrier function,39,40 some of which are associated with mucus disruption during inflammatory bowel diseases like ulcerative colitis and Crohn’s disease.40,41In this study, it is feasible that Muribaculaceae, which was highly upregulated by stress and was recently found to exhibit robust mucus degrading properties,42 may be driving changes to mucus integrity and bacterial translocation observed in response to stress. Indeed, our data coincide with previous reports of social stress-induced bacterial translocation20,43 and highlight the need for further research into the role of colonic mucosal integrity as a mechanism by which endogenous microbes (or immune-stimulating bacterial components) reach host circulation during stress. Future studies using gnotobiotic models (monocolonization or multi-strain colonization) will be needed to help ascertain the specific microbes responsible for stress-induced IEC transcriptional responses, mucosal layer degradation and barrier disruption.
It is likely that exogenous signals, in addition to direct microbial stimulation, contribute to increased activity of IECs. This includes Reg3b and Reg3g, antimicrobial C-type lectins whose transcription activity within IECs are strongly upregulated by exogenous signals.44,45 While not a focus of this study, cytokines released in response to bacterial signaling by local immune cells (e.g. innate lymphoid cells & Th17 cells) can activate anti-microbial defense pathways in epithelial cells.46,47 In support of this, our transcriptome data revealed Str-induced gene transcription profiles centered around activation of the Janus kinase/Signal transducer of activated transcription factor-3 (JAK/STAT3) pathway, which is activated downstream of IL-22 and IL-17 (among other cytokines) and is the primary route of Reg3b and Reg3g transcription in IECs.48The specific effects of stress on the colonic immune cell niche, however, remains understudied. Nevertheless, our network analysis of IEC expression profiles revealed Str-induced upregulation in genes involved in Th17 differentiation (e.g. Saa1/3), highlighting a potential role of IECs in driving local changes to the innate and adaptive immune cell compartments, which may ultimately feedback to control IEC physiology.35 Future studies will need to delineate the mechanisms and implications of an immune-epithelial cell axis in response to stress.”
See the full study abstract here as published on the National Institutes of Health website.
