The commensal microbiota exacerbate infectious colitis in stressor-exposed mice

Abstract

Exposure to a prolonged restraint stressor disrupts the colonic microbiota community composition, and is associated with an elevated inflammatory response to colonic pathogen challenge. Since the stability of the microbiota has been implicated in the development and modulation of mucosal immune responses, we hypothesized that the disruptive effect of the stressor upon the microbiota composition directly contributed to the stressor-induced exacerbation of pathogen-induced colitis. In order to establish a causative role for stressor-induced changes in the microbiota, conventional mice were exposed to prolonged restraint to change the microbiota. Germfree mice were then colonized by microbiota from either stressor-exposed or non-stressed control mice. One day after colonization, mice were infected with the colonic pathogen, Citrobacterrodentium. At six days post-infection, mice that received microbiota from stress-orexposed animals had significant increases in colonic pathology and pro-inflammatory cytokine (e.g. IL-1β) and chemokine (e.g. CCL2) levels after C. rodentium infection in comparison with mice that received microbiota from non-stressed mice. 16S rRNA gene sequencing revealed that microbial communities from stressed mice did not have any detectable Bifidobacterium present, a stark contrast with the microbial communities from non-stressed mice, suggesting that stressor-induced alterations in commensal, immunomodulatory Bifidobacterium levels may predispose to an increased inflammatory response to pathogen challenge. This study demonstrates that the commensal microbiota directly contribute to excessive inflammatory responses to C. rodentium during stressor exposure, and may help to explain why gastrointestinal disorders are worsened during stressful experiences.

Stressor exposure has prolonged effects on colonic microbial community structure in Citrobacter rodentium-challenged mice

“…Moreover, recent, major life events are more common in patients with severe IBD vs. those patients that are in remission52. The mechanisms linking stress with exacerbation of these diseases are not completely understood, but the results of this study are consistent with others from our group indicating that stressor-induced changes in the composition of the gut microbiota contribute to dysregulation of mucosal inflammatory responses15. Future studies involving assessment of microbial community functions are needed to better understand how stressor-induced alterations of the gut microbiota contribute to dysregulation of colonic inflammation and whether microbial community functions are involved with the beneficial effects of probiotic L. reuteri in stressor-exposed animals.…”

“…Disruptions in the microbiota can have serious consequences on host physiology and immunity, and those induced by stress may be associated with aggravation of colonic inflammation. For example, C. rodentium -induced colonic inflammation was greater in germfree mice that were colonized with microbiota from donor mice exposed to a prolonged restraint stressor when compared to germfree mice colonized with microbiota from non-stressed control donors15. Thus, it is now evident that stressor exposure changes the composition of the gut microbiota that can then lead to exacerbations of colonic inflammation.…”

“…The aggressive intruder attacks and defeats the test mice over the course of two hours as previously described15222324. This process is repeated for a total of six evenings, from 1700 to 1900 hr, the beginning of the mouse active cycle.…”

“…For example, exposure to stress prior to oral challenge with C. rodentium changed gut microbiota composition and increased subsequent colonic inflammatory responses to C. rodentium 6. Transplanting the microbiota from stressor-exposed mice to germfree mice prior to challenge with C. rodentium resulted in an exaggerated colonic inflammatory response compared to germfree mice that received microbiota from non-stressed donors15, demonstrating the impact that the effects of stress on the microbiota can have on the susceptibility to and severity of C. rodentium infection. However, because inflammation in the intestines can significantly change microbial community composition16, it is not immediately clear whether stressor-induced changes in gut microbiota composition are still evident in mice with C. rodentium -induced colonic inflammation, and whether the effects of the stressor are evident in probiotic-treated animals.…”

Gut Reactions: Breaking Down Xenobiotic–Microbiome Interactions

“…Preclinical studies indicate that stress exposure across the life span can impact on gut microbiome composition. This includes early-life prenatal (Golubeva et al, 2015) or postnatal stressors (O'Mahony et al, 2009) as well as stress experienced during adulthood (Bharwani et al, 2016;Burokas et al, 2017;Galley et al, 2017). atherosclerosis in humans (Miller et al, 2014).…”