Stress is a trigger for flares of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Patients with IBD, and at least a subset of patients with IBS, also have alterations in the gut microbiota (aka dysbiosis) and alterations in the gut immune responses. While studies have demonstrated that immune responses can have effects on GI motility and symptoms, a major gap in our understanding of stress as a trigger for IBD and IBS flares is how, and if, stress is causal in dysbiosis and in alterations in gut immune responses and if these changes contribute to symptoms. We discovered that patients with diarrhea predominant IBS (IBSd) had dysbiosis on 16S rDNA sequencing of feces and increased binding of secretory IgA to fecal bacteria, indicating that IBSd patients had increased antigen specific immune responses to their gut bacteria. Using a mouse model, we found that stress likewise induced diarrhea, visceral hypersensitivity, dysbiosis and increased IgA binding to gut bacteria, recapitulating our findings in human IBSd patients. Notably the GI symptoms following stress were dependent upon the microbiota as germ free mice did not develop diarrhea following stress. Further, fecal microbiota transplantation (FMT) of microbiota from stressed, but not control, mice recapitulated the immunologic features of stress. Moreover, we observed that stress-induced dysbiosis allows the translocation of commensal bacteria to the mesenteric lymph node (MLN) facilitated by the formation of colonic goblet cell associated passages (GAPs), a pathway also known to deliver luminal antigens to antigen presenting cells (APCs) in the lamina propria (LP) for the induction of T cell responses in the MLN. However, which bacteria the immune system is responding to during stress and whether this immune response contributes to dysbiosis and symptoms remains a significant gap in our understanding of stress as a trigger for flares of IBD and IBS. We hypothesize that dysbiosis of the gut microbiota following stress allows for the translocation and adaptive immune responses to specific bacterial taxa which serves to perpetuate dysbiosis and contribute to stress induced GI symptoms. To pursue this hypothesis, we propose the following specific aims:
Aim 1. Define the taxa and pathways involved in bacterial translocation (BT) following stress, and how that relates to the changes in the luminal microbiota.
Aim 2. Define the gut bacterial antigen specific immune response to stress induced dysbiosis and BT Aim 3. Define the requirement of immune responses to commensal bacteria and the loss of gut bacterial taxa following stress in inducing and maintaining dysbiosis and GI symptoms

Public Health Relevance

Stress is a trigger for flares of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), however, the pathophysiology behind stress as a trigger for flares of IBS and IBD has remained enigmatic. These studies will provide a mechanistic basis for the pathophysiology of stress as a trigger for flares by linking stress-induced dysbiosis with antigen specific immune responses to gut bacteria to induce GI symptoms and perpetuate stress-induced dysbiosis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rothermel, Annette L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code