Does functional abdominal pain have an organic explanation? Gut-localized immune responses offer new clues for patients with functional gastrointestinal disorders

Irritable bowel syndrome (IBS) is a prevalent condition affecting 11% of the global population, accompanied by chronic abdominal pain and concurrent constipation or diarrhea. In addition to abdominal pain and abnormal bowel movements, IBS can negatively affect brain function and has been linked to psychiatric conditions such as depression. As such, IBS has been named a microbiome-gut-brain axis disorder. However, there is a current lack of easy-to-spot indicators of disease that explain patients’ symptomatology.

Some triggers of IBS symptoms include gastroenteritis, stress and changes in gut microbiota composition or activities. Now, new findings in mice and humans reveal a novel mechanism that can contribute to chronic abdominal pain.

Aguilera-Lizarraga and colleagues have shown that a bacterial gut infection can change local immune responses in the gut, resulting in certain food being perceived as harmful and thereby causing persistent abdominal pain.

The authors hypothesized that pathogenic bacteria can trigger a breakdown of oral tolerance to harmless food antigens, leading to a reaction by the immune system that underlies abdominal pain. They studied how this might occur in mice exposed to the pathogenic bacterium Citrobacter rodentium and the protein ovalbumin.

The repeated ingestion of ovalbumin alone did not lead to abdominal pain. When mice however were simultaneously infected with the bacterium Citrobacter rodentium, the gut barrier lost its integrity and ovalbumin peptides and microorganisms residing in the gut lumen entered the lamina propria, thereby triggering an immune response and activating sensory nerves. Immune cells in the gut targeted both C. rodentium and ovalbumin by releasing inflammatory molecules and IgE antibodies that recognize them. As a result of the infection and the defense molecules released, abdominal pain (measured by the distension of the mice’s colon and rectum) emerged.

When mice had recovered from the infection and the pain response had resided, the renewed administration of ovalbumin only was sufficient to cause intense abdominal pain and diarrhea. The investigators showed that re-administration of ovalbumin led mast cells to degranulate and release histamine. The attachment of histamine to its receptors in surrounding sensory neurons led to abdominal pain due to mast-cell response to food. The involvement of such an immune mechanism was supported by the prevention of abdominal pain when the degranulation of mast cells or the histamine H₁ receptor found on sensory neurons was blocked. Interestingly, IgE antibodies released by immune cells in the gut against ovalbumin were only present in the colon but not systematically. Indeed, this type of antibody seemed to be crucial in abdominal pain generated after ovalbumin ingestion, as if mice lacking in IgE or that were administered an anti-IgE antibody were protected.

When the authors injected solutions of soy, wheat, gluten and milk into the colon of 12 people who had IBS and 8 healthy people, all those with IBS and two healthy individuals showed an immune reaction to at least one of the foods. Further results suggested that this local reaction resulted from IgE dependent mast cell activation, and occurred in the absence of systemic immunity against these food antigens. In addition, the proportion of fecal samples from people with IBS that were positive for infection by Staphylococcus aureus was higher than in healthy controls. This bacterium is a known bacterial commensal of the human nares and skin and has the ability to manipulate innate and adaptive immune responses. The findings in a small sample of participants suggest the involvement of immune responses in boosting gut pain in at least part with IBS.

Altogether, the findings in mice show the involvement of local immune responses in the colon mediated by IgE antibodies and histamine released by mast cells in enhancing gut pain in mice. Although the study disentangles underlying mechanisms associated with post-infectious IBS, it would be worth exploring whether this mechanism also applies in the context of diarrhea-predominant IBS, constipation-predominant IBS or mixed IBS, which is the most common subtype of IBS.

The authors also suggested some potential therapeutic avenues of exploration in the context of the clinical setting. They included improving intestinal barrier function to limit the access of gut microbes and food in the lumen to the lamina propria or targeting key components involved in triggering gut pain after gastroenteritis, such as histamine released by mast cells or IgE antibodies against harmless foods.

References:

Aguilera-Lizarraga J, Florens MV, Viola MF, et al. Local immune response to food antigens drives meal-induced abdominal pain. Nature. 2021. doi: 10.1038/s41586-020-03118-2.

Brierley SM. Food for thought about the immune drivers of gut pain. Nature News & Views. 2021. doi: 10.1038/d41586-020-03661-y.