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Food for thought about the immune drivers of gut pain

Debilitating gut pain is common, but the underlying cause is often unclear. It emerges that gut infection triggers localized immune responses that cause normally innocuous foods to be perceived as harmful, leading to persistent pain.
Stuart M. Brierley is in the College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia 5042, Australia, and at the Hopwood Centre for Neurobiology, South Australian Health and Medical Research Institute, Adelaide.
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Pain evolved to alert us to and protect us from actual or potential tissue damage. There are three common forms: nociceptive pain, which is associated with the detection of damaging stimuli; inflammatory pain, associated with inflammation or infection; and chronic pain, which is a maladaptive, long-term form of pain1. Writing in Nature, Aguilera-Lizarraga et al.2 report evidence from mice and humans indicating a previously unknown mechanism that contributes to chronic gut pain.

When an individual has an obvious injury, such as a broken arm, we can readily appreciate that they are in pain. But if the injury site can’t be easily pinpointed, it can be difficult to determine the origin of the pain. This is a common problem for people who have pain in their internal organs, with some forms of such pain being easier to diagnose than others. For instance, people who have inflammatory bowel disease might have easy-to-spot indicators of disease, such as gastrointestinal bleeding, inflammation of the intestinal lining, or the presence of distinctive biomarker molecules in faecal or blood samples3. However, people who have irritable bowel syndrome (IBS), a condition that affects 11% of the global population4, lack such clear hallmarks of illness, and no obvious cause explains their chronic abdominal pain and concurrent constipation or diarrhoea.

Previous studies indicate that IBS is more common in women than in men4, with IBS symptoms being triggered by factors such as stress4, gastroenteritis (a disease caused by the ingestion of contaminated food or water)4, alterations in gut microorganisms5, and changes in communication between the gut and brain6. Aguilera-Lizarraga et al. now show that a bacterial gut infection can profoundly change local immune responses in the gut, resulting in certain foods being perceived as harmful, and thereby causing persistent gut pain (Fig. 1).

Figure 1

Figure 1 | An immune response to harmless food causes pain. Aguilera-Lizarraga et al.2 reveal a previously unknown cause of gut pain. a, Immune cells in the gut, including mast cells, which contain histamine molecules, don’t usually target food or microorganisms that normally reside there (commensal bacteria). If mice are infected with the bacterium Citrobacter rodentium, immune cells respond when the gut barrier breaks down (gut cells lose their connectivity), and food and bacteria leave the gut lumen and enter the body. Immune cells target C. rodentium by releasing defence molecules, and also target the harmless food present by producing antibodies that recognize it. Pain occurs as a result of the infection. b, After infection, repair of the gut barrier begins. Mast cells become primed to respond by moving near to neurons and expressing a receptor (generated on the basis of the antibody made previously) that recognizes a fragment of the food called an antigen. c, On subsequent ingestion of the food, mast cells recognize it and release histamine through a process called degranulation. Histamine binds to a receptor on sensory neurons, activating them and causing pain.

In healthy individuals, a process called oral tolerance results in the immune system ‘ignoring’ orally consumed substances7,8. An exception to this tolerance occurs for substances perceived by our bodies as being dangerous, such as harmful (pathogenic) bacteria, parasites and viruses. Our bodies identify foreign invaders by detecting molecular fragments called antigens, which provide a type of ‘barcode’ enabling our immune systems to specifically identify the intruders. Our immune systems can tag these antigens by producing antibodies that recognize them, enabling the pathogen to be quickly targeted if it appears again. Our defences should focus only on the ‘bad guys’, and leave the innocent bystanders alone. However, Aguilera-Lizarraga and colleagues hypothesized that a failure in oral tolerance might result in an indiscriminate targeting of both friend and foe.

To determine how this proposed breakdown in tolerance might occur in mice, the team used a model system that harnessed the pathogenic bacterium Citrobacter rodentium and ovalbumin, a protein found in egg white. Repeated ingestion of ovalbumin alone did not evoke signs of gut pain, as determined by the measurement of abdominal contractions in response to distension of the animals’ colon and rectum. However, the administration of ovalbumin after the mice had recovered from a C. rodentium infection accompanied by dietary ovalbumin caused gut pain and diarrhoea.

The animals also had a ‘leaky gut’, as shown by higher than normal intestinal permeability. This finding suggests that the intestinal lining did not provide its normal function as a physical barrier, and instead allowed intestinal contents to access the underlying tissue, thereby triggering an immune response and activating sensory nerves. In addition, the authors found that specific antibodies to ovalbumin were present in the colon but not elsewhere in the body.

The increased gut pain experienced by the treated animals could be prevented either by genetically engineering them to lack IgE, a type of antibody, or by giving them an anti-IgE antibody to block the actions of ovalbumin-specific IgE antibodies produced by the animals’ immune system. Conversely, the presence of ovalbumin-specific IgE antibodies in the animals’ colon mimicked the effect of enhanced gut pain generated after ovalbumin ingestion, in mice that had not been infected with C. rodentium.

Aguilera-Lizarraga and colleagues went on to unravel some molecular details underlying this pain response. They showed that after C. rodentium infection and ovalbumin treatment, immune cells in the mouse colon called mast cells underwent degranulation, an event that releases molecules, including histamine, that are needed for defence. If this process was blocked, either by using a drug that prevents mast-cell degranulation or by genetically engineering mice to lack mast cells, this lessened or prevented the enhanced gut pain the animals experienced on ovalbumin ingestion after infection.

The authors present evidence indicating that histamine release triggers pain by affecting sensory neurons in the gut. Supernatant liquid taken from the colons of these mice increased the in vitro sensitivity of sensory neurons that signal pain. This effect could be prevented either by using a drug to block the histamine H1 receptor, which is found on sensory neurons, or by using mice genetically engineered to lack this receptor.

The authors next injected solutions of soy, wheat, gluten and milk — all of which have been linked to food allergies and can cause gut symptoms, including bloating and abdominal pain7 — directly into the colorectum of 12 people who had IBS and 8 healthy individuals. All of those with IBS, but only two of the healthy individuals, showed signs of an immune reaction to at least one of the foods. People with IBS had more mast cells in close proximity to nerve fibres compared with healthy individuals, suggesting more-effective transfer of information between the mast cells and nerve endings of the sensory neurons.

The authors report that 23% of the faecal samples from people with IBS were positive for infection by the bacterium Staphylococcus aureus, compared with only 9% from healthy subjects. This finding is intriguing because S. aureus is one of the main microbial sources of ‘superantigens’ – potent antigens that have been linked to nonspecific activation of immune cells called T cells9. Indeed, 47% of faecal samples from people with IBS were positive for at least one superantigen, compared with only 17% of such samples from healthy volunteers. These findings might suggest that previous infection and the presence of superantigens promote enhanced gut pain in some people with IBS by priming their immune-system response.

The authors’ study raises several points for further consideration. For example, the mechanisms involved were determined using ingestion of an antigen in mice, whereas the food solutions tested in humans were injected directly into the gut mucosa (mucous membranes). It would be interesting to determine whether specific human diets containing the ingredients tested recapitulate the authors’ findings. Also, this mechanism of a breakdown in oral tolerance does not explain why women have a greater predisposition to developing IBS than men4. Although Aguilera-Lizarraga and colleagues’ study has relevance for mechanisms associated with post-infectious IBS (as in gastroenteritis), it would be interesting to investigate whether this mechanism is relevant for other types of IBS, such as constipation-predominant IBS, diarrhoea-predominant IBS or IBS with mixed bowel habits.

The authors used C. rodentium as the pathogenic organism for their mouse model system. However, infections by other harmful microorganisms, such as Escherichia coli, Salmonella, Giardia and Shigella, can also precede the onset of IBS. Clinical epidemiology studies suggest that gut infections by these pathogens increase the likelihood that a person will develop IBS10.

Does this mechanism apply only to the colorectum, or is it also relevant to other gut regions such as the stomach, small intestine and proximal colon? If so, and if the same type of immune response occurs in other gut locations, different sensory nerves might be activated there, triggering different symptoms, such as nausea, discomfort and bloating, that are relevant to other gut-pain disorders, for example a condition called functional dyspepsia4.

Aguilera-Lizarraga and colleagues’ work presents numerous potential options to consider for therapeutic intervention. These include: improving intestinal-barrier function to reduce gut access to the intestinal immune system; targeting IgE antibodies that are specific to the food substance of interest; reducing mast-cell degranulation; targeting molecules released by mast cells or the receptors on which they act; and blocking the colonic sensory nerves that transmit the noxious information and cause pain.

From a dietary point of view, can oral tolerance, once lost, be reacquired? In this regard, food-allergy studies suggest that eliminating the offending foods from people’s diets, and then gradually reintroducing them, can improve the long-term prognosis11. Exclusion diets are increasingly popular for remedying gastrointestinal symptoms, including gluten-free diets for coeliac disease and, for IBS, diets low in a group of carbohydrates that are not completely digested or absorbed in the intestine (called FODMAPs — fermentable molecules of oligosaccharides, disaccharides, monosaccharides and polyols)12. Aguilera-Lizarraga and colleagues’ study provides information on the mechanisms underlying abdominal pain, and gives added meaning to the saying, ‘you are what you eat’.

Nature 590, 41-43 (2021)

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