An infection may contribute to irritable bowel syndrome (IBS) by damaging the gut nervous system

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Sometimes the end of an intestinal infection is just the beginning of more misery.

Of those who contract traveler’s diarrhea, for example, an unlucky few go on to develop irritable bowel syndrome (IBS), a chronic inflammation of the intestinal tract.

Scientists aren’t sure exactly how this happens, but some think an infection may contribute to IBS by damaging the gut nervous system.

A new Rockefeller study takes a close look at why neurons in the gut die and how the immune system normally protects them.

Conducted with mice, the experiments described recently in Cell offer insight on IBS and could point toward potential new treatment approaches.

Keeping inflammation in check

In a healthy gut, the immune system must strike a careful balance between responding to threats and keeping that response in check to avoid damage.

Inflammation helps the gut ward off an infection, but too much of it can cause lasting harm,” says Daniel Mucida, an associate professor and head of the Laboratory of Mucosal Immunology. “Our work explores the complex mechanisms that prevent inflammatory responses from destroying neurons.”

To understand the effects of an infection on the nervous system, Mucida and his colleagues gave mice a weakened form of Salmonella, a bacterium that causes food poisoning, and analyzed neurons within the intestine.

They found that infection induced a long-lasting reduction of neurons, an effect they attributed to the fact these cells express two genes, Nlrp6 and Caspase 11, which can contribute to a specific type of inflammatory response.

This response, in turn, can ultimately prompt the cells to undergo a form of programmed cell death. When the researchers manipulated mice to eliminate these genes specifically in neurons, they saw a decrease in the number of neurons expiring.

“This mechanism of cell death has been documented in other types of cells, but never before in neurons,” says Fanny Matheis, a graduate student in the lab. “We believe these gut neurons may be the only ones to die this way.”

Macrophages to the rescue

It’s not yet clear exactly how inflammation causes neurons to commit cell suicide, yet the scientists already have clues suggesting it might be possible to interfere with the process.

The key may be a specialized set of gut immune cells, known as muscularis macrophages.

Previous work in Mucida’s lab has shown that these cells express inflammation-fighting genes and collaborate with the neurons to keep food moving through the digestive tract.

If these neurons die off, as happens in an infection, a possible result is constipation – one of a number of unpleasant IBS symptoms.

In their recent report, the team demonstrate how macrophages come to the neurons’ aid during an infection, ameliorating this aspect of the disorder.

Their experiments revealed that macrophages possess a certain type of receptor molecule that receives stress signals released by another set of neurons in response to an infection. Once activated, this receptor prompts the macrophage to produce molecules called polyamines, which the scientists think might interfere with the cell death process.

Getting back to normal

In other experiments, the researchers found that Salmonella infection alters the community of microbes within the guts of mice—and when they restored the animals’ intestinal flora back to normal, the neurons recovered.

“Using what we learned about the macrophages, one could think about ways to disrupt the inflammatory process that kills the neurons,” says Paul Muller, a postdoctoral fellow in the lab.

For instance, it might be possible to develop better treatments for IBS that work by boosting polyamine production, perhaps through diet, or by restoring gut microbial communities.

Since short-term stress responses also appear to have a protective effect, Muller thinks it may also be helpful to target that system.


Irritable bowel syndrome (IBS) is one of the most commonly diagnosed gastrointestinal diseases. IBS, in the absence of any other causative disease, is defined as the presence of abdominal pain or discomfort with altered bowel habits.

Diagnosis of IBS has evolved since its first discovery, and today the Rome IV diagnostic criteria are used to diagnose IBS. Depending on the subclass of IBS, symptoms can be managed by a variety of medications and nonpharmaceutical agents. Nonetheless, IBS treatment should be individualized, and a significant factor in management remains a strong patient-physician relationship.[1]

Etiology

The etiology of IBS is broad and not clearly understood. However, as below in the pathophysiology section, motility, visceral sensation, brain-gut interaction, and psychosocial distress can all play a role in the development of IBS.

Epidemiology

Nearly 12 percent of patients seek medical care in primary care practices for IBS related complaints.[1][2] Studies have demonstrated that the prevalence of IBS ranges between ten and fifteen percent, however, the majority of these patients do not seek medical care.[1] IBS is most prevalent in South America at approximately 21 percent and least prevalent in Southeast Asia at 7 percent.[3][4] In the United States, Canada, and Isreal, IBS symptoms are 1.5 to 2 times more prevalent among women than men.[5] 

Moreover, women are more likely to report abdominal pain and constipation whereas men are more likely to report diarrhea.[5] The prevalence of IBS also decreases with age.[3] IBS can also be broken down into more specific diagnoses which includes IBS with diarrhea (IBS-D), IBS with constipation (IBS-C), and IBS with mixed bowel patterns (IBS-M).

The prevalence of these three diagnoses differs in the United States versus Europe. In the United States, there is an equal distribution of these diagnoses whereas in Europe IBS-C or IBS-M can be more prevalent.[6]

Pathophysiology

The pathophysiology of IBS is broad and includes abnormalities involving motility, visceral sensation, brain-gut interaction, and psychosocial distress.[3] One of these can usually be demonstrated in the majority of IBS patients however not all symptoms can be attributed to them.[3]

 Recent studies have also shown altered gut immune activation, and intestinal and colonic microbiome are associated with IBS[3][7][8]. Environmental contributors to IBS include early life stressors, food intolerance, antibiotics, and enteric infections.[3] Patients often complain that IBS symptoms are related to food intake. However, a true food allergen has a limited contribution to IBS.[3][9]

Histopathology

Histopathology examination of the intestinal mucosa in those with IBS can show chronic inflammatory cells, mast cells, enteroendocrine cells, and enteric nerves.[10]. IBS-D is typically associated with a greater increase in mucosal T-lymphocytes than IBS-C.[10][11] Moreover, there can be an increased number of nerve fibers that stain positive for neuron-specific enolase, substance P and 5-HT.[10][12] There also appears to be a significantly increased density of nerve fibers around mast cells.[10][12]

History and Physical

IBS typically consists of abdominal pain or discomfort, altered bowel habits along with either constipation, diarrhea or both. Other complaints in patients with IBS include bloating, distention, symptoms brought on by food intake, and a change in pain location, and stool pattern with time.[3].

Concerning features would include onset after age 50 years old, severe or progressive symptoms, unexplained weight loss, nocturnal diarrhea, rectal bleeding, iron deficiency anemia, or a family history of organic gastrointestinal diseases such as colon cancer, celiac disease, or inflammatory bowel disease.[3] Additional history that would be important would include travel and social history.

The Rome IV criteria is used to diagnose IBD, which requires at least 3 days a month in the last 3 months associated with 2 or more of the following: improvement in abdominal pain or discomfort with defecation, onset associated with a change in frequency of stool, and/or an onset accompanied by a change in form or appearance of stool[3].

Evaluation

If no alarm findings exist (weight loss, hematochezia, iron deficiency), routine diagnostic testing is not recommended.[1] If symptoms are not typical of IBS or alarm symptoms are present then a complete blood cell count, comprehensive metabolic panel, inflammatory markers such as erythrocyte sedimentation rate or C-reactive protein, and thyroid stimulating hormone level should be checked.[1] 

If diarrhea is predominant, fecal leukocytes and stool tests for Clostridium difficile, Giardia, and Cryptosporidium when appropriate should be ordered.[1] Testing for celiac disease may be needed as well, and a tissue transglutaminase or TTG-IgA can be obtained.[1] 

A colonoscopy may be beneficial when there is a family history of inflammatory bowel disease, colon cancer, or alarm symptoms.[1] If the patient has diarrhea, random biopsies should be done on colonoscopy.[1]

Treatment / Management

One of the most important goals in the management of IBS patients is to develop a trusting patient-physician relationship by actively listening, showing empathy, and setting realistic expectations for treatment.[3][13] IBS is a symptom-based disorder, and thus treatment goals are aimed at resolving symptoms such as pain, bloating, cramping, and diarrhea or constipation.[3] 

For constipation, fiber supplements and laxatives can be helpful whereas, in those with diarrhea, medications such as loperamide or probiotics can be helpful.[3] Moreover, increased physical activity can increase colonic transit time and improve symptoms.[3][14]

 Patients also often associate food intake with IBS symptoms. Foods such as wheat products, onions, fruits, vegetables, sorbitol, and some dairy can include short-chain, poorly absorbed, highly fermentable carbohydrates, which are known as FODMAPs. FODMAPs have been associated with increased gastrointestinal symptoms in IBS patients.[3] 

For patients with constant and chronic abdominal symptoms, oftentimes they can have a response to low dose tricyclic antidepressants (TCAs), or serotonin reuptake inhibitors (SSRIs)[1] Alosetron can be used to treat IBS-D in females but can cause ischemic colitis.

Differential Diagnosis

The differential diagnosis of IBS is broad and ultimately depends on whether the patient has predominant diarrhea or constipation.  If a patient has IBS with diarrhea, the differentials includes lactose intolerance, caffeine intake, alcohol intake, gastrointestinal infections (Giardia, Amoeba, HIV), inflammatory bowel disease, medication-induced diarrhea (antibiotic use, proton pump inhibitor, nonsteroidal anti-inflammatory drugs, ACE inhibitor, chemotherapy), celiac disease, malignancies, colorectal cancer, hyperthyroidism, VIPoma, and ischemic colitis.[15] 

If constipation is the predominant symptoms, then the differentials can include inadequate fiber intake, immobility, Parkinson’s disease, multiple sclerosis, spinal injury, diabetes, hypothyroidism, hypercalcemia, medication-induced (opiates, calcium-channel blockers, antidepressants, clonidine), malignancies, bowel obstruction, endometriosis, and diverticular disease. If a patient’s history indicates one of these diseases, then appropriate lab testing should be pursued.[15]

Prognosis

IBS has a good prognosis, and the diagnosis is unlikely to change on follow-up.[16] The use of ambulatory health services by IBS patients can be reduced if a positive physician-patient interaction if developed.[16]

Consultations

Important consults include a gastroenterologist and a nutritionist. Gastroenterologists often sub-specialize in IBS care and are invaluable members of the treatment team. A gastroenterologist can tailor treatment plans for the patient and are also likely to be more aware of advancements in the field of IBS. Given that patients often believe certain food intake is associated with their symptoms, and the findings of FODMAPs association with IBS, nutritionists are vital to providing dietary recommendations for the patient.

Deterrence and Patient Education

If a patient has concerns about abdominal pain, bloating, cramping, and changes in bowel habits, a visit to a primary care physician is advised. If IBS is diagnosed, a gastroenterology consultation will be needed as they can guide management and treatment.

Pearls and Other Issues

IBS can be sub-classified into IBS-C, IBS-D, or IBS-M. Although some treatments are the same between the groups, each subclassification is unique and have different treatments focused on the different symptomatologies. 

Enhancing Healthcare Team Outcomes

IBS can be a very disabling syndrome for patients, and it has been shown to be a very common reason for seeking medical attention. It is vital that there is an interprofessional approach when it comes to the care of these patients as it can improve the quality of life, reduce medications needed, and manage the symptoms of IBS much better.[17] 

The team can include primary care providers, gastroenterologists, specialty trained nurses, and pharmacists. Nurses provide education to patients and their families, monitor response to treatment, and report patient status to the team. Pharmacists review prescribed medications for dose and interactions, as well as review usage and side effects with patients. [Level 5]


More information: Fanny Matheis et al, Adrenergic Signaling in Muscularis Macrophages Limits Infection-Induced Neuronal Loss, Cell (2020). DOI: 10.1016/j.cell.2019.12.002

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