As is customary every two years, IBS Days, the major conference addressing the most recent research and discoveries in IBS, was held in Bologna, Italy, from June 17 to 19, 2024. Professor Giovanni Barbara from the University of Bologna chaired the congress, which was endorsed by the European Society of Neurogastroenterology and Motility.

 

What is new and relevant in the pathophysiology of IBS?

Although the etiology of IBS has not yet been completely elucidated, several factors have a role, including the composition of the gut microbiome, immune activation, intestinal permeability, the microbiota-gut-brain axis, and sex and gender. A novel Consensus under development involving the Rome Foundation and Neurogastroenterology & Motility Scientific Societies, presented by Jan Tack, MD PhD, from the University of Leuven, will update the plausibility and clinical relevance of pathophysiological mechanisms in IBS.

Susanna Walter, MD PhD, from Linköping University, addressed how sex and gender impact the microbiota-gut-brain axis, and how it plays a role in the gastrointestinal function on health and IBS. Women appear to be more sensitive to pain, with emerging preclinical and clinical evidence suggesting sex/gender differences in the function of colonic mast cells, gut microbiota composition and function, autonomic nervous system, hypothalamic-pituitary-adrenal axis, and serotonin levels.

Maria Vicario, PhD, from Vall d’Hebron University Hospital (Spain), updated the role of eosinophils in IBS and functional dyspepsia. While eosinophils are normal resident cells of the GI tract (except the esophagus), they can increase and/or become activated in the small intestine and colon and contribute to the pathophysiology of disorders of gut-brain interaction. Recent findings presented by Vicario showed the increased activity of eosinophils (high production and release of corticotropin-releasing factor) that are in close contact with nerve endings in the jejunal mucosa IBS-D are correlated with clinical severity. However, eosinophil numbers did not increase in the small intestine but did so in the colon. While awaiting further research, it seems plausible that eosinophil activity in the gut microenvironment should be kept in balance for normal gastrointestinal physiology.

 

Eosinophils may contribute to the pathophysiology of disorders of gut-brain interaction at multiple levels.
Source: Maria Vicario’s talk at IBS Days 2024.

 

Premysl Bercik, MD, from McMaster University, explored how gut bacteria communicate with the brain and presented new findings about the role of colonization in inducing changes in neuro-immune genes and central neural plasticity. A similar phenomenon may occur during infectious gastroenteritis or severe stress, thus explaining the development of psychiatric comorbidities in IBS.

Guy Boeckxstaens, PhD, from KU Leuven (Belgium) reviewed the role of mast cell activation following a local IgE response to food in abnormal visceral pain perception in IBS. This affects 30-60% of IBS patients and is associated with symptom severity. The most extensively studied triggers leading to mast cell activation include food, psychological stress, and infections. Boeckxstaens also introduced antihistamines as a novel treatment option to manage chronic abdominal pain in patients with IBS.

 

A randomized, placebo-controlled phase 2 study showed Ebastine to be a potential treatment for patients with non-constipated IBS.
Source: Guy Boeckxstaens’s talk at IBS Days 2024.

 

IBS mimickers

There are common conditions that mimic or co-occur with IBS. Overall, these conditions can explain why some patients do not respond to conventional dietary and medical interventions for IBS. It is therefore crucial that healthcare professionals do not miss them in the differential diagnosis of IBS so that they can be managed appropriately.

Lin Chang, MD, from the David Geffen School of Medicine at UCLA, and Giovanni Barbara, MD, from the University of Bologna, presented an updated list of the six conditions and their respective pathophysiology’s that are commonly misdiagnosed as IBS: celiac disease, inflammatory bowel disease, microscopic colitis, acute diverticulitis, bile acid malabsorption, and acute gastroenteritis, the latter including post-COVID-19 IBS. A consensus document is under development by the International Organization for the Study of Inflammatory Bowel Disease on the diagnosis, and the pharmacological and non-pharmacological interventions for overlapping IBD-IBS.

 

IBS is a micro-organic disorder characterized by many mechanisms of action that can occur simultaneously.
Source: Giovanni Barbara’s talk at IBS Days 2024.

 

Bile acid diarrhea is a poorly recognized disorder that affects about 1% of the general population and 25-50% of patients with IBD-D/functional diarrhea. Michael Camilleri, MD PhD, from Mayo Clinic, explained that bile acid malabsorption should be suspected in patients with urgent and liquid diarrhea -that can occur at night, in contrast to IBS symptoms that do not usually happen at night-and episodes of fecal incontinence. Interestingly, idiopathic bile acid diarrhea in patients with IBS-D impairs the permeability of the small and large intestine, which is associated with more severe symptoms, according to findings from Beatriz Lobo and colleagues from Vall Hebron Institut de Recerca in Barcelona, Spain.

Bile acid sequestrants (Colesevelam, cholestyramine, and colestipol) are the first-line treatments for bile acid diarrhea. Recently, the glucagon-like peptide-1 receptor agonist liraglutide has been shown to be superior to Colesevelam in reducing stool frequency with moderate-to-severe primary bile acid diarrhea. A low-fat diet could help improve symptoms if medicines are not fully effective. Major components of the human gut microbiome are involved in secondary bile acid production through bile salt hydrolases, and administering probiotics that promote ileal bile acid deconjugation and fecal bile acid excretion may offer new treatments in the near future.

 

Treating bile acid diarrhea with liraglutide.
Source: Michael Camilleri’s talk at IBS Days 2024.

 

Anorectal disorders also overlap with IBS. Over 40% of adults undergoing specialist assessment had a coexistent diagnosis of fecal incontinence and constipation, and one in four patients with IBS reported fecal incontinence. As this overlap increases anxiety and depression and leads to poor quality of life, physicians should routinely ask patients with IBS about fecal incontinence. Giuseppe Chiarioni, MD, from the University of North Carolina, suggests a straightforward method for diagnosing the issue, which is to ask the patient which muscles they use to defecate. If the patient answers anal muscles, there is an 84% positive predictive value that the diagnosis will be dyssynergic defecation. If the patient answers both belly and anal muscles, there is a 96% of likelihood that he does not have the condition.

 

Symptom subgroups taking the psychological burden into account: a step forward in IBS management?

Experiencing abdominal pain, diarrhea, constipation, and/or distension/bloating can be accompanied by non-GI symptoms that may lead to increased healthcare utilization and reduced work productivity and activity. According to human data presented by Magnus Simren, MD, PhD, from the University of Gothenburg, holistic management of IBS, taking patients’ clinical, dietary, lifestyle, and psychosocial factors into account, is the next frontier. This approach will enhance the management of patients with IBS, by improving the current medical treatment methods for IBS that focus on addressing the patient’s most troublesome symptoms. The treatment options for patients will vary depending on the group or cluster to which they belong, ranging from reassurance and lifestyle and dietary advice in people with mild symptoms of IBS to drugs acting peripherally and/or centrally in patients with both gastrointestinal and psychological symptoms.

All these models take into account mental comorbidities that are highly prevalent in patients with IBS, such as anxiety and depressive symptoms, which are commonly reported by a significant percentage. Sarah Ballou, PhD, from Beth Israel Deaconess Medical Center in Boston, explained that some of the most studied mechanisms in IBS include the microbiome, genetic susceptibility, and differences in the brain volume. While it is not the gastroenterologist’s responsibility to diagnose or treat mental health comorbidities, it can be helpful to assess them with your patients to normalize the impact of IBS on mental health and vice versa. Integrated mental health care, together with diet and medical management, is the gold standard treatment for IBS. Cognitive behavioral therapy, mindfulness-based therapy, interpersonal psychotherapy, and supportive therapies are some examples of psychotherapies that provide benefits for patients with IBS. Physical exercise, meditation/yoga, and herbal supplements are other non-pharmacological means to improve gut and mental health.

 

Psychological assessment and treatment needs will vary among patients with IBS, and they should be combined with diet and medical care.
Source: Sarah Ballou’s talk at IBS Days 2024.

 

Manipulating the gut microbiome as a treatment for IBS. What’s new?

Growing evidence suggests that an altered gut microbiota composition and function may contribute to the development of IBS symptoms. As a result, modulating the gut microenvironment has emerged as a potential indirect approach for managing IBS.

Diet is often the initial approach taken for managing IBS symptoms. Notably, more than 80% of adults and more than 90% of children and adolescents with IBS can identify at least one food trigger and tend to avoid more foods than people without the condition. Self-perceived food intolerances are associated with IBS severity according to data from Bruno Chumpitazi, MD, from Duke University School of Medicine. The fact that 28% of symptoms occur within 15 minutes and 93% within 3 hours suggests that the role of  small intestine in IBS may have been underestimated.

 

Mechanisms underlying food-related symptoms in children and adults.
Source: Bruno Chumpitazi’s talk at IBS Days 2024.

 

Florencia Carbone, MSc, PhD, from Leuven University Hospitals (Belgium), reviewed the effectiveness of personalized diet interventions in IBS. Soluble fiber supplementation, a low FODMAP diet, a Mediterranean-style diet, and, more recently, a low carbohydrate diet have been studied for IBS, but each of these has its own advantages and disadvantages. The majority of studies for the low FODMAP diet were performed in the first elimination phase. New findings from a blinded randomized reintroduction phase showed a specific pattern of symptom recurrence, indicating that fructans and mannitol were the most commonly associated factors. However, the low FODMAP diet is challenging to follow; it is restrictive and involves a careful reintroduction of foods to assess their tolerance.

A new randomized controlled trial in women and men with moderate to severe IBS found 76% of those in the low-FODMAP group and 71% of those in the low-carbohydrate group reported a significant decrease in IBS symptoms. This is higher than the 58% of participants who experienced improvements after receiving a medication for their primary complaint. The method of diet delivery (gastroenterologist-delivered or app/written information supervised by a dietitian) is also important. Some evidence suggests the short-term clinical advantage of using the FODMAP app over a spasmolytic agent in improving IBS symptoms. The gold standard is dietary delivery and monitoring under the supervision of a dietitian. It is important to bear in mind that when anxiety and depression present together with gastrointestinal symptoms, healthy and inclusive eating based on the principles of a Mediterranean diet is preferred over complex and restrictive diets.

 

Future challenges in the dietary management of IBS.
Source: Florencia Carbone’s talk at IBS Days 2024.

 

Eamonn Quigley, MD, from Houston Methodist Hospital, updated the dos and don’ts of prebiotics, probiotics, postbiotics, and fecal microbiota transplantation to alleviate IBS symptom severity by modulating gut microbiota, gut barrier integrity, and immune activity. The clinical benefits of prebiotics are dependent on their type and dose. A beta-galactooligosaccharide prebiotic at low doses (1.37 g/d) for 4 weeks led to a reduction in symptoms similar to that of the low FODMAP diet. However, the prebiotic led to an increase in fecal bifidobacteria, and the low FODMAP diet increased the pathobiont Bilophila wadsworthia. The decrease in symptoms persisted during the 2-week follow-up after cessation of the prebiotic while reappearing immediately when patients stopped the low FODMAP diet.

The latest meta-analysis showed Escherichia and Lactobacillus probiotic strains have moderate-low certainty of evidence for global IBS symptoms and Saccharomyces cerevisiae I-3856, Bifidobacterium strains, and combination probiotics have low certainty of evidence for abdominal pain.

Some postbiotics in the form of lysates of bacteria and heat-treated bacteria also showed benefits in alleviating global IBS symptoms and abdominal pain. There is a growing interest in defined bacteria consortia compared to fecal microbiota transplants, as the latter have shown mixed results in treating IBS. MRx1234 is the first live biotherapeutic product that has been shown to be safe for patients with IBS-C or IBS-D.

Gianluca Ianiro, MD, updated future microbiome therapeutics (microbial consortia, postbiotics, phages, and engineered bacteria) and shared advice on how to close the gap between research and clinical practice in the microbiome field. Some caveats in microbiome-targeted therapeutics include reproducibility, heterogeneity of IBS phenotypes, and making interventions sustainable in the long term.

 

The role of microbiome clinicians in moving microbiome science from bench to bedside.
Source: Gianluca Ianiro’s talk at IBS Days 2024.

 

Systemic nickel allergy syndrome, or nickel allergy, is a little-known condition that affects 8-18% of the population in the US and Europe. It can alter gut microbiota and mirror some of IBS symptoms. Cristiano Caruso, MD PhD, from Fondazione Policlinico A. Gemelli (Italy) presented a small pilot study of the potential of a low nickel diet and a probiotic blend over three months to help restore the gut microbiota in patients with systemic nickel allergy syndrome.

 

Progress and challenges on probiotics in IBS.
Source: Eamonn Quigley’s talk at IBS Days 2024.

 

References and recommended reading:

  1. Pathophysiological mechanisms in IBS:

 

  1. IBS mimickers:

Anorectal disorders:

 

Bile acid diarrhea:

 

  1. Symptom cluster and mental comorbidities in IBS:

 

  1. Microbiota modulation in IBS