Personalized Probiotic Treatments for Irritable Bowel Syndrome

Irritable Bowel Syndrome (IBS)

Gut microbiota, Probiotics, IBS, Precision medicine, N of 1 trials, Histamine, LPC, LPA

Irritable bowel syndrome (IBS) is characterized by stomach pain and altered bowel habits. It affects about 5 million people in Canada. Doctors don't fully understand what causes IBS, so treatments often don't work well. Many patients say certain foods make their symptoms worse. This may be due to how gut bacteria break down food. Some bacteria produce harmful chemicals like histamine and lysophosphatidylcholine (LPC)/lysophosphatidic acid (LPA), which can cause pain and gut problems. These chemicals may affect about 35% of IBS patients. The goal is to find out which patients have these bacteria. Then, doctors can give them treatments that match their gut bacteria. This could help reduce symptoms and improve their lives. If the study is successful, it could change how we understand, diagnose, and treat IBS, leading to new treatments that focus on personalized microbiota-directed treatments targeting specific causative mechanisms.

Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder characterized by chronic abdominal pain and abnormal bowel habits, affecting 5 million Canadians. Its pathophysiology is incompletely understood and treatments, directed at symptoms, are only 10-15% more effective than a placebo. In the absence of specific mechanistic biomarkers to guide the right treatment for the right patient, clinicians employ the classical "trial-and-error" therapeutical approach. This is often not successful, negatively impacting patients' quality of life and imposing a significant socioeconomic burden.Growing evidence suggests that diet-microbiota interactions play a key role in IBS, leading to low-grade inflammation and symptom genesis. Indeed, up to 84% of IBS patients link their symptoms to ingestion of specific foods. There are likely multiple food-related mechanisms that underlie symptom generation in IBS, including bacterial fermentation of dietary fiber, immunostimulatory effects of proteins contained in wheat, or inflammation-mediated sensitization to food antigens. We recently demonstrated that bacterial production of histamine and/or bioactive phospholipids lysophosphatidyl-choline (LPC) and lysophosphatidic acid (LPA) trigger visceral hyperalgesia and gut dysfunction in subgroups of patients, and which together can account for symptom genesis in approximately 35% of patients with IBS.The concept of precision (personalized) medicine has gained prominence in last few decades, moving away from a 'one-size-fits-all' approach, acknowledging significant variability in disease expression and treatment responses, and recognizing that the conventional approach based on large clinical trials is directed at "average patients". Despite its potential, precision medicine has seen limited adoption in clinical practice. Precision medicine for IBS has not yet been considered, because it is not perceived as life threatening and because of our limited understanding of its causes. However, during the last decade we have made significant strides in understanding the pathophysiology of IBS, identifying gut bacteria and diet as key factors, which can be modified. We recently showed that 20-25% IBS patients have bacteria that convert dietary histidine into histamine, a known pain mediator. Bacterial histamine drives accumulation and activation of mast cells, leading to the development of visceral hypersensitivity. A low fermentable carbohydrate (FODMAP) diet or lactic acid bacteria mitigate these effects by changing the acidity of the colon milieu, as bacterial histidine decarboxylase is highly pH-sensitive. Our on-going pilot study (NCT04364750) suggests that patients' symptoms and bacterial histamine change significantly with 3-day challenges or treatment with mixture of lactobacilli. Further, we found that additional 15-20% patients with IBS have altered bacterial metabolism of dietary phosphatidylcholine (PC) with increased production of LPC and its metabolite LPA, known mediators of neuropathic pain. IBS patient have higher levels of fecal LPC and LPA during periods of severe abdominal pain and mice colonized with their microbiota develop increased pain responses when fed a PC-enriched diet. Altogether, this suggests a synergistic effect between diet and microbiome in symptoms genesis in two subsets of patients with IBS. Therefore, this proposal seeks to establish a transformative process to optimize personalized treatment of patients with IBS, focusing on diet-microbiota interactions as key drivers of symptoms and intestinal pathology. N-of-1 trials, also called "personalized trials," employ a repeated randomized crossover design in a single patient to compare different blinded treatments or challenge effects. This design is most feasible when the treatment/challenge effects have a rapid onset and offset of action, as is the case in IBS patients, especially with food related symptoms. Indeed, these may occur as soon as 15 minutes postprandially, and may last for several hours. In addition, the microbiome and its metabolites are quickly affected by diet and dietary changes, with significant changes occurring within the first 24 hours in an in vitro model and within 48 hours in healthy volunteers. As in traditional crossover trials, carryover effects must be considered with n-of-1 design, but can be addressed through wash-out periods and focusing on the symptoms in the latter part of each treatment period. In general, n-of-1 trials are shorter lasting only months, while conventional randomized controlled trials (RCT) can take up to several years. When a series of n-of-1 trials are conducted in similar patients, the results can be aggregated to produce population-level estimates of treatment effects (equivalent to RCT meta-analyses). In this project, we will first identify IBS patients with histamine and LPC/LPA producing microbiota, and then treat them using "n-of-1" trial design using specific probiotics, either lactic acid-producing bacteria know to inhibit production of histamine through effects on histidine-decarboxylase4 or probiotics impairing conversion of phosphatidylcholine into LPC, in a fast-track bench-to-bedside approach.

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