Cramping. Abdominal pain. Bloating, gas, and diarrhea. These are unpleasant words to read and even more troublesome to endure physically. But that’s the day-to-day experience of those who suffer from irritable bowel syndrome, or IBS, the most common gastrointestinal condition worldwide. IBS affects an estimated 10-15% of the U.S. population and nearly 12% of all primary care patients, contributing to 3.1 million ambulatory care visits each year.1,2 What makes IBS especially discouraging is the lack of multi-symptom treatments beyond experimental dietary and lifestyle recommendations.
Seed, a team of gastroenterologists, and 24 genetically distinct microorganisms (🤓) are teaming up to research IBS and the influence of a synbiotic combination.
What makes this possible now is a breaking development on the regulatory front. The FDA recently authorized an Investigational New Drug (IND) application for DS-01™ (Daily Synbiotic), a broad spectrum probiotic with 24 genetically distinct microorganisms across 12 species, plus a non-carbohydrate prebiotic. An IND is an important research milestone because it grants permission for a company to begin clinical trials to investigate the safety and efficacy of a drug, food, or dietary supplement.
And that’s exactly what’s happening now, as Dr. Anthony Lembo and a team of world-renowned gastroenterologists at Beth Israel Deaconess Medical Center, a teaching hospital of Harvard Medical School, initiates a Phase II randomized, triple-blind, and placebo-controlled clinical trial. The trial will investigate the role of the gut microbiome in patients with IBS, as well as the impact of DS-01™ on both intestinal cells and on the release of metabolites (the products of metabolism) from gut microbes native to the patient.
Plus — and perhaps most importantly — they’ll record how the patients feel, from their daily abdominal pain to overall quality of life.
Background: What causes irritable bowel syndrome?
Although the underlying cause of IBS is unknown, several broad factors have been thought to play a role, including genetic and epigenetic factors, muscle contractions in the intestines, abnormal communication between the brain and intestines, infection, adverse life events (including trauma), and changes in the composition of gut microbes (including that caused by repeated antibiotic use). Food, stressful events, and toxins then contribute to the onset of IBS symptoms.
Scientists are now beginning to track back the causes of IBS with greater specificity. Recent studies3 have shown a link between IBS and an altered gut immune response, particularly in relation to intestinal microbial disruption. The current working hypothesis? Abnormal gut microbes drive impaired intestinal permeability and dysregulated immune responses, causing gastrointestinal distress.4,5
What is the link between the microbiome and IBS?
Many existing research studies have demonstrated a link between microbial imbalances in the gut and the prevalence of IBS.6 For example, one study7 conducted in Sweden, Norway, Denmark, and Spain, showed that patients diagnosed with IBS had dysbiosis (that is, a microbial imbalance) at a frequency of 73% compared to roughly 16% in healthy individuals. Further studies have begun to illustrate the different bacteria that seem to be contributing to the microbial imbalances associated with IBS. Some studies have also examined the effects of probiotic and prebiotic therapies on IBS patients, with one meta-analysis8 pointing to possible benefits of specific combinations of probiotics for global IBS symptoms — but ultimately unable to draw definitive conclusions about efficacy.
And this puts us at the forefront of research into the relationship between the microbiome and IBS, where Seed and the team at Beth Israel Deaconess Medical Center will embark on their work. Very few previous studies have looked at how synbiotics (combinations of prebiotics and probiotics, like DS-01™) affect the microbial communities of individuals with IBS. This study will assess whether intake of the DS-01™ leads to compositional and/or metabolic shifts in the gut microbiome of IBS patients, and whether these may be correlated to symptomatic changes.
Additionally, while previous trials have attempted to target the gut microbiota and gastrointestinal tract with live microorganisms, they’ve had limited success due to empiric strain selection, small study population sizes, and inadequate trial design to control for the inherently high placebo response9 rates. In other words, this trial seeks to improve upon issues recently highlighted by the American Gastroenterology Association (AGA), including “major variation” in probiotic formulations and the need for “well-defined clinical trials” to establish the safety of specific formulations on clinical conditions relevant to gastroenterology.
How is this IBS clinical trial designed?
This trial will include participants with multiple subtypes of IBS: IBS with constipation (IBS-C), and IBS “mixed,” (IBS-M) for patients who struggle with alternating constipation and diarrhea. Throughout the 12-week trial, half of the participants will receive DS-01™, and half will receive a placebo. Researchers will be studying IBS and the microbiome on the molecular level as well as the everyday experiences of the participants, contributing to the scientific body of evidence and to solutions for the millions of people struggling with symptoms each day.
On the molecular level, the trial will assess metagenomic stability, measured through shotgun metagenomic DNA sequencing, alongside metabolic output of the gut microbiota. On the phenotypic level, this study will assess the following IBS symptoms:
- Daily abdominal pain
- Daily stool consistency
- Daily abdominal discomfort
- Daily abdominal bloating
- Number of bowel movements per day
- Gut permeability
- Overall quality of life
One especially unique feature of this study is that participants will use a mobile companion application to report on their day-to-day gastrointestinal symptoms and quality of life. This technology should help address a weakness of previous studies, many of which have relied on often inconsistent manual reporting.
Why is this IBS clinical trial important for microbiome research?
This clinical research is an exciting advancement for the field of microbiome research and the study of probiotics/synbiotics. Despite the global prevalence of IBS and its connections to the composition of the microbiome, existing research on microbiota-based interventions for IBS is inconsistent and inconclusive.
This is also the first of several Seed clinical studies that will generate both mechanistic and clinical data specific to DS-01TM (Daily Synbiotic). (As results of these studies are published in peer-reviewed journals, we’ll share them here and in Seed’s other outlets, including our monthly newsletter and on social media.)
This new research is vital to deepening our understanding of both the underlying mechanisms of IBS, and of what can be done to influence the disease and improve quality of life for the millions of persons living with IBS around the globe.
1. Occhipinti, K., & Smith, J. W. (2012). Irritable bowel syndrome: a review and update. Clinics in Colon and Rectal Surgery, 25(1), 46–52. DOI: 10.1055/s-0032-1301759.
2. Saito, Y. A., Schoenfeld, P., & Locke, G. R., 3rd (2002). The epidemiology of irritable bowel syndrome in North America: a systematic review. American Journal of Gastroenterology, 97(8), 1910–1915. DOI: 10.1111/j.1572-0241.2002.05913.x.
3. Chey, W.D., Kurlander, J., & Eswaran, S. (2015). Irritable Bowel Syndrome: A Clinical Review. JAMA, 313(9):949–958. DOI: 10.1001/jama.2015.0954.
4. Black, C. J., & Ford, A. C. (2020). Global burden of irritable bowel syndrome: trends, predictions and risk factors. Nature Reviews. Gastroenterology & Hepatology, 17(8), 473–486. https://doi.org/10.1038/s41575-020-0286-8
5. Quigley E. (2017). Gut microbiome as a clinical tool in gastrointestinal disease management: are we there yet? Nature Reviews. Gastroenterology & Hepatology, 14(5), 315–320. https://doi.org/10.1038/nrgastro.2017.29
6. Chong, P. P., Chin, V. K., Looi, C. Y., Wong, W. F., Madhavan, P., & Yong, V. C. “The Microbiome and Irritable Bowel Syndrome – A Review on the Pathophysiology, Current Research and Future Therapy.” Frontiers in Microbiology vol. 10 1136. 10 Jun. 2019, doi:10.3389/fmicb.2019.01136
7. Casén, C., Vebø, H. C., Sekelja, M., Hegge, F. T., Karlsson, M. K., Ciemniejewska, E., Dzankovic, S., Frøyland, C., Nestestog, R., Engstrand, L., Munkholm, P., Nielsen, O. H., Rogler, G., Simrén, M., Öhman, L., Vatn, M. H., & Rudi, K. (2015). Deviations in human gut microbiota: a novel diagnostic test for determining dysbiosis in patients with IBS or IBD. Alimentary pharmacology & therapeutics, 42(1), 71–83. https://doi.org/10.1111/apt.13236
8. Ford, A. C., Harris, L. A., Lacy, B. E., Quigley, E., & Moayyedi, P. (2018). Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Alimentary pharmacology & therapeutics, 48(10), 1044–1060. https://doi.org/10.1111/apt.15001
9. Ballou, S., Beath, A., Kaptchuk, T. J., Hirsch, W., Sommers, T., Nee, J., Iturrino, J., Rangan, V., Singh, P., Jones, M., & Lembo, A. (2018). Factors Associated With Response to Placebo in Patients With Irritable Bowel Syndrome and Constipation. Clinical Gastroenterology and Hepatology, 16(11), 1738–1744.e1. DOI: 10.1016/j.cgh.2018.04.009.