Mechanism of Action
Holigos® IBS contains glycans identical to those in human milk and the mucus layer of the GI tract
The glycans in Holigos® IBS play a critical, multi-functional role in promoting and maintaining good gastrointestinal development and health. For example, in infants1 they:
- Modulate the microbiota to increase bifidobacteria, prevent pathogen attachment, and reduce proteolytic bacteria that impair the mucus layer
- Moderate nociceptive stimuli to reduce abdominal pain and colic
- Increase production of short-chain fatty acids that are key to gut barrier function
- Modulate gene expression in epithelial cells to increase mucin production
- Regulate and develop the immune response at the gut barrier level
In IBS patients, Holigos® IBS drives towards intestinal homeostasis through 3 core mechanisms
1. Holigos® IBS specifically modulates the intrinsic intestinal microbiota, improving microbial metabolites, including short chain fatty acids and bile acids
At least a subset of IBS patients has an abnormal microbiota composition and particularly a reduction in bifidobacteria2. This is associated with IBS symptoms3 including abdominal pain4. Intestinal models show that Holigos® impacts the gut microbiota in various sections of the intestine, balancing the composition by stimulating the growth of beneficial bacteria such as bifidobacteria5. Also, clinical studies in healthy children, healthy adults and IBS patients (all subtypes) show that Holigos® beneficially modulates the microbiota and increases bifidobacteria. No foreign bacteria are introduced; the glycans in Holigos® IBS modulate the patient’s intrinsic microbiota.
Importantly, if the intestinal microbiota is out of balance, metabolites produced by the bacteria are likely to be out of balance. These metabolites include short chain fatty acids, essential vitamins, bile acids and neuromodulators. Impaired bile acid metabolism has been observed in IBS patients6. Normally primary bile acids in the colon are converted by certain bacteria to secondary bile acids. However, this may be impaired in IBS patients where higher concentrations of primary bile acids have been measured when compared to healthy controls. This has been correlated with abdominal pain and frequency of stool evacuation7. Holigos® has been shown to decrease primary bile acids in an in vitro gut model simulating an imbalanced microbiota as compared to control8.
2. Holigos® IBS improves the gut barrier function of IBS patients by increasing the production of nutrients critical for epithelial cells
The gut microbiota is a source of an extensive array of nutrients critical for host health9. Key among these nutrients are short chain fatty acids (SCFAs) which arise from the bacterial fermentation of dietary fibers. The SCFA butyrate is the primary fuel for intestinal epithelial cells. Also SCFAs help maintain immune homeostasis10, making SCFAs essential for gut barrier functioning. Impaired gut barrier functioning (“leaky gut”) is common in many IBS patients and SCFAs have been suggested as a potential diagnostic marker of IBS11. Holigos™ improves the profile of bacterial metabolites, increasing the concentration of SCFAs, specifically butyrate and acetate, and decreasing detrimental metabolites4,5. This improvement of bacterial metabolites impacts gut barrier functioning by decreasing intestinal permeability12.
3. Holigos® IBS modulates the mucosal immune system, driving it towards homeostasis
The mucosal immune system may be unbalanced in at least a subset of IBS patients. This may be due to interactions between a dysbiotic microbiota and the mucosal immune system or due to an impaired gut barrier13. In addition, associations between the mucosal immune system and clinical symptoms have been found14,15. By beneficially modulating the intestinal microbiota and improving gut barrier function, Holigos® IBS modulates the mucosal immune system and drives it towards homeostasis.
1 Bode L, The functional biology of human milk oligosaccharides, Early Hum Dev; 2015, Nov;91(11):619-22. 2 Rajilic-Stojanovic M, Jonkers DM, Salonen A, et al. Intestinal microbiota and diet in IBS: causes, consequences, or epiphenomena? Am J Gastroenterol; 2015; 110:278–287. 3 Tap J, Derrien M, Tornblom H, et al. Identification of an intestinal microbiota signature associated with severity of irritable bowel syndrome. Gastroenterology; 2017; 152:111–123 e8. 4 Jalanka-Tuovinen J, Salonen A, Nikkila J, et al. Intestinal microbiota in healthy adults: temporal analysis reveals individual and common core and relation to intestinal symptoms. PLoS One; 2011; 6:e23035. 5 Vigsnaes, L. et al., The 11th Vahouny Fiber Symposium, 2017, Washington, US. 6 Duboc, H., et al., Increase in fecal primary bile acids and dysbiosis in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil, 2012. 24(6): p. 513-20, e246-7. 7 Dior, M., et al., Interplay between bile acid metabolism and microbiota in irritable bowel syndrome. Neurogastroenterol Motil, 2016. 28(9): p. 1330-40. 8 Prodigest, Bile acid metabolism-mediated effect of 2 HMOs against C. difficile using the SHIME® technology platform. Internal Report (Unpublished), 2018. 9 Postler TS, Ghosh S. Understanding the holobiont: how microbial metabolites affect human health and shape the immune system. Cell Metab; 2017; 26:110–30. 10 Martin-Gallausiaux C, et al. Butyrate Produced by Commensal Bacteria Down-Regulates Indolamine 2,3-Dioxygenase 1 (IDO-1) Expression via a Dual Mechanism in Human Intestinal Epithelial Cells. Front Immunol; 2018; Dec 11;9:2838. 11 Farup, P.G., et al., Faecal short-chain fatty acids - a diagnostic biomarker for irritable bowel syndrome? BMC Gastroenterol; 2016. 16(1): p. 51. 12 Quadram Institute Report., Internal Report (Unpublished), 2018. 13 Brint, E.K., et al., Differential expression of toll-like receptors in patients with irritable bowel syndrome. Am J Gastroenterol, 2011. 106(2): p. 329-36. 14 Bennet, S.M., et al., Global Cytokine Profiles and Association With Clinical Characteristics in Patients With Irritable Bowel Syndrome. Am J Gastroenterol, 2016. 111(8): p. 1165-76. 14 Bennet, S.M., et al., Global Cytokine Profiles and Association With Clinical Characteristics in Patients With Irritable Bowel Syndrome. Am J Gastroenterol, 2016. 111(8): p. 1165-76. 15 Bennet, S.M.P., et al., Altered intestinal antibacterial gene expression response profile in irritable bowel syndrome is linked to bacterial composition and immune activation. Neurogastroenterol Motil, 2018. 30(12): p. e13468.