The Gut Microbiome in Inflammatory Bowel Disease and Implications for Treatment

By Malini Williams

Inflammatory bowel disease (IBD) is a chronic autoinflammatory disease affecting the gastrointestinal tract. The two most common forms of IBD are ulcerative colitis and Crohn’s disease. Ulcerative colitis is characterized by continuous inflammation in the colon which is mostly confined to the mucosa and sub-mucosa. In contrast, Crohn’s disease can affect any part of the gastrointestinal tract, most commonly the ileum, and is associated with deeper and patchier areas of inflammation (Khor, Gardet, & Xavier, 2011). Symptoms include frequent bowel movements which can contain blood, mucus, or pus, abdominal pain, and fatigue (Crohn’s & Colitis UK). It is a lifelong disease with periods of remission and relapse, and although there is no cure, treatment can help reduce inflammation in the gut so that patients can enter remission (Crohn’s & Colitis UK).

The precise causes of IBD are still unknown, but genome-wide association studies have found multiple risk loci associated with either ulcerative colitis or Crohn’s disease, or both (Khor, Gardet, & Xavier, 2011). In addition to these genetic susceptibility loci, alteration of the gut microbiota is also implicated as a factor in IBD (Khan et al, 2019). The risk loci are generally involved in innate and adaptive immune responses such as nuclear oligomerization domain (NOD) 2, which is an intracellular sensor of microbes, and the interleukin (IL)-12/IL23R pathway, which regulates host response to microbes (Sheehan & Shanahan, 2017). Thus, the most accepted hypothesis suggests that the cause of IBD is triggering of an abnormal immune response against gut microbiota by environmental factors in genetically susceptible individuals (Matsuoka & Kanai, 2015).

Over 90% of the human gut microbiome contains four major phyla: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria (Matsuoka & Kanai, 2015). Commensal bacteria represent most of the microbial community, but fungi, archaea, and viruses are also involved (Khan et al, 2019). In a healthy host, gut microbiota helps in the fermentation of undigested polysaccharide polymers, production of short-chain fatty acids, and prevention of infection by pathogenic microbes, along with many other functions that are just beginning to be understood (Khan et al, 2019). In patients with IBD, this microbial diversity is decreased, with the most loss of diversity in the Firmicutes (Matsuoka & Kanai, 2015). Additionally, the composition of gut microbiota varies between periods of relapse and remission and can be impacted by medication (Matsuoka & Kanai, 2015). 

Treatment for IBD often involves immunomodulatory or anti-inflammatory drugs to help maintain remission. These can involve humanized monoclonal antibodies (mAbs), such as Adalimumab, or small molecule inhibitor drugs, such as Tofacitinib (Crohn’s & Colitis UK). Adalimumab blocks tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine implicated in ulcerative colitis pathogenesis (Sandborn et al, 2012). Tofacitinib is a small molecule inhibitor that blocks the pro-inflammatory Janus kinase pathway (D’Amico et al, 2019). Other treatments involve immunosuppressants, such as azathioprine and methotrexate, and steroids (Crohn’s & Colitis UK). However, many of these treatments come with serious negative side effects or can stop working over time. The immune system can sometimes form antibodies to mAbs, preventing them from working. Steroids can cause anxiety, depression, eye problems and raise blood pressure (Crohn’s & Colitis UK). Immunosuppressants leave patients open to other infections and can sometimes cause cancer. Adalimumab, when taken in combination with azathioprine, can cause a rare, life-threatening type of cancer known as hepatosplenic T-cell lymphoma (Crohn’s & Colitis UK). Because of these negative side effects and poor efficacy, developing more natural treatments that enhance the gut microbial community could be beneficial in improving the quality of life for many IBD patients. 

Studies have shown that supplementing gut microbiota in patients with IBD can lead to better chances of remission. Administration of E. coli Nissle 191J, a non-pathogenic E. coli, was as effective at maintaining remission in ulcerative colitis patients as mesalazine, an aminosalicylate that reduces inflammation (Cammarota et al, 2015). Additionally, a probiotic cocktail of microbes known as VSL#3, which includes one strain of Streptococcus, three strains of Bifidobacteria, and four strains of Lactobacilli, was shown to maintain clinical remission in ulcerative colitis patients, as well as helping to manage active disease (Cammarota et al, 2015). Studies involving patients with Crohn’s disease are far less conclusive than those seen in ulcerative colitis and have mostly been performed only in small-scale clinical trials (Cammarota et al, 2015). 

Another therapeutic strategy proposed for ulcerative colitis is fecal microbiota transplantation (FMT), which may help repopulation of healthy microbial communities (Tian et al, 2019). In a study involving 20 ulcerative colitis patients, diarrhea, abdominal pain, bloody stool, and intestinal mucosal lesions were reduced after 5 rounds of FMT (Tian et al, 2019). FMT has only been used very rarely as a treatment for ulcerative colitis but is beginning to be explored in more clinical trials as the importance of the microbiota in IBD pathogenesis is becoming more understood (Lopetuso et al, 2020).

Understanding the role and diversity of commensal microbial communities in IBD is important to creating informed treatment strategies that are more natural, safer, and effective for longer periods of time than many of the drugs that are typically prescribed for IBD. Providing long-term remission while minimizing the negative side effects of treatments is crucial for good quality of life for patients with IBD. Emerging research and clinical trials into fecal microbiota transplantation and probiotic supplements is promising for these therapies, which may become a mainstream treatment option for IBD patients in the future. 

References:

Cammarota, G., Ianiro, G., Cianci, R., Bibbò, S., Gasbarrini, A., & Currò, D. (2015) The involvement of gut microbiota in inflammatory bowel disease pathogenesis: Potential for therapy. Pharmacology & Therapies. 149, 191-212. Available from: doi: 10.1016/j.pharmthera.2014.12.006

Crohn’s & Colitis UK. (n.d) About Crohn’s and Colitis. Available from: https://www.crohnsandcolitis.org.uk/about-crohns-and-colitis/ [Accessed 13 June 2021]

D’Amico, F., Parigi, T. L., Fiorino, G., Peyrin-Biroulet, L., & Danese, S. (2019) Tofacitinib in the treatment of ulcerative colitis: efficacy and safety from clinical trials to real-world experience. Therapeutic Advances in Gastroenterology. 12. Available from: doi: 10.1177/17562848631

Khan, I., Ullah, N., Zha, L., Bai, Y., Khan, A., Zhao, T., Che, T., & Zhang, C. (2019) Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): Cause or Consequence? IBD Treatment Targeting the Gut Microbiome. Pathogens. 8 (3). Available from: doi: 10.3390/pathogens8030126

Khor, B., Gardet, A., & Xavier, R. J. (2011) Genetics and pathogenesis of inflammatory bowel disease. Nature. 474, 307-317. Available from: doi: 10.1038/nature10209.

Lopetuso, L. R., Ianiro, G., Allegretti, J. R., Bibbò, S., Gasbarrini, A., Scaldaferri, F., & Cammarota, G. (2020) Fecal transplantation for ulcerative colitis: current evidence and future applications. Expert Opinion on Biological Therapy. 20 (4), 343-351. Available from: doi: 10.1080/14712598.2020.1733964

Matsuoka, K., & Kanai, T. (2015) The gut microbiota and inflammatory bowel disease. Seminars in Immunopathology. 37, 47-55. Available from: doi: 10.1007/s00281-014-0454-4

Sandborn, W. J., van Assche, G., Reinisch, W., Colombel, J., D’Haens, G., Wolf, D. C., Kron, M., Tighe, M. B., Lazar, A., & Thakkar, R. B. (2012) Adalimumab Induces and Maintains Clinical Remission in Patients with Moderate-to-Severe Ulcerative Colitis. Gastroenterology. 142 (2), 257-265. Available from: doi: 10/1053/j.gastro.2011.10.032

Sheehan, D. & Shanahan, F. (2017) The Gut Microbiota in Inflammatory Bowel Disease. Gastroenterology Clinics of North America. 46 (1), 143-154. Available from: doi: 10.1016/j.gtc.2016.09.011

Tian, Y., Zhou, Y., Huang, S., Li, J., Zhao, K., Wen, X., & Li, X. (2019) Fecal microbiota transplantation for ulcerative colitis: a prospective clinical study

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