Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) which causes patients to experience a higher than normal number of daily stools, bloody or disrupted stools, diarrhea, pain, weight loss, inflammation, and bloating. UC causes damage to intestinal tissues via cycles of inflammation and tissue retraction, and is progressively degenerative, leading it to be potentially fatal if untreated for a long enough time. As a result of modern medicine, however, UC is rarely fatal.
Clinicians have treated UC pharmacologically for nearly 60 years, but, despite drug development over that time, a cure remains elusive. With conventional UC management regimens, clinicians prescribe pharmacotherapies like specialized anti-inflammatory drugs and immunosuppressants to keep symptoms under control and vary the specific medications within the general categories based on the patient’s maintenance of remission. When symptoms flare up and end remission, clinicians prescribe rescue medications like corticosteroids and, more recently, tumor necrosis factor alpha (TNFa) inhibitors to control inflammation and prevent further tissue damage. If the intestinal tract has areas that are severely damaged due to treatment failure, they may be surgically removed and resected.
While conventional regimens typically improve patient quality of life and allow for a normal lifespan, treatment efficacy varies and there are many drawbacks that keep researchers looking for better therapies.In an effort to identify the most effective UC treatments for each state of the disease’s progression or remission, researchers are now comparing the efficacy and challenges of UC treatments to identify the best management strategies for creating lasting relief from symptoms. As awareness of the impact of both UC and UC treatments on the gut microbiome grows, these management strategies are increasingly integrating therapies designed to support microbiome health.
Measuring the Efficacy of Treatments for UCresearch group led by Dr. Fabio Teixeira, the efficacy of conventional UC treatments was examined in the contexts of the disease’s progression, severity, location in the intestinal tract, and treatment resistance. Upon comparison, older treatments were shown to be significantly less effective than newer options. In particular, TNFa inhibitors were found to be the most effective “rescue” (remission-inducing rather than remission-maintaining) therapy, suggesting that many patients who are currently prescribed corticosteroids may benefit from revised treatment plans. However, all the therapies examined can have a damaging impact on the gut microbiome, potentially causing relapse or the emergence of new symptoms. As a result, clinicians and patients must be cognizant of potential disruptions and seek to support microbiome health for optimal treatment results.
The oldest, most commonly used, and most studied therapy for UC are the 5-ASA class drugs, which are anti-inflammatories that are administered topically, orally, or as a suppository for both remission maintenance and remission induction. 5-ASA class drugs like mesalazine are the first line of treatment in inducing UC remission in mild to moderate cases regardless of the specific area of the intestinal tract. Dr. Texeira’s analysis found that across 38 clinical trials investigating the use of 5-ASAs, there was unanimous consensus regarding their superiority to placebos.
However, patients treated with 5-ASAs often have difficulty tolerating treatment. While effective enough to induce remission for 52.1% of patients in mild to moderate cases of UC, 5-ASAs cause side effects like nausea, weight loss, vomiting, anemia, and potentially organ damage. As a result of these side effects, Dr. Texeira’s analysis states that “adherence to treatment with salicylates [5-ASAs] is a serious problem that can impact about 40–60% of patients.”
In addition to tolerability issues, 5-ASAs also disrupt the microbiome by inhibiting the immune system’s ability to regulate normal bacterial populations, allowing harmful microbiota to flourish and cause delayed onset inflammation. Furthermore, while effective to maintain remission for many mild to moderate UC cases, 5-ASAs alone often aren’t enough to induce remission during moderate and severe flare-ups. If patients are still symptomatic after the first round of treatment, 5-ASAs are often administered alongside corticosteroids to control moderate severity flare-ups, presenting augmented risks to the microbiome.
Corticosteroids are second-line treatments for inflammation during UC flare-ups and are intended for short-term use only, typically in conjunction with 5-ASAs. Unfortunately, corticosteroids operate very slowly for the purposes of rescuing a moderately symptomatic patient. This is caused by a lengthy treatment process that requires initial dosing based on symptom severity, which is then titrated to higher doses if the patient isn’t responding to treatment. Given that corticosteroids must be titrated before therapeutic levels are reached, total treatment time may be close to 8 or 10 weeks, which leaves many clinicians and patients looking for a more effective solution. Dr. Texeira’s group points out that the limit of second-line treatment for UC is a maximum dosage of corticosteroids such as prednisone for as long as 4-6 weeks before tapering off.
The effect of corticosteroids on the microbiome also presents concerns. While not known to produce immediately uncomfortable side effects, corticosteroids behave as minor immunosuppressants for immune cells like neutrophils, preventing their migration from the circulatory system into tissues. This allows unwanted gut microbiota to flourish in gaps of the intestinal epithelia caused by tissue damage characteristic in UC, which may cause subsequent inflammation and a relapse in symptoms.
Immunosuppressant drugs are the third line of treatment for UC and typically used for maintenance of remission rather than rescue. When used to maintain remission, Dr. Teixeira’s analysis found that 2/3 patients benefited from the use of one of the examined immunosuppressants, 6-mercaptopurine. However, there are multiple immunosuppressant class drugs, and clinicians can rotate through them to find one which durably maintains remission.
Unfortunately, immunosuppressant drugs have serious but invisible side effects like increased risk of infections and anemia. The general state of immune suppression also disrupts the immune system’s ability to regulate the microbiome, which may become overrun with harmful bacteria and cause inflammation, potentially making future flare-ups more likely.
While imperfect, immunosuppressants have a place in the future of UC management because they’re typically administered to increase the potency the newest and most effective treatment: TNFa inhibitors.
When other therapies fail, clinicians turn to TNFa inhibitors to control UC symptoms rapidly. TNFa inhibitors are typically artificial antibodies that bind to the TNFa receptor on T cells, inhibiting proinflammatory chemical release. Dr. Teixeira’s team found that TNFa inhibitors were the most effective therapy overall for inducing remission and had an average treatment duration of less than two weeks before remission. This supports the findings of a previous study led by Dr. Siddharth Singh, which suggested that TNFa inhibitors may now be considered a second-line treatment, potentially replacing older therapies like corticosteroids. Significantly, both Dr. Teixeira and Dr. Singh found that treatment with TNFa inhibitors led to superior intestinal healing when compared with placebo, which makes them unique among the therapies for UC. The importance of inducing healing is hard to overstate; Dr. Teixeira goes as far as to say that the TNFa inhibitors should make intestinal healing a new treatment objective to be pursued clinically and quantified by future research.
However, TNFa inhibitors come with the potential for a number of side effects, including an increased chance of infections, psoriasis, lymphoma, and nerve disorders. TNFa inhibitors also cause microbiome disruptions in mouse models, which are tentatively documented in a study led by Dr. Yava L. Jones-Hall. Jones-Hall’s team found that TNFa inhibitors caused mouse microbiomes to become less diverse and certain populations of bacteria to be far more abundant than expected. In humans, these disruptions likely increase inflammation and subsequent relapse risk.
Nutritional Supplementation for Ulcerative Colitis
While pharmacological interventions are the mainstay of UC treatment, a number of diet-based interventions have shown significant promise for addressing the effects of both UC and UC medications. In particular, Dr. Teixeira’s group underlines the need for solutions to malnutrition and poor nutrient absorption, which can arise both from the illness itself and from pharmacological treatments. As such, treatment plans should ideally address patient malnutrition through dietary therapies. Iron supplementation, for example, may be useful to slow UC progression or recover from flare-ups. Likewise, vitamin B supplementation could head off vitamin B deficiencies caused by pharmacological treatments, inhibiting the development of anemia.
Because UC therapies often compromise the immune system’s ability to maintain a healthy gut microbiome, nutritional supplements that promote microbiome health may also be critical. In a weakened immune system, unwanted bacterial colonies can flourish, preventing absorption of nutrients and causing inflammation. The body’s efforts to repair microbiome disruptions caused by UC or UC treatment may be bolstered by short chain fatty acid supplements such as butyrate, which has been shown to reduce UC symptoms. Butyrate is a necessary cell signaling molecule in the GI tract which ensures the intestinal epithelia get enough nutrients and thus have the ability to repair themselves and damage caused by UC while supporting of a healthier and more resilient microbiome.
Toward Multidisciplinary Ulcerative Colitis Managementa multidisciplinary approach to UC management that combines pharmacotherapy with tailored nutritional intervention could help patients ensure the best outcomes.
Hallert C, Bjorck I, Nyman M, Pousette A, Granno C, et al. 2003. Increasing fecal butyrate in ulcerative colitis patients by diet: controlled pilot study. Inflammatory Bowel Diseases. 9:116–121. http://onlinelibrary.wiley.com/doi/10.1097/00054725-200303000-00005/full
Jones-Hall YL, Kozik A, Nakatsu C. 2015. Ablation of tumor necrosis factor is associated with decreased inflammation and alterations of the microbiota in a mouse model of inflammatory bowel disease. Plos One. 10. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119441
Singh S, Fumery M, Sandborn WJ, Murad MH. 2017. Systematic review with network meta-analysis: first- and second-line pharmacotherapy for moderate-severe ulcerative colitis. Alimentary Pharmacology & Therapeutics. 47:162–175. http://onlinelibrary.wiley.com/doi/10.1111/apt.14422/full
Teixeira FV, Hosne RS, Sobrado CW. 2015. Management of ulcerative colitis: a clinical update. Journal of Coloproctology. 35:230–237. https://www.researchgate.net/publication/282388103_Systematic_review_of_management_of_ulcerative_colitis_a_clinical_update