Updated on January 3, 2023
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that 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 chronically untreated. As a result of modern medicine, however, UC is rarely fatal.
Although clinicians have treated UC pharmacologically for 60 years, and despite drug development over that time, a cure remains elusive. In conventional UC management regimens, clinicians prescribe pharmacotherapies, like specialized anti-inflammatory drugs and immunosuppressants, to control symptoms and vary 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 arrest further tissue damage. If the intestinal tract has areas that are severely damaged, then they can be surgically removed and resected.
Although conventional regimens typically enhance quality of life and allow for a normal lifespan, therapy efficacy varies, and there are many drawbacks that are keeping researchers looking for better options. In an effort to identify the most effective UC therapies for each state of the disease’s progression or remission, researchers are now comparing the efficacy and challenges of UC therapies to identify the best management strategies for creating lasting relief from symptoms. As awareness of the impact of both UC and UC therapy on the gut microbiome grows, these management strategies are increasingly integrating therapies designed to support microbiome health.
In a recent meta-analysis of UC therapies by a research group led by Dr. Fabio Teixeira, the efficacy of conventional UC therapies was examined in the contexts of the disease’s progression, severity, location in the intestinal tract, and therapy resistance. Upon comparison, older therapies 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 can benefit from revised therapies. 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 should be cognizant of potential disruptions and seek to support microbiome health for optimal results.
The oldest, most commonly used, and most studied therapy for UC are the 5-ASA class drugs 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 therapy 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 therapy. Although effective enough to induce remission for 52.1 percent of patients in mild to moderate UC cases, 5-ASAs can cause side effects of nausea, weight loss, vomiting, anemia, and potentially organ damage. As a result of these side effects, Dr. Texeira’s analysis states that, “Adherence to [therapy] with salicylates [5-ASAs] is a serious problem that can impact about 40–60 percent of patients.”
In addition to tolerability issues, 5-ASAs also disrupt the microbiome by inhibiting the immune system’s ability to support normal bacterial populations, thus allowing harmful microbiota to flourish and cause delayed onset inflammation. Furthermore, while effective in maintaining 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 therapy, then 5-ASAs are often administered alongside corticosteroids to control moderate-severity flare-ups, presenting augmented risks to the microbiome.
Corticosteroids are second-line therapy 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. This is the result of a lengthy therapy process that requires initial dosing based on symptom severity, which is then titrated to higher doses if the patient isn’t responding to therapy. Given that corticosteroids must be titrated before therapeutic levels are reached, total therapy time can be close to 8 or 10 weeks, leaving many clinicians and patients looking for a more effective solution. Dr. Texeira’s group points out that the limit of second-line UC therapy is a maximum dosage of corticosteroids, such as prednisone, for as long as 4-6 weeks before tapering off.
The potential adverse effects 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), arresting their migration from the circulatory system into tissues. This allows unwanted gut microbiota to flourish in gaps of the intestinal epithelia caused by the tissue damage characteristic in UC, which can cause subsequent inflammation and symptom relapse.
Immunosuppressant drugs are the third line of UC therapy and are typically used for maintenance of remission rather than rescue. When used to maintain remission, Dr. Teixeira’s analysis found that two-thirds of 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 that durably maintains remission.
Unfortunately, immunosuppressant drugs have serious side effects like higher risk of infections and anemia. The general state of immune suppression also disrupts the immune system’s ability to support the microbiome, which can become overrun with harmful bacteria and cause inflammation, potentially making future flare-ups more likely.
Although imperfect, immunosuppressants have a place in the future of UC management because they are typically administered to enhance the potency of the newest and most effective therapy: TNFa inhibitors.
When other therapies fail, clinicians turn to TNFa inhibitors to rapidly control UC symptoms. TNFa inhibitors are typically artificial antibodies that bind to the TNFa receptor on T cells, inhibiting pro-inflammatory chemical release. Dr. Teixeira’s team found that TNFa inhibitors are the most effective therapy overall for inducing remission and had an average therapy 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 can now be considered a second-line therapy, potentially replacing older therapies like corticosteroids. Significantly, both Dr. Teixeira and Dr. Singh found that TNFa inhibitor therapy led to superior intestinal healing when compared with a placebo, which makes them unique among the UC therapies. 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 therapy objective to be pursued clinically and quantified by future research.
However, TNFa inhibitors come with the potential for a number of side effects, including a higher chance of infection, psoriasis, lymphoma, and nerve disorders. TNFa inhibitors also caused 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 cause mouse microbiomes to become less diverse and certain populations of bacteria to be far more abundant than expected. In humans, these disruptions can lead to inflammation and risk of higher relapse.
Although pharmacological interventions are the mainstay of UC therapy, 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 therapies. As such, regimens should ideally address patient malnutrition through dietary therapies. Iron supplementation, for example, might be useful to slow UC progression or to recover from flare-ups. Likewise, vitamin B supplementation could head off a vitamin B deficiency caused by pharmacological therapies, 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 can also be critical. In a weakened immune system, unwanted bacterial colonies can flourish and cause inflammation. The body’s efforts to repair microbiome disruptions caused by UC or UC therapy can be bolstered by short-chain fatty acid supplements, such as butyrate, which has been shown to provide nutritional support in addressing UC symptoms. Butyrate is a necessary cell signaling molecule in the GI tract that ensures the intestinal epithelia get sufficient nutrients and thus have the ability to repair themselves and damage caused by UC while supporting a healthy and resilient microbiome.
As our knowledge of UC expands, clinicians and patients will be able to make more informed therapy choices to achieve durable relief from symptoms. With TNFa inhibitors becoming more established in conventional therapies, the use of corticosteroids will likely fall, changing the way UC is treated in millions of people. Given Dr. Jones-Hall’s analysis of TNFa inhibitors’ impact on the gut microbiome, however, this can cause new disruptions in the microbiome. To protect the microbiome and to promote durable symptom remission, nutritional strategies, including supplementation, should thus be a central component of therapy planning. As Dr. Teixeira points out, taking a multidisciplinary approach to ulcerative colitis management that combines pharmacotherapy with tailored nutritional intervention can help patients ensure the best outcomes.Tesseract Medical Research brings you the latest research and news about gastrointestinal disorders, such as ulcerative colitis, and therapy options.
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Hallert C, Bjorck I, Nyman M, Pousette A, Granno C, et al. 2003. Inflammatory Bowel Diseases. 9:116–121.
Jones-Hall YL, Kozik A, Nakatsu C. 2015. Plos One. 10.
Singh S, Fumery M, Sandborn WJ, Murad MH. 2017. Alimentary Pharmacology & Therapeutics. 47:162–175.
Teixeira FV, Hosne RS, Sobrado CW. 2015. Journal of Coloproctology. 35:230–237.