Park SK, Kang SB, Kim SS, et al. Additive effect of probiotics (Mutaflor) on 5-aminosalicylic acid therapy in patients with ulcerative colitis. Korean J Intern Med. 2022;37(5):949-957.
To assess the effect of Escherichia coli Nissle 1917 (EcN, brand name Mutaflor®) in patients with ulcerative colitis (UC) taking aminosalicylate (5-ASA) medicines and determine whether EcN therapy impacts clinical outcomes and health-related quality of life when compared with placebo
Multicenter, double-blind, randomized, placebo-controlled study
Investigators randomly assigned 133 patients (mean age 46 years; 64% male in the EcN group and 73% male in the placebo group) with mild-to-moderate UC (Mayo score 3–9) to receive either EcN or placebo. Overall, 118 patients (EcN, 58; placebo, 60) completed the study.
Exclusion criteria included proctitis, medication other than 5-ASA, and hospitalization.
Participants received sealed, single-dose sachets containing either EcN at a dose of 2.5 billion colony forming units (CFU) or a placebo. Patients were asked to take EcN once daily in the morning (1 capsule/day from day 1 to day 4 and 2 capsules/day from day 5 through the end of the 8-week study period).
Patients continued taking 5-ASA (mesalamine or balsalazide) either orally or as suspension enemas at stable doses for the duration of the 8-week study. Other medications, such as steroids, antibiotics, probiotics, and antidiarrheal drugs, were not administered.
Study Parameters Assessed
Inflammatory bowel disease questionnaire (IBDQ) score
Primary Outcome Measure
The primary outcome was an increase in the IBDQ score of more than 16 points from baseline at 8 weeks.
Secondary outcomes included:
- Clinical remission (partial Mayo score ≤ 1, assessed at week 4, or Mayo score ≤ 2, assessed at week 8)
- Clinical response (> 2-point reduction in partial Mayo score assessed at week 4 or > 3-point reduction in Mayo score assessed at week 8)
- Improved endoscopic scores and remission (endoscopic subgroup Mayo score = 0 at week 8)
- Endoscopic response (> 1-point reduction in endoscopic subgroup score at week 8)
- Microbial composition changes in the stool
Primary endpoint: At the end of the treatment period, both groups showed statistically significant increases in IBDQ scores (mean increase in the EcN group, 22 points, P<0.001; mean increase in the placebo group, 19 points, P<0.001). Therefore, researchers did not find EcN to be superior to placebo in this regard. However, they did find that IBDQ scores decreased in significantly fewer patients in the EcN group than in the placebo group (1 [1.7%] vs 8 [13.3%]; intention to treat [ITT], P=0.02).
At week 4, a significantly higher number of patients in the EcN group showed a clinical remission (decreased Mayo score) than patients in the placebo group (23 [39.7%] vs 13 [21.7%], P=0.04).
Researchers detected no differences in clinical remission or clinical response rates between the 2 groups at week 8 and no differences in stool frequency at 4 or 8 weeks.
Significantly more patients in the EcN group reported abdominal pain improvement than patients in the placebo group at 4 weeks (91.4% vs 61.7%, P<0.001) and 8 weeks (86.2% vs 66.7%, P<0.001).
Significantly more patients in the EcN group achieved endoscopic remission than patients in the placebo group (26 [46.4%] vs 16 [27.1%], P=0.03).
Researchers observed no statistically significant differences in α-diversity or β-diversity in stool samples from the placebo and EcN groups, either at baseline or at week 8.
Nor did they observe any significant differences in the abundance of the Escherichia or Shigella genera, even in patients who showed a clinical response in the EcN group.
This trial was registered as NCT04969679 and funded by Kangbuk Samsung Hospital, Republic of Seoul, Korea.1 The authors did not have any disclosures in the article.
E coli Nissle 1917 (brand name Mutaflor) contains 2.5 billion viable organisms per capsule and requires refrigeration. It’s typically used at 1 capsule by mouth twice daily (after a 4-day lead-in of 1 cap per day to reduce flatulence and other minor side effects), or the contents of 1 to 2 capsules in 40 mL of water by rectum for patients with UC. This fascinating probiotic was first isolated in 1917 by Professor Alfred Nissle, after he noticed a soldier who did not develop infectious diarrhea like his comrades despite being stationed in a region heavily contaminated with Shigella. After further investigation of the soldier’s intestinal flora, Nissle determined that EcN was responsible for the soldier’s impressive resistance to the pathogen, and he used the strain to develop the probiotic product Mutaflor.2
EcN is not distributed in the United States due to US Food and Drug Administration (FDA) restrictions (allegedly due to concern that the US public would have trouble distinguishing between pathogenic E coli and probiotic E coli). Still, US consumers may be able to purchase Mutaflor from international sources.
Mechanism of action
EcN is a nonpathogenic strain of E coli that does not produce any known toxins. It can effectively colonize the human intestine by adhering to intestinal cells, forming biofilms, and successfully competing with pathogens for tissue-binding sites. EcN has been shown to have antimicrobial properties against several pathogenic strains of E coli, both by stimulating intestinal epithelial-cell defensin production and blocking toxin synthesis. It additionally acts as an inflammation modulator to decrease serum levels of pro-inflammatory cytokines while increasing levels of anti-inflammatory cytokines. Furthermore, EcN is able to regulate T cell expansion within the intestinal mucosa without interfering with tissue-bound T cell function, leading to lower levels of gut inflammation. EcN is also thought to contribute to gut integrity by upregulating the expression of zonula occludens proteins (ZO-1 and ZO-2) to reinforce tight junctions.2
EcN is not associated with adverse effects in the majority of published clinical trials. Side effects are often similar to those noted in the control group and, therefore, not attributed to EcN. In a multicenter clinical trial studying EcN as a treatment for functional gastrointestinal disease or chronic inflammatory bowel disease in 1,074 patients, only 1.5% of cases reported adverse reactions that needed treatment or led to termination of the therapy, while 2.8% of cases reported initial side effects that resolved without the need for treatment.3 Similarly, a study that used stem cell–derived human intestinal organoid tissues found EcN to be safe, inducing no mucosal damage, and even to have protective qualities against pathogenic E coli.4
In a 2021 open-label trial testing the additive effect of EcN on UC patients in remission, 7 out of 94 patients experienced side effects possibly associated with EcN therapy and were prompted to discontinue the probiotic and begin steroid therapy. The symptoms leading to discontinuation were diarrhea and hematochezia, which are also symptoms of UC, so these may have been UC symptoms that were not prevented by EcN, rather than symptoms caused by EcN; the authors recommended that randomized controlled trials be conducted to help understand this better. The study concluded that the probiotic is relatively safe and suggested that clinicians should monitor for side effects within the first 3 months of treatment since this seems to be the time frame within which side effects arise.5
This fascinating probiotic was first isolated in 1917 by Professor Alfred Nissle, after he noticed a soldier who did not develop infectious diarrhea like his comrades despite being stationed in a region heavily contaminated with Shigella
EcN is registered as a drug in several European countries and recommended by the Korean Association for the Study of Intestinal Diseases6 and the European Crohn’s and Colitis Organisation2 for maintenance of UC remission. A sizable body of evidence regarding EcN’s effect on UC exists. A 2015 systematic review comparing EcN to mesalazine for UC patients recommended EcN as an alternative to mesalazine for the maintenance of remission in UC, based on the results of 4 trials.7 Data from the only study comparing EcN to mesalazine for induction of remission trended in favor of EcN, but did not reach statistical significance.7 In the time since that systematic review was published (and before the paper we are reviewing here was published), 1 other clinical trial on oral EcN was conducted—a 2021 open-label trial for UC patients in clinical remission with elevated calprotectin. It concluded that EcN may have the ability to substantially decrease some UC symptoms and lower some biomarkers without impacting calprotectin.5
In addition, rectally administered EcN may be effective, in a dose-dependent manner, at shortening the time to remission and inducing mucosal healing in patients with UC taking mesalazine.8
EcN has also shown promise in a variety of other gastrointestinal conditions, including Crohn disease,9 diverticulitis,10 chronic constipation,11 and functional bowel diseases.3 The data on EcN and irritable bowel syndrome (IBS) are mixed. EcN may provide benefit superior to placebo, particularly in the subgroups of those who experienced gastroenteritis and/or took antibiotics prior to developing IBS12 and those with diarrheal IBS (IBS-D), although EcN may worsen difficult straining in those with a mixed diarrhea/constipation variety of IBS (IBS-M).13 Additionally, EcN therapy has been shown to improve liver function and lower endotoxemia in patients with liver cirrhosis when compared to placebo.14,15 In patients with hepatic encephalopathy, EcN was able to reduce ammonia content and serum proinflammatory cytokines while also normalizing Bifidobacteria/Lactobacilli abundance and improving cognitive function.16
E coli Nissle’s benefits have even been shown to extend to dermatalogic conditions. In a 2016 randomized controlled trial, 89% of patients with acne, papular-pustular rosacea, or seborrheic dermatitis who treated with conventional topical therapy, vegetarian diet, and oral EcN responded with significant improvement or complete recovery, compared to 56% in the group receiving only topical and diet therapy. EcN also seemed to prompt a shift toward Bifidobacteria and Lactobacilli and a decrease in pathogenic microbes in the majority of patients compared to no change in the control group without E coli Nissle.17
This ability of EcN to modify the composition of the gut microbiome was again demonstrated in a study involving newborn infants orally inoculated with EcN over the first 5 days after birth. Colonization with true and potential bacterial pathogens was significantly reduced in infants receiving EcN compared to placebo, both with respect to numbers of pathogens and the spectrum of species.18
This study further confirms what we’ve seen in previous trials and systematic reviews: E coli Nissle is a safe probiotic for our patients with UC, especially when abdominal pain is a predominant symptom. If exacerbation of UC symptoms occurs while a patient is on EcN, it’s most likely to happen in the first 3 months of use. EcN appears to be about as effective as standard-of-care 5-ASA drugs at maintaining clinical remission, improving some UC symptoms, and accelerating tissue healing, including in UC patients in remission who still have elevated fecal calprotectin. Use a lead-in dose of 1 capsule per day for the first 4 days to reduce minor adverse events, and then maintain at 1 capsule orally twice daily, ongoing. EcN may additionally benefit our UC patients with comorbid IBS-D, but it may exacerbate straining difficulties in those with IBS-M.