Study: Specific E-Coli strain for ulcerative colitis

reference

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.

Study objective

To assess the effectEscherichia coliNissle 1917 (EcN, brand name Mutaflor^®) in patients with ulcerative colitis (UC) taking aminosalicylate drugs (5-ASA) and determine whether EcN therapy compared with placebo affects clinical outcomes and health-related quality of life

design

Multicenter, double-blind, randomized, placebo-controlled study

Participant

Researchers randomly assigned 133 patients (mean age, 46 years; 64% men in the EcN group and 73% men in the placebo group) with mild to moderate UC (Mayo score 3-9) to receive either EcN or placebo. A total of 118 patients (EcN: 58; placebo: 60) completed the study.

Exclusion criteria included proctitis, medications other than 5-ASA, and hospitalization.

intervention

Participants received sealed single-dose bags 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 to 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 antidiarrheals were not administered.

Evaluated study parameters

Evaluation of the Inflammatory Bowel Disease Questionnaire (IBDQ).

Primary outcome measure

The primary outcome was an increase in IBDQ score of more than 16 points from baseline at 8 weeks.

Secondary outcomes included:

1. Klinische Remission (partieller Mayo-Score ≤ 1, beurteilt in Woche 4, oder Mayo-Score ≤ 2, beurteilt in Woche 8)

2. Klinisches Ansprechen (> 2-Punkte-Reduktion des partiellen Mayo-Scores, ermittelt in Woche 4, oder > 3-Punkte-Reduktion des Mayo-Scores, ermittelt in Woche 8)

3. Verbesserte endoskopische Scores und Remission (endoskopischer Subgruppen-Mayo-Score = 0 in Woche 8)

4. Endoskopisches Ansprechen (> 1-Punkt-Reduktion im endoskopischen Subgruppen-Score in Woche 8)

5. Die mikrobielle Zusammensetzung im Stuhl verändert sich

Key findings

Primary endpoint: At the end of the treatment period, both groups showed a statistically significant increase 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, the researchers did not conclude that EcN is superior to placebo in this regard. However, they found 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 demonstrated clinical remission (decreased Mayo score) than patients in the placebo group (23 (39.7%) versus 13 (21.7%).P=0.04).

Researchers found no differences in clinical remission or clinical response rate between the two groups at week 8 and no differences in stool frequency at 4 or 8 weeks.

Significantly more patients in the EcN group reported an improvement in abdominal pain after 4 weeks than patients in the placebo group (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%) versus 16 (27.1%).P=0.03).

The researchers did not observe any statistically significant differences in α or β diversity in stool samples from the placebo and EcN groups at either baseline or week 8.

They also found no significant differences in frequencyEscherichiaorShigellagenera, including in patients who showed a clinical response in the EcN group.

transparency

This attempt was registered asNCT04969679 and funded by Kangbuk Samsung Hospital, Republic of Seoul, Korea.¹ The authors did not provide any information in the article.

Effects on practice

E. coliNissle 1917 (brand name Mutaflor) contains 2.5 billion viable organisms per capsule and requires refrigeration. Typically, 1 capsule is taken orally twice daily (after a 4-day introduction of 1 capsule per day to reduce bloating and other minor side effects), or the contents of 1 to 2 capsules in 40 ml of water are taken rectally in patients with UC. This fascinating probiotic was first isolated by Professor Alfred Nissle in 1917 after he noticed a soldier who, like his comrades, did not develop infectious diarrhea despite being stationed in a heavily contaminated regionShigella. After further studying the soldier's intestinal flora, Nissle determined that EcN was responsible for the soldier's impressive resistance to the pathogen and used the strain to develop the probiotic product Mutaflor.²

EcN is not sold in the United States due to U.S. Food and Drug Administration (FDA) restrictions (ostensibly due to concerns that the U.S. public would have difficulty distinguishing between pathogens).E. coliand probioticE. coli). Still, U.S. consumers may be able to obtain Mutaflor from international sources.

Mechanism of action

EcN is a non-pathogenic strain ofE. coli that produces no known toxins. It can effectively colonize the human intestine by attaching to intestinal cells, forming biofilms, and successfully competing with pathogens for tissue binding sites. EcN has been shown to possess antimicrobial properties against several pathogenic strainsE. coli, both by stimulating defensin production of intestinal epithelial cells and by blocking toxin synthesis. In addition, it acts as an inflammatory modulator to reduce serum levels of pro-inflammatory cytokines while increasing the levels of anti-inflammatory cytokines. Furthermore, EcN is able to regulate T cell expansion within the intestinal mucosa without affecting tissue-associated T cell function, resulting in lower levels of intestinal inflammation. EcN is also thought to contribute to intestinal integrity by upregulating the expression of zonula occludens proteins (ZO-1 and ZO-2) to strengthen tight junctions.²

Side effects

EcN is not associated with side effects in most published clinical studies. The side effects are often similar to those of the control group and are therefore not attributed to EcN. In a multicenter clinical trial evaluating EcN for the treatment of functional gastrointestinal disorders or inflammatory bowel disease in 1,074 patients, only 1.5% of cases reported side effects that required treatment or led to discontinuation of therapy, while 2.8% of cases reported initial side effects that resolved without the need for treatment.³Similarly, a study using stem cell-derived human intestinal organoid tissues found that EcN is safe, does not cause mucosal damage, and even has protective properties against pathogensE. coli.⁴

In a 2021 open-label study testing the additive effect of EcN in UC patients in remission, 7 of 94 patients experienced side effects possibly related to EcN therapy and were asked to discontinue the probiotic and start steroid therapy. The symptoms that led to discontinuation were diarrhea and hematochezia, which are also symptoms of UC. So it may be that these were UC symptoms that were not prevented by EcN rather than symptoms caused by EcN; The authors recommended conducting randomized controlled trials to better understand this. The study concluded that the probiotic is relatively safe and suggested that doctors should monitor for side effects within the first three months of treatment, as this appears to be the time frame in which side effects occur.⁵

This fascinating probiotic was first isolated by Professor Alfred Nissle in 1917 after he noticed a soldier who, like his comrades, did not develop infectious diarrhea despite being stationed in a heavily contaminated regionShigella

EcN is registered as a drug in several European countries and is recommended by the EUKorean Association for Research on Intestinal Diseases⁶and thatEuropean Organization for Crohn's Disease and Colitis²to maintain UC remission. There is ample evidence for the effect of EcN on UC. In a 2015 systematic review comparing EcN with mesalazine in UC patients, EcN was recommended as an alternative to mesalazine for maintaining remission in UC based on the results of 4 studies.⁷Data from the only study comparing EcN with mesalazineinductionRemission trended in favor of EcN but did not reach statistical significance.⁷In the period since the publication of this systematic review (and prior to the publication of the article we are reviewing here), another clinical trial of oral EcN was conducted - a 2021 open-label trial for UC patients in clinical remission with elevated calprotectin. It concluded that EcN may be able to significantly relieve some UC symptoms and lower some biomarkers without affecting calprotectin.⁵

In addition, rectally administered EcN may be effective in a dose-dependent manner to shorten the time to remission and induce mucosal healing in patients with UC taking mesalazine.⁸

EcN has also shown promise in a variety of other gastrointestinal diseases, including Crohn's disease,⁹diverticulitis,¹⁰chronic constipation,¹¹and functional bowel diseases.³Data on EcN and irritable bowel syndrome (IBS) are mixed. EcN may provide better benefit than placebo, particularly in subgroups of those who had gastroenteritis and/or were taking antibiotics before developing irritable bowel syndrome¹²and in patients with diarrheal IBS (IBS-D), although EcN may exacerbate severe distress in patients with mixed diarrhea/constipation variant of IBS (IBS-M).¹³In addition, EcN therapy has been shown to improve liver function and reduce endotoxemia in patients with liver cirrhosis compared to placebo.^14.15In patients with hepatic encephalopathy, EcN was able to reduce and at the same time normalize serum ammonia levels and proinflammatory cytokinesBifidobacteria/LactobacilliFullness and improvement of cognitive function.¹⁶

E. coliThe benefits of Nissle have even been proven to extend to dermatological diseases. In a 2016 randomized controlled trial, 89% of patients with acne, papular-pustular rosacea, or seborrheic dermatitis treated with conventional topical therapy, vegetarian diet, and oral EcN responded with significant improvement or complete recovery, compared to 56% in the group receiving topical therapy only and diet therapy. EcN also appeared to cause a shift in directionBifidobacteriaAndLactobacilliand a decrease in pathogenic microbes in the majority of patients compared to no change in the control group withoutE. coli Nissle.¹⁷

This ability of EcN to alter the composition of the gut microbiome was again demonstrated in a study of newborns vaccinated orally with EcN in the first 5 days after birth. Colonization with real and potential bacterial pathogens was significantly reduced in infants receiving EcN compared to placebo, both in terms of pathogen numbers and species range.¹⁸

This study further confirms what we have seen in previous studies and systematic reviews:E. coliNissle is a safe probiotic for our patients with UC, especially when abdominal pain is a predominant symptom. If a worsening of UC symptoms occurs while a patient is taking EcN, it will most likely occur in the first three months of use. EcN appears to be about as effective as standard 5-ASA drugs in maintaining clinical remission, improving some UC symptoms, and accelerating tissue healing, even in UC patients in remission who still have elevated fecal calprotectin. Use a starting dose of 1 capsule per day for the first 4 days to reduce minor adverse events and then maintain 1 capsule orally twice daily on an ongoing basis. EcN may additionally benefit our UC patients with comorbid Irritable Bowel Syndrome D, but it may exacerbate exercise problems in patients with Irritable Bowel Syndrome.