Nonsteroidal anti-inflammatory drugs (NSAIDs) are among one of the most frequently prescribed drugs that often cause mucosal lesions in the gastrointestinal tract. However, there are few effective agents for treating small intestinal lesions. As such, developing effective treatments for managing NSAID-induced small intestinal lesions is a priority.
In mice and humans, the gut microbiota, bile salt acids and the enterohepatic circulation of NSAIDs may contribute to the complex pathogenesis of NSAID-induced small intestinal damage. As a result, probiotics have emerged as potential therapeutic candidates for NSAID-induced small intestinal damage.
A new double-blind, placebo-controlled trial, a collaborative effort of Mercy University Hospital and University college in Cork (Ireland), APC Microbiome Ireland and companies Clinical Microbiomics and Chr. Hansen, has found that a Bifidobacterium probiotic strain may alleviate Aspirin-induced ulcers in healthy volunteers.
According to coauthor Clodagh Murphy, which corresponded with GMFH editors: “There is experimental pre-clinical evidence for the role of bifidobacteria in protection against NSAID-associated ulceration (here; here) and to reduce pathogen-induced colonic inflammation (here)”.
Previous mice findings revealed that a pilus-associated protein and an induction of interleukin-10-producing T cell subset in the colon might be involved in the way B. breve promote colonic epithelial proliferation and prevent intestinal inflammation.
Such findings prompted the authors to explore the involvement of the probiotic B. breve Bif195 in alleviating Aspirin-induced ulcers.
With this objective, seventy-five healthy volunteers were given 300mg/d of Aspirin for 6 weeks and were randomly assigned oral capsules of B. breve Bif195 (n = 35; each dose included at least 5 x 10^10 colony-forming units of Bif195) or placebo (n = 31) daily for 8 weeks.
Although the Aspirin dose used isn’t the standard one for cardioprotective reasons, O’Grady acknowledged that the dose assessed in the study is based on a recent study suggesting that aspirin dosing for cardioprotective reasons should be weight based and therefore, in most cases, increased. In addition, 300 mg is available to purchase over-the-counter, which also justified the dose chosen in the study.
The authors objectively evaluated Aspirin-induced small intestinal enteropathy with six serial video capsule endoscopies, using the area under curve for intestinal damage (Lewis score) and number of ulcers.
The probiotic group (n = 35) showed the lowest Lewis score for intestinal damage and was also the lowest in terms of ulcer numbers.
Although 32 adverse events were reported from 22 participants, none was determined to be related to the probiotic and, rather, was presumed to be related to Aspirin intake.
The administration of B. breve Bif195 led to an increase in the abundance of B. breve in all fecal samples. In contrast, the probiotic did not affect either overall gut microbiome composition or specific taxa. These findings show that successful probiotic intervention does not necessarily associate with changes in microbiome composition of the human digestive tract.
Moreover, the observation that B. breve Bif195 did not alter Aspirin-induced changes in serum prostaglandin E2 and thromboxane B2 suggest that this probiotic bacterium may not interfere with the cardiovascular-protective functions of aspirin.
On the whole, the study demonstrates the short-term benefits of the probiotic B. breve Bif195 in reducing Aspirin-related intestinal damage. The long-term benefits must be explored before making systematic recommendations of its use in protecting against small intestinal damage caused by Aspirin in the clinical setting.
Regarding how these findings might impact on clinical practice in the foreseeable future, Murphy highlights: “[Our study] could lead to future co-prescription of Bif195 and NSAIDs in order to help decrease the risk of small bowel damage”.
As the dose of Aspirin used in the trial is typically higher than the dose used for cardio protective purposes, Murphy also points out that further research is required to confirm whether these findings might extrapolate to patients with cardiovascular disease.
According to co-author Brynjulf Mortensen: “Due to the nature of the present trial being a relatively short-term challenge model in healthy volunteers, future more long-term intervention clinical trials are needed to truly confirm if Bif195 has long-term clinical efficacy in a larger population of chronic users of low-dose Acetylsalicylic Acid”.
Uejima M, Kinouchi T, Kataoka K, et al. Role of intestinal bacteria in ileal ulcer formation in rats treated with a nonsteroidal antiinflammatory drug. Microbiol Immunol. 1996; 40(8):553-60. doi: 10.1111/j.1348-0421.1996.tb01108.x.
Kinouchi T, Kataoka K, Bing SR, et al. Culture supernatants of Lactobacillus acidophilus and Bifidobacterium adolescentis repress ileal ulcer formation in rats treated with a nonsteroidal anti-inflammatory drug by suppressing unbalanced growth of aerobic bacteria and lipid peroxidation. Microbiol Immunol. 1998; 42(5):347-55. doi: 10.1111/j.1348-0421.1998.tb02294.x.
Collins JW, Akin AR, Kosta A, et al. Pre-treatment with Bifidobacterium breve UCC2003 modulates Citrobacter rodentium-induced colonic inflammation and organ specificity. Microbiology. 2012; 158(Pt 11):2826-34. doi: 10.1099/mic.0.060830-0.
O’Connell Motherway M, Houston A, O’Callaghan G, et al. A Bifidobacterial pilus-associated protein promotes colonic epithelial proliferation. Mol Microbiol. 2019; 111(1):287-301. doi: 10.1111/mmi.14155.
Jeon SG, Kayama H, Ueda Y, et al. Probiotic Bifidobacterium breve induces IL-10-producing Tr1 cells in the colon. PLoS Pathog. 2012; 8(5):e1002714. doi: 10.1371/journal.ppat.1002714.
Mortensen B, Murphy C, O’Grady J, et al. Bifidobacterium breve Bif195 protects against small-intestinal damage caused by acetylsalicylic acid in healthy volunteers. Gastroenterology. 2019; 157(3):637-46. doi: 10.1053/j.gastro.2019.05.008.
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