Source: American Gastroenterological Association
Healthy volunteers given aspirin and Bif195 had significantly less damage and fewer ulcers in their small intestines than did control participants who received aspirin alone, reported lead author Brynjulf Mortensen, PhD, an employee of Chr. Hansen A/S, and colleagues in Gastroenterology. These findings may be relevant for millions of people, the investigators noted, because 30% of Americans older than 40 years take low-dose acetylsalicylic acid (ASA/aspirin) for cardiovascular disease (CVD).
NSAID-associated gastrointestinal issues are a long-standing and well-known problem, but the pathogenesis of this process in the small intestine appears more complex than in the stomach. The investigators pointed out that proton pump inhibitors, which limit gastropathy by suppressing acid, may actually worsen issues in the small intestine via disruption of microbiota.
“Whereas acid and pepsin are the principal luminal aggressors in NSAID-gastropathy, bile and indeed bacteria are the luminal factors in NSAID-enteropathy,” the investigators wrote.
“Given that deleterious compositional changes to the microbiota, in addition to direct effects on mucus and epithelial tissue, may increase the risk of NSAID-enteropathy, we hypothesized that an intervention targeting microbiome-host interactions may offer an attractive, preventative strategy,” the investigators wrote. They noted that previous human trials using probiotics for NSAID-enteropathy have been inconsistent; however, they suggested that Bifidobacteria remain worthy candidates because of their reported abilities to outcompete pathogenic bacteria, strengthen the intestinal epithelial layer, and modulate inflammation. “Our strain selection was based on the anti-inflammatory properties of certain Bifidobacteria and experimental preclinical evidence for a role of Bifidobacteria in NSAID-associated ulceration as well as unpublished preclinical screening data suggesting a particular potential of efficacy for the specific strain belonging to this genus.”
The double-blind, placebo-controlled trial involved 75 healthy volunteers aged 18-40 years who lived a sedentary lifestyle; during the study, they refrained from medications and bacterial products that might alter gastrointestinal function. Participants were randomized in a 1:1 ratio to received Bif195 or placebo for 8 weeks. Aspirin 300 mg was given daily to all participants for the first 6 weeks. At six points in time, video capsule endoscopy (VCE) was performed to determine the effect of treatment. The primary endpoint was intestinal damage, reported as area under the curve (AUC) for Lewis score, which incorporates stenosis, villous edema, and ulcers. The main secondary endpoint focused on ulcers, quantified by a separate AUC. Six other secondary endpoints evaluated symptoms, blood intestinal fatty acid binding protein (I-FABP), red spots visualized on VCE, and calprotectin.
After the 8-week period, 66 of 75 participants remained in the trial. Significantly less intestinal pathology was encountered among patients who received Bif195 than among those who did not. Specifically, for Lewis score, AUC in the Bif195 group was 3,040 plus or minus 1,340 arbitrary units (au), compared with 4,351 plus or minus 3,195 au in the placebo group (P = .0376). For ulcers alone, the Bif195 cohort had an AUC ulcer number of 50.4 plus or minus 53.1 au, versus 75.2 plus or minus 85.3 au for the placebo arm (P = .0258). Fecal calprotectin was also significantly lower in the Bif195 group than in the placebo group, whereas the remaining five secondary endpoints, which included symptom measurement, did not achieve statistical significance.
“Interestingly, fecal microbiome analysis revealed changes were limited to a marked increase in the total B. breve population in the Bif195 arm,” the investigators wrote. “These data provide further evidence that microbial intervention strategies targeting the microbiome can be clinically efficacious without inducing major alterations in the overall microbial population structure.”
Both aspirin and Bif195 were well tolerated during the trial, without statistically significant differences in adverse events between the treatment and placebo arms. No adverse events were considered related to Bif195.
“The trial results indicate that Bifidobacterium breve Bif195 confers significant and objectively verifiable protection against small-intestinal damage caused by a 6-week ASA challenge in healthy volunteers,” the investigators wrote.
“Further clinical trials are required to test whether the strain has clinical efficacy also in other settings and populations, i.e. in chronic users of ASA,” they concluded.
The study was funded by Chr. Hansen A/S. One author reported additional support from the Science Foundation Ireland.
SOURCE: Mortensen B et al. Gastroenterology. 2019 May 13. doi: 10.1053/j.gastro.2019.05.008.