A CCEPTED MANUSCRIPT
response as well as compete with potential bacterial aggressors. The molecular details of
bifidobacterial-mediated protection against small-intestinal epithelial injury are currently under
investigation, but one candidate includes the pilus-associated protein Tad E which exerts a
proliferative effect on host colonic epithelium following oral consumption of B. breve 18 . This
appears to be a characteristic of all B. breve and supports our choice of the stain used in this trial.
Interestingly, fecal microbiome analysis revealed changes were limited to a marked increase in the
total B. breve population in the Bif195 arm. 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.
Our 6-week ASA challenge model yielded minor responses in the GSRS questionnaire and in the
biomarkers of damage, I-FABP in blood and calprotectin in blood and feces. Although trends were
observed for I-FABP, only the fecal calprotectin endpoint reached statistical significance indicating
MANUSCRIPT
a modest Bif195 protective effect. Our data suggest that VCE is the method of choice when
conducting human challenges with mild induction of small-intestinal damage by NSAIDs over a
limited time period.
Although encouraging, the present clinical trial has limitations in terms of translation to a real-life
clinical setting. The relatively short-term challenge in healthy volunteers, for proof-of-concept, used
a higher dose of ASA than is most commonly prescribed for primary CVD prevention. However, it
is a dose that is readily available for over-the-counter usage. It is also noteworthy, that a recent
report suggested that the current cardioprotective dosage of ASA may be insufficient
and recommended doses based on a mg/kg basis 23 .
Due to our AUC approach based on a polynomic curve fitted to data-points obtained from 6
different visits, data imputation is not feasible for drop-out subjects where only baseline data are
available. Therefore, we acknowledge that long-term intervention clinical trials will be needed to
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