Fleming, P; Wilks, M; Eaton, S; Panton, N; Hutchinson, R; Akyempon, A; Hardy, P; ... Costeloe, K; + view all Fleming, P; Wilks, M; Eaton, S; Panton, N; Hutchinson, R; Akyempon, A; Hardy, P; Millar, MR; Costeloe, K; - view fewer (2020) Exploratory studies from the PiPS trial fail to find evidence that Bifidobacterium breve BBG-001 modifies intestinal barrier function. Pediatric Research 10.1038/s41390-020-01135-5. (In press).

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Abstract

BACKGROUND: Uncertainty remains about the role of probiotics to prevent necrotising enterocolitis (NEC) some of which arises from the variety of probiotic interventions used in different trials, many with no prior evidence of potential efficacy. Mechanistic studies of intestinal barrier function embedded in a large probiotic trial could provide evidence about which properties of probiotics might be important for NEC prevention thus facilitating identification of strains with therapeutic potential. METHODS: Intestinal permeability, stool microbiota, SCFAs and mucosal inflammation were assessed from the second postnatal week in babies enrolled to a randomised controlled trial of B. breve BBG-001 (the PiPS trial). Results were compared by allocation and by stool colonisation with the probiotic. RESULTS: Ninety-four preterm babies were recruited across six nested studies. B. breve BBG-001 content was higher by allocation and colonisation; Enterobacteriaceae and acetic acid levels were higher by colonisation. No measure of intestinal barrier function showed differences. The PiPS trial found no evidence of efficacy to reduce NEC. CONCLUSIONS: That the negative results of the PiPS trial were associated with failure of this probiotic to modify intestinal barrier function supports the possibility that the tests described here have the potential to identify strains to progress to large clinical trials. IMPACT: Uncertainty about the therapeutic role of probiotics to prevent necrotising enterocolitis is in part due to the wide range of bacterial strains with no previous evidence of efficacy used in clinical trials.We hypothesised that mechanistic studies embedded in a probiotic trial would provide evidence about which properties of probiotics might be important for NEC prevention.The finding that the probiotic strain tested, Bifidobacterium breve BBG-001, showed neither effects on intestinal barrier function nor clinical efficacy supports the possibility that these tests have the potential to identify strains to progress to large clinical trials.Fig. 1FOETAL INTESTINE: THE INTESTINAL LUMEN (A) IN THE FOETUS IS STERILE; INTESTINAL MUCUS (B) IS WATERY; TLR4 RECEPTORS (C) ARE ABUNDANTLY EXPRESSED ON ENTEROCYTES; LARGE PROTEINS FROM AMNIOTIC FLUID (D) ARE EASILY ABSORBED BETWEEN WIDELY SPACED ENTEROCYTES (E) AND ENTER THE CIRCULATION (F).: Preterm neonatal intestine: the intestinal lumen (A) contains a higher proportion of potentially pathogenic (purple) than beneficial (green) bacteria; intestinal mucus is more abundant but still watery (B); potentially pathogenic bacteria are in close proximity to TLR4 receptors (C); in the absence of food, the intercellular gap remains wide (D); fluctuations in intestinal blood flow produces vasodilating substances (e.g. nitric oxide) (E). Necrotising enterocolitis: potentially pathogenic bacteria (purple) outnumber other bacteria in the intestinal lumen (A); intestinal mucus (B) may be interrupted allowing some bacteria to adhere to TLR4 receptors (C); activation of TLR4 leads to downstream production of IL8 through the NF-κB pathway (D) initiating further inflammation; bacterial translocation occurs through (E) and between (F) enterocytes into the systemic circulation.

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