Metabolites from Bifidobacterium adolescentis provide protection against inflammation-induced colonic barrier disruption in vitro and in vivo

Bifidobacteria are common and beneficial members of the gastrointestinal (GI) microbiome. Cultivars of bifidobacterial species common in infants have been better studied and used more frequently as probiotics than adult-type bifidobacteria, in part because they are more tolerant of oxygen. We sought to identify interactions between B. adolescentis – an oxygen-sensitive species that is the most prevalent and abundant Bifidobacterium species in the adult gut microbiome – and the colonic epithelium. Using an asymmetric oxygen system (AOS) that maintains constant oxygen concentrations on the basolateral side of colonic epithelial monolayers and anoxic conditions on the luminal side, we found that monolayers in the AOS behaved more like in vivo epithelia than monolayers cultured under 20% oxygen atmospheres. Co-culturing colonic monolayers with Bifidobacterium adolescentis U269-1 in the anoxic apical chamber mitigated loss of the barrier function in monolayers exposed to inflammatory cytokines. We identified indole lactic acid (ILA) as one metabolite from B. adolescentis U269-1 that provides dose-dependent protection against inflammatory cytokines. Oral administration of ILA was well tolerated in mice and provided protection against immunotherapy-induced (anti-CTLA4) colitis in female (but not male) mice. The present study yielded strong evidence for the beneficial effects of Bifidobacterium adolescentis on the maintenance of colonic barrier function in an in vitro organoid model under physiological conditions. Bacterial metabolite ILA was implicated in this protection, and beneficial effects were observed in a mouse model of colitis. The AOS scaled reproducibly to 96-well plates, providing the capacity for future mid-throughput screening of microbes and microbial metabolites under physiologically relevant conditions.