Bifidobacterium brevereduces apoptotic epithelial cell shedding in an exopolysaccharide and MyD88-dependent manner

Abstract

Certain members of the microbiota genus Bifidobacterium are known to positively influence host well-being. Importantly, reduced bifidobacterial levels are associated with inflammatory bowel disease (IBD) patients, who also have impaired epithelial barrier function, including elevated rates of apoptotic extrusion of small intestinal epithelial cells (IECs) from villi—a process termed ‘cell shedding’. Using a mouse model of pathological cell shedding, we show that mice receiving Bifidobacterium breve UCC2003 exhibit significantly reduced rates of small IEC shedding. Bifidobacterial-induced protection appears to be mediated by a specific bifidobacterial surface exopolysaccharide and interactions with host MyD88 resulting in downregulation of intrinsic and extrinsic apoptotic responses to protect epithelial cells under highly inflammatory conditions. Our results reveal an important and previously undescribed role for B. breve, in positively modulating epithelial cell shedding outcomes via bacterial- and host-dependent factors, supporting the notion that manipulation of the microbiota affects intestinal disease outcomes.

The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

“…Many intestinal inflammatory disorders present clinically in adolescents and adults, and we have previously shown that it is possible to dampen down pathological cell shedding in adult mice by supplementing with an early life microbiota member (i.e. Bifidobacterium breve) [16]. However, it has been suggested that early life events, which directly impact the infant/neonatal microbiota (such as diet and antibiotics), may shape the initiation of inflammatory cascades and IEC barrier integrity [22].…”

“…We previously demonstrated that IP administration of LPS induced potent cell shedding in adult mice with peak response 90 minutes post injection as determined by cleaved caspase-3 (CC3) staining [16,19]. To assess cell shedding response of neonatal mice, 14 and 21 day old mice were administered with either low (1.25mg kg-1) or high (10mg kg-1) dose LPS (or PBS vehicle control) and sacrificed 90 minutes post-administration ( Figure 1A).…”

“…More recently, research, including our own, has shown important links between members of the intestinal microbiota and the cell shedding response in vivo, demonstrating that early life members of the gut microbial community (i.e. Bifidobacterium) can drive protection against pathological cell shedding in adult mice [16,17].…”

Exploring the role of the microbiota member Bifidobacterium in modulating immune-linked diseases

“…Further investigation is required to provide mechanistic correlation, but we hypothesise that bifidobacteria may potentially modulate foetal immune development at the very first stages of life. and links to specific bifidobacteria molecules [40,41], such as pili and exopolysaccharide (EPS), on immune responses [5,42,43]. However, it is apparent that the bifidobacteria-immune field requires a greater number of investigations detailing key mechanistic targets and pathways in different immune compartments and immune cell types.…”

“…In a mouse model of epithelial cell shedding, B. breve UCC2003 was shown to reduce the number of apoptotic IECs and corresponding apoptosis signalling molecules. This was mediated via the bifidobacterial EPS capsule and host immune-associated adaptor protein MyD88 [40]. In an IBD-like experimental model, administration of B. longum subsp.…”