Can probiotics modulate human disease by impacting intestinal barrier function?

Abstract

Intestinal barrier integrity is a prerequisite for homeostasis of mucosal function, which is balanced to maximise absorptive capacity, while maintaining efficient defensive reactions against chemical and microbial challenges. Evidence is mounting that disruption of epithelial barrier integrity is one of the major aetiological factors associated with several gastrointestinal diseases, including infection by pathogens, obesity and diabetes, necrotising enterocolitis, irritable bowel syndrome and inflammatory bowel disease. The notion that specific probiotic bacterial strains can affect barrier integrity fuelled research in which in vitro cell lines, animal models and clinical trials are used to assess whether probiotics can revert the diseased state back to homeostasis and health. This review catalogues and categorises the lines of evidence available in literature for the role of probiotics in epithelial integrity and, consequently, their beneficial effect for the reduction of gastrointestinal disease symptoms.

Keywords: CD Crohn’s disease; NEC necrotising enterocolitis; TJ tight junction; TLR Toll-like receptor; UC ulcerative colitis; Gastrointestinal disorders; Gut barrier; Gut microbiota; Immunity; Probiotics.

Fig. 1

Direct and indirect mechanisms by which commensals or probiotics can antagonise pathogens. Graphical display of exemplary direct (a) and indirect (b) mechanisms of barrier function modulation by bacterial (probiotic) interaction. (a) Direct mechanisms of barrier function modulation by interaction of commensals and probiotics. Bacteria can compete with enteric pathogens by competition for carbohydrates depending on the diet^{( 227 )}. A probiotic strain of Lactobacillus salivarius UCC118 produces a bacteriocin in vivo that can significantly protect mice against infection with the invasive foodborne pathogen Listeria monocytogenes ^{( 36 )}. In diverse Bacteroides species, a type VI secretion system (T6SS) mediates cell-contact-dependent mechanisms of inter-bacterial antagonism via the export antibacterial proteins^{( 228 )}. Probiotics have been shown to inhibit the colonisation of pathogens through competition for common receptors of adhesion^{( 48 )}. (b) Indirect mechanisms of pathogen antagonism. Recognition of microbe-associated molecular patterns by host pattern recognition receptors such as TLR and NLR activate immune defences and protect against infection. TLR signalling induces expression of defensins in enterocytes and antimicrobial factors in Paneth cells via the myeloid differentiation primary response 88 (MYD88) activation of NF-κB leading to the production of antimicrobial peptides. Similarly, nucleotide-binding oligomerisation domain 2 (NOD2) recognition of bacterial peptidoglycan induces cryptdin expression by Paneth cells. Sensing of an unknown signal from commensal microbes stimulates type 3 innate lymphoid cells (ILC) to secrete IL-22, which signals through the receptor (IL-22R) on intestinal epithelial cells to increase expression of the fucosyltransferase (FUT), mucin expression and antimicrobials, including regenerating family member 3 (Reg3) proteins. Segmented filamentous bacteria (SFB) closely associate with the ileum epithelium and stimulate maturation of the B- and T-cell compartments leading to enhanced IgA production by B cells and serum amyloid A (SAA)-dependent T helper 17 (Th17) cell differentiation. Th17 cells produce inflammatory cytokines and IL-22, which stimulate innate immune defence mechanisms to fight off infections.