Intestinal mucus affinity and biological activity of an orally administered antibacterial and anti-inflammatory peptide

Abstract

Our findings demonstrate the anti-inflammatory activity and mucus affinity of the synthetic AMP Pep19-2.5 and characterise the influence on microbiota composition and enteropathogen infection after oral administration.

Antimicrobial peptides and the enteric mucus layer act in concert to protect the intestinal mucosa

“…peptide-mucin interaction does not affect peptide activity and is reversible. 2,13 In accordance, cryptdin-coated bacteria were visualized within the mucus layer.…”

“…Despite these technical obstacles, a number of studies during the past decade have revealed the synthesis and structural organization of the mucus matrix and its critical role during homeostasis and antimicrobial host defense. [1][2][3] Using the mucus preserving Carnoy fixative, Matsuo et al and Swidsinski et al demonstrated the existence of a bacteria-free zone separating the enteric epithelium from the microbiota. [4][5] Later, Johansson et al showed the presence of bacteria within the outer, but not the inner, colonic mucus layer consistent with the finding that mucus represents an important nutrient source of enteric commensals.…”

“…2 In the small intestine, Paneth cells situated at the crypt basis are the main producers of antimicrobial peptides, mainly a-defensins and cryptdin related sequence (CRS) peptides as well as lysozyme. Lack of proteolytic defensin maturation or transgene expression of human defensin (HD) 5 in mice alters the susceptibility to enteropathogenic infection as well as the microbiota composition.…”

“…22 The positively charged antimicrobial peptides appear not to diffuse into the gut lumen but to remain attached to the polyanionic sulfated and sialylated mucin glycoproteins. 1,2,13 The enrichment of antimicrobial peptides within the mucus layer facilitates the peptide concentrations required to efficiently kill bacteria and simultaneously reduces the pressure on luminal commensal bacteria to acquire resistance. The antimicrobial Figure 1.…”

“…2,24,25 The presence of antimicrobial peptides in bacteria/host cell co-cultures simultaneously caused bacterial killing and abrogated the cellular innate immune response. 2 With respect to the enteric mucus layer, this could allow immunologically "silent" killing and help to restrict the proinflammatory activity of microbiota-derived immunostimulatory molecules to the gut lumen. Consistent with this hypothesis, a 1000-fold gradient of the endotoxin concentration was found between the intestinal lumen and the epithelial cell layer.…”