G.I. pros: Antimicrobial defense in the gastrointestinal tract

Abstract

The gastrointestinal tract is a complex environment in which the host immune system interacts with a diverse array of microorganisms, both symbiotic and pathogenic. As such, mobilizing a rapid and appropriate antimicrobial response depending on the nature of each stimulus is crucial for maintaining the balance between homeostasis and inflammation in the gut. Here we focus on the mechanisms by which intestinal antimicrobial peptides regulate microbial communities during dysbiosis and infection. We also discuss classes of bacterial peptides that contribute to reducing enteric pathogen outgrowth. This review aims to provide a comprehensive overview on the interplay of diverse antimicrobial responses with enteric pathogens and the gut microbiota.

Keywords: Antimicrobial peptides; Bacteriocins; Enteric pathogens; Microbiota; Microcins; Nutritional immunity.

Figure 1. In vivo functions of intestinal antimicrobial peptides

(A) Paneth cell secretion of human defensin 5 (HD5) contributes to decreasing intestinal S. Typhimurium burden and (B) also strongly reduces the levels of commensal segmented filamentous bacteria (SFB). (C) Contrary to HD5, HD6 contributes to host defense against S. Typhimurium through formation of oligomers that entrap the pathogen. (D) Furthermore, mouse α-defensins (cryptdins) promote host defense against S. Typhimurium. (E) Epithelial cell-derived murine CRAMP (mCRAMP) contributes to killing of C. rodentium and enterohemorrhagic E. coli (EHEC). Robust production of interleukin (IL)-22 induces Paneth cells to express the C-type lectins RegIIIγ and RegIIIβ. (F) RegIIIγ maintains spatial separation between the microbiota and the epithelial cell layer and also facilitates clearance of pathogenic L. monocytogenes. (G) Members of the microbiota can furthermore induce the expression of RegIIIγ, which promotes resistance to Vancomycin-Resistant Enterococcus (VRE). (H) RegIIIβ is important for host protection against enteric Y. pseudotuberculosis but can also (I) target the enteric microbiota and consequently prolong S. Typhmurium infection. (J) Secretion of lysozyme by Paneth cells promote the reduction of intestinal S. Typhimurium burden. (K) Lastly, interferon gamma (IFNγ)-inducible chemokines, such as CXCL9, mediate clearance of the mouse pathogen C. rodentium by a mechanism independent of their chemotactic ability.

Figure 2. Mechanisms of nutritional immunity in the inflamed intestine

(A) During infection with enteric pathogens, high levels of interleukin (IL)-17 and IL-22 stimulate intestinal epithelial cells to express the antimicrobial protein calprotectin, which sequesters zinc and manganese, and lipocalin-2, which sequesters iron. (B) In addition, IL-17 and IL-22 also stimulate epithelial-dependent CXC-chemokine production, which recruit polymorphonucleaer cells (PMNs) to provide an additional source of lipocalin-2 and calprotectin. Nutrient-limitation by these two antimicrobial proteins restricts growth of the commensal microbiota. (C) However, successful pathogens like S. Typhimurium can overcome iron restriction by producing salmochelin, a “stealth” siderophore that is not bound by lipocalin-2. (D) Moreover, S. Typhimurium encodes high-affinity ZnuABC, MntH, SitABCD transporters to acquire zinc and manganese, which counteracts calprotectin-dependent sequestration of these metals.

Figure 3. Activity of bacterial-derived antimicrobial peptides in the intestine

Production of bacterocins from Gram-positive bacteria is typically a characteristic of probiotic strains. (A) Specifically, Abp118 of L. salivarius strain UCC118 is able to target pathogenic L. monocytogenes, while (B) B. thuringiensis DPC 6431 restricts C. difficile expansion through the activity of thuricin CD. (C) An E. faecalis strain ectopically expressing the bacteriocin Bac-21 is able to specifically target Vancomycin-Resistant Enterococcus (VRE) while maintaining the integrity of commensal bacteria. (D) In contrast to probiotic bacteria, some epidemic strains of the Listeria spp. produce Listeriolysin S (LLS) to promote virulence by targeting the host microbiota. Microcins are peptides from Gram-negative bacteria that are smaller than 10 kDa. (E) E. coli Nissle 1917 (EcN) synthesis of microcin M (MccM) and microcin H47 (MccH47) facilities clearance of pathogenic S. Typhimurium and adherent-invasive E. coli (AIEC) in the inflamed intestine, when iron is limited.