Secreted enteric antimicrobial activity localises to the mucus surface layer

Meyer‐Hoffert, Ulf; Hornef, Mathias W.; Henriques‐Normark, Birgitta; Axelsson, Lars-Göran; Midtvedt, Tore; Pütsep, Katrin; Andersson, Mats

doi:10.1136/gut.2007.141481

Cited by 249 publications

(193 citation statements)

References 50 publications

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“…As bacteria must become mucosa associated before uptake by DCs for translocation to MLN or before invasion into the lamina propria, Paneth cells could limit bacterial penetration of host tissues by controlling the numbers of mucosa-associated bacteria. This idea is consistent with the fact that secreted Paneth cell antibacterial factors are retained by the mucus layer that overlies the intestinal epithelium, but are virtually absent from luminal content (29). This relatively impermeable mucus barrier may thus define a confined space that allows the host to specifically monitor and regulate bacteria that are in close contact with the intestinal surface.…”

Section: Discussionsupporting

confidence: 62%

Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface

Vaishnava¹,

Behrendt²,

Ismail³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

877

751

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The intestinal epithelium is in direct contact with a vast microbiota, yet little is known about how epithelial cells defend the host against the heavy bacterial load. To address this question we studied Paneth cells, a key small intestinal epithelial lineage. We found that Paneth cells directly sense enteric bacteria through cell-autonomous MyD88-dependent toll-like receptor (TLR) activation, triggering expression of multiple antimicrobial factors. Paneth cells were essential for controlling intestinal barrier penetration by commensal and pathogenic bacteria. Furthermore, Paneth cell-intrinsic MyD88 signaling limited bacterial penetration of host tissues, revealing a role for epithelial MyD88 in maintaining intestinal homeostasis. Our findings establish that gut epithelia actively sense enteric bacteria and play an essential role in maintaining host-microbial homeostasis at the mucosal interface.commensal bacteria ͉ epithelium ͉ innate immunity ͉ intestine ͉ toll-like receptors H umans harbor nearly 100 trillion intestinal bacteria that are essential for health. Millions of years of coevolution have molded this human-microbe interaction into a symbiotic relationship in which gut bacteria make essential contributions to human nutrient metabolism and in return occupy a nutrient-rich environment (1). However, bacterial invasion of tissue can result in breakdown of this symbiotic association and lead to pathologies such as inflammatory bowel disease (2). Intestinal epithelia constitute the major interface between the microbiota and internal host tissues. Despite the enormous numbers of commensal bacteria, microbial incursions across mucosal surfaces are relatively rare, suggesting that intestinal epithelia harbor highly effective mechanisms for controlling microbial interactions with the host mucosal interface. However, little is known about how intestinal epithelial cells maintain homeostasis with vast, complex populations of enteric bacteria.The Paneth cell is a specialized small intestinal epithelial lineage that resides at the base of crypts of Lieberkühn and contributes to intestinal innate immunity by secreting a diverse repertoire of antimicrobial proteins (3). Several antimicrobial factors in Paneth cells are expressed under the control of indigenous microorganisms (4, 5). In addition, ex vivo studies on isolated small intestinal crypts indicate that secretion of antimicrobial products is triggered by bacterial signals (3). However, itis not yet clear whether Paneth cells detect bacteria through cell-autonomous mechanisms. Furthermore, although Paneth cells are known to secrete abundant antimicrobial factors (3), the in vivo functional role of Paneth cells in maintaining homeostasis with commensal bacterial populations has not been established.In this report, we show that Paneth cells detect enteric bacteria through cell-autonomous MyD88 activation, triggering expression of multiple antimicrobial factors. We show that Paneth cell-intrinsic MyD88 signaling limits bacterial penetration of host tissues, disclo...

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Section: Discussionsupporting

confidence: 62%

Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface

Vaishnava¹,

Behrendt²,

Ismail³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

877

751

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“…Then the surviving bacilli travel to the colon carried by the mucous flow, rich with HD5 and other AMPs (62), which constrains their replicative capacity and protects the host from C. difficile colonization. This hypothesis is supported by experiments showing that HD5 persists in an intact and functional form throughout the all intestinal tract, including the colon (52), and is active throughout a broad pH range (pH 5.5 to 8.0) (36).…”

Section: Discussionmentioning

confidence: 99%

New Role for Human α-Defensin 5 in the Fight against Hypervirulent Clostridium difficile Strains

et al. 2015

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Clostridium difficile infection (CDI), one of the most common hospital-acquired infections, is increasing in incidence and severity with the emergence and diffusion of hypervirulent strains. CDI is precipitated by antibiotic treatment that destroys the equilibrium of the gut microbiota. Human ␣-defensin 5 (HD5), the most abundant enteric antimicrobial peptide, is a key regulator of gut microbiota homeostasis, yet it is still unknown if C. difficile, which successfully evades killing by other host microbicidal peptides, is susceptible to HD5. We evaluated, by means of viability assay, fluorescence-activated cell sorter (FACS) analysis, and electron microscopy, the antimicrobial activities of ␣-defensins 1 and 5 against a panel of C. difficile strains encompassing the most prevalent epidemic and hypervirulent PCR ribotypes in Europe (012, 014/020, 106, 018, 027, and 078). Here we show that (i) concentrations of HD5 within the intestinal physiological range produced massive C. difficile cell killing; (ii) HD5 bactericidal activity was mediated by membrane depolarization and bacterial fragmentation with a pattern of damage peculiar to C. difficile bacilli, compared to commensals like Escherichia coli and Enterococcus faecalis; and (iii) unexpectedly, hypervirulent ribotypes were among the most susceptible to both defensins. These results support the notion that HD5, naturally present at very high concentrations in the mucosa of the small intestine, could indeed control the very early steps of CDI by killing C. difficile bacilli at their germination site. As a consequence, HD5 can be regarded as a good candidate for the containment of hypervirulent C. difficile strains, and it could be exploited in the therapy of CDI and relapsing C. difficile-associated disease.

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“…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.…”

mentioning

confidence: 99%

“…1,13 Immunostaining and proteomic analysis of the intestinal mucus identified lysozyme as well as a number of antimicrobial peptides with well-known antibacterial function in the mucus layer (see Table 1). …”

mentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Dupont¹,

et al. 2014

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Secreted enteric antimicrobial activity localises to the mucus surface layer

Cited by 249 publications

References 50 publications

Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface

Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface

New Role for Human α-Defensin 5 in the Fight against Hypervirulent Clostridium difficile Strains

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

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