The pathogenesis of inflammatory bowel disease (IBD) is multifactorial with data suggesting the role of a disturbed interaction between the gut and the intestinal microbiota. A defective mucosal barrier may result in increased intestinal permeability which promotes the exposition to luminal content and triggers an immunological response that promotes intestinal inflammation. IBD patients display several defects in the many specialized components of mucosal barrier, from the mucus layer composition to the adhesion molecules that regulate paracellular permeability. These alterations may represent a primary dysfunction in Crohn's disease, but they may also perpetuate chronic mucosal inflammation in ulcerative colitis. In clinical practice, several studies have documented that changes in intestinal permeability can predict IBD course. Functional tests, such as the sugar absorption tests or the novel imaging technique using confocal laser endomicroscopy, allow an in vivo assessment of gut barrier integrity. Antitumor necrosis factor-α (TNF-α) therapy reduces mucosal inflammation and restores intestinal permeability in IBD patients. Butyrate, zinc, and some probiotics also ameliorate mucosal barrier dysfunction but their use is still limited and further studies are needed before considering permeability manipulation as a therapeutic target in IBD.

/pdf/intestinal-permeability-in-inflammatory-bowel-disease-29lofcdzjy.pdf

Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut

The intestine is a unique organ inhabited by a tremendous number of microorganisms Intestinal epithelial cells greatly contribute to the maintenance of the symbiotic relationship between gut microbiota and the host by constructing mucosal barriers, secreting various immunological mediators and delivering bacterial antigens Mucosal barriers, including physical barriers and chemical barriers, spatially segregate gut microbiota and the host immune system to avoid unnecessary immune responses to gut microbes, leading to the intestinal inflammation In addition, various immunological mediators, including cytokines and chemokines, secreted from intestinal epithelial cells stimulated by gut microbiota modulate host immune responses, maintaining a well-balanced relationship between gut microbes and the host immune system Therefore, impairment of the innate immune functions of intestinal epithelial cells is associated with intestinal inflammation

/pdf/roles-of-intestinal-epithelial-cells-in-the-maintenance-of-1vniz7wvh2.pdf

Roles of intestinal epithelial cells in the maintenance of gut homeostasis.

The gut barrier plays a crucial role by spatially compartmentalizing bacteria to the lumen through the production of secreted mucus and is fortified by the production of secretory IgA (sIgA) and antimicrobial peptides and proteins. With the exception of sIgA, expression of these protective barrier factors is largely controlled by innate immune recognition of microbial molecular ligands. Several specialized adaptations and checkpoints are operating in the mucosa to scale the immune response according to the threat and prevent overreaction to the trillions of symbionts inhabiting the human intestine. A healthy microbiota plays a key role influencing epithelial barrier functions through the production of short-chain fatty acids (SCFAs) and interactions with innate pattern recognition receptors in the mucosa, driving the steady-state expression of mucus and antimicrobial factors. However, perturbation of gut barrier homeostasis can lead to increased inflammatory signaling, increased epithelial permeability, and dysbiosis of the microbiota, which are recognized to play a role in the pathophysiology of a variety of gastrointestinal disorders. Additionally, gut-brain signaling may be affected by prolonged mucosal immune activation, leading to increased afferent sensory signaling and abdominal symptoms. In turn, neuronal mechanisms can affect the intestinal barrier partly by activation of the hypothalamus-pituitary-adrenal axis and both mast cell-dependent and mast cell-independent mechanisms. The modulation of gut barrier function through nutritional interventions, including strategies to manipulate the microbiota, is considered a relevant target for novel therapeutic and preventive treatments against a range of diseases. Several biomarkers have been used to measure gut permeability and loss of barrier integrity in intestinal diseases, but there remains a need to explore their use in assessing the effect of nutritional factors on gut barrier function. Future studies should aim to establish normal ranges of available biomarkers and their predictive value for gut health in human cohorts.

https://www.physiology.org/doi/pdf/10.1152/ajpgi.00048.2015

Homeostasis of the Gut Barrier and Potential Biomarkers.

The intestine is inhabited by a tremendous number of microorganisms, which provide many benefits to nutrition, metabolism and immunity. Mucosal barriers by intestinal epithelial cells make it possible to maintain the symbiotic relationship between the gut microbiota and the host by separating them. Recent evidence indicates that mucosal barrier dysfunction contributes to the development of inflammatory bowel disease (IBD). In this review, we focus on the mechanisms by which mucosal barriers maintain gut homeostasis. Gut mucosal barriers are classified into chemical and physical barriers. Chemical barriers, including antimicrobial peptides (AMPs), are chemical agents that attack invading microorganisms, and physical barriers, including the mucus layer and the cell junction, are walls that physically repel invading microorganisms. These barriers, which are ingeniously modulated by gut microbiota and host immune cells, spatially segregate gut microbiota and the host immunity to avoid unnecessary immune responses to gut commensal microbes. Therefore, mucosal barrier dysfunction allows gut bacteria to invade gut mucosa, inducing excessive immune responses of the host immune cells, which result in intestinal inflammation. Gut mucosal barriers constructed by intestinal epithelial cells maintain gut homeostasis by segregating gut microbiota and host immune cells. Impaired mucosal barrier function contributes to the development of IBD. However, the mechanism by which the mucosal barrier is regulated by gut microbiota remains unclear. Thus, it should be further elucidated in the future to develop a novel therapeutic approach to IBD by targeting the mucosal barrier.

/pdf/maintenance-of-intestinal-homeostasis-by-mucosal-barriers-ess4dhdxbu.pdf

Maintenance of intestinal homeostasis by mucosal barriers.

https://escholarship.org/content/qt0rb2r6q2/qt0rb2r6q2.pdf?t=qmgkaj

Translocation of Viable Gut Microbiota to Mesenteric Adipose Drives Formation of Creeping Fat in Humans

Background
The intestinal barrier is a delicate structure composed of a single layer of epithelial cells, the mucus, commensal bacteria, immune cells, and antibodies. Furthermore, a wealth of antimicrobial peptides (AMPs) can be found in the mucus and defend the mucosa. Different lines of investigations now point to a prominent pathophysiological role of defensins, an important family of AMPs, in the pathogenesis of inflammatory bowel disease and, particularly, in small intestinal Crohn’s disease.

Inflammatory bowel disease: an impaired barrier disease

Acute and chronic inflammations of mucosal surfaces are complex events in which the effector mechanisms of innate and adaptive immune systems interact with pathogenic and commensal bacteria. The role of constitutive and inducible antimicrobial peptides in intestinal inflammation has been investigated thoroughly over the recent years, and their involvement in various disease states is expanded ever more. Especially in the intestines, a critical balance between luminal bacteria and the antimicrobial peptides is essential, and a breakdown in barrier function by impaired production of defensins is already implicated in Crohn's disease. In this paper, we focus on the role of antimicrobial peptides in inflammatory processes along the gastrointestinal tract, while considering the resident and pathogenic flora encountered at the specific sites. The role of antimicrobial peptides in the primary events of inflammatory bowel diseases receives special attention.

/pdf/antimicrobial-peptides-in-gastrointestinal-inflammation-4pe1a30bg3.pdf

Antimicrobial peptides in gastrointestinal inflammation.

We would like to comment on the comprehensive review of Karantanos and Gazouli in Annals of Gastroenterology [1] about genetics and innate immunity in inflammatory bowel disease (IBD).

The authors appreciate the important role of innate immune sensing and the production of antimicrobial peptides in maintaining the integrity of the mucosal barrier. Pertinent studies on the subject are presented and the authors concur with the current understanding of Crohn’s disease (CD) as the manifestation of an abnormal immune response to the intestinal microbiome in individuals with genetic susceptibility.

Yet, in our view, the body of literature justifies the proposition of an integrative model of pathogenesis for ileal CD (iCD), focusing on the role of the Paneth cell (PC) products, the α-defensins human defensin 5 (HD-5) and HD-6. Associations between PCs and defensins in small intestinal inflammation are plentiful, and we feel that in the interpretation by Karantanos’ article, this aspect is not given the due attention.

PCs, a characteristic epithelial cell line of the small intestine localized at the bottom of the intestinal crypts, constitutively secrete considerable amounts of antimicrobial peptides (AMP), the expression levels of α-defensins thereby exceeding those of other PC antimicrobials like lysozyme and sPLa2 by a factor of up to 100 [2].

Activation of pattern recognition receptors (e.g. Toll-like receptors, nucleotide-binding oligomerization domain (NOD)-like receptors, RIG-I-like receptors) by pathogen-associated molecular patterns (PAMPs, derived from resident and pathogenic bacteria) leads to the release of PC secretions into the intestinal lumen [3]. Expression of intracellular receptors like NOD2 itself depends on the presence of commensal bacteria [4]. In turn, the composition of microbial species found in the small intestinal lumen can be regulated by the luminal antimicrobials [2,5].

A link between NOD2 and iCD has already been demonstrated by Cuthbert et al [6] in 2002, when the mutations R702W, G908R and 3020insC were identified as strong independent risk factors (in patients of Caucasian descent). NOD2 protein and mRNA were found to be most prominently expressed in the terminal ileum, with localization to crypt base cells and mononuclear cells of the lamina propria [7]. Subsequent work from our group reported decreased α-defensin mRNA levels in ileal biopsy specimens, which were even more pronounced in patients carrying NOD2 mutations [8]. On a functional level, Petnicki-Ocweija et al showed that the bactericidal activity of crypt secretions of the terminal ileum was severely compromised by NOD2 deletion in a murine model [4]. Studies with other knock-out animals, lacking functional cryptdins (mouse-homologs to defensins are called cryptdins) due to deficiency of the cryptdin-processing enzyme matrilysin, revealed that intestinal crypt secretions had decreased antimicrobial activity [9], and that these mice are more susceptible to orally administered bacterial pathogens or to DSS-induced colitis.

NOD2 mutations are but one of the findings that underline the link between PC, defensins and iCD. In 2007, a genome-wide association study identified ATG16L1 as susceptibility locus for small intestinal CD [10]. ATG16L1 protein mediates degradation of phagocytosed or invasive bacteria, although it is commonly known for its involvement in autophagy, a process responsible for the degradation of intracellular structures. Cadwell et al provided evidence that in mice with conditional Atg16l1 knock-out, granule exocytosis is abnormal [11] and that in patients with the variant T300A, morphologic distortions in PC can be observed. As PC granules contain huge amounts of α-defensins, impaired exocytosis of these antimicrobials presumably weakens the mucosal barrier. This could explain part of the increased disease susceptibility found with mutations in ATG16L1, though other mechanisms for the phenotypic development of iCD with this genetic background have to be considered as well. ATG16L1 deficient macrophages for example exhibit proinflammatory properties [12], which points to an additional involvement of myeloid cells in disease pathogenesis.

A conditional deletion of X-Box binding protein (Xbp)-1 shed light on the association of Xbp-1 variants with IBD (CD and ulcerative colitis). Xbp-1 normally functions as transcription factor for the unfolded protein response under conditions of endoplasmic reticulum (ER) stress, maintaining proper folding, export and degradation of proteins by the ER. Knock-out of Xbp-1 in the intestinal epithelium led to spontaneous small bowel inflammation, altered PC morphology and a decreased antimicrobial activity of crypt secretions [13]. These findings furthermore support the concept that different genetic alterations lead to dysfunctional PCs, resulting in a weakened mucosal barrier and disease susceptibility.

Yet another association between iCD and defensins becomes apparent when alterations in the Wnt pathway, which governs PC differentiation [14], are considered. More specifically, the transcription factor TCF-4 has been linked to α-defensin expression, as heterozygous Tcf-4 knock-out mice with decreased levels of Tcf-4 exhibit compromised cryptdin expression and weakened antimicrobial activity of crypt extracts [15]. Furthermore, a reduced mRNA expression of Tcf-4 was observed in patients with iCD. Following investigations aimed at the regulatory regions of Tcf-4 revealed that in iCD, a SNP in the Tcf-4 promoter region (rs3814570) was significantly more frequent than in controls, solely colonic CD or ulcerative colitis [16]. Taken together, the genetic variant in the promoter of Tcf-4 gives a further rationale for the α-defensin deficiency in iCD on the basis of PC malfunction.

In a murine model, inhibition of the K+-pump/Ca2+ channel KCNN4, which regulates Ca2+-fluxes important for the secretion mechanisms for AMPs from PC, led to a reduced bactericidal activity and AMP secretion [17]. An association of the SNP r2306801 with CD in general, and with iCD the strongest, was recently observed in a combined cohort from Australia and New Zealand [18], though the reproduction of these results in a larger cohort is not yet available. KCNN4 mRNA expression in non-inflamed mucosal biopsies of individuals with NOD2 mutations was reduced, leading to the assumption that functional NOD2 is important for the expression of KCNN4.

All the mentioned different genetic variants and functional studies converge on the PC and its ability to provide the crypt lumen with functional antimicrobial peptides, which are, in the end, predominantly α-defensins. With this addendum, we depict our PC model of defensin deficiency in iCD (Fig.1), which respects the interplay between genetic variants, host factors like AMPs and the microbiome in the pathogenesis of small intestinal inflammation [19]. It should be noted that compromised defensin expression is also a feature of colonic CD [20], although the details are beyond the scope of this comment. We recommend that the important role of defensins in IBD pathogenesis should be given credit.



Figure 1

Paneth cells and granules at the crypt base. The original photograpy is from Josef Paneth‘s paper in Archiv fur mikroskopische Anatomie, 1888. The figure is adapted from Wehkamp J, Stange EF. Journal of Crohn’s and Colitis (2010). ...

/pdf/innate-immunity-includes-defensins-1cebr7qxo8.pdf

Innate immunity includes defensins

The pathogenesis of inflammatory bowel disease (IBD) is a complex and multifactorial process. In the last decades, IBD was thought to originate from dysregulation of adaptive immunity networks and classified as autoimmune disorder. Recent years have witnessed a revision of this dogma, and spurred by the findings of genome-wide association studies, defects in the mucosal barrier are now regarded as central to IBD pathogenesis. The major components of the barrier are the epithelial cell lining, the mucus layer, commensal bacteria, and an arsenal of antimicrobial peptides (AMPs). The expression pattern of these antimicrobials (e.g., defensins or cathelicidin-LL-37) in the human intestine has been elucidated over the last years, and numerous alterations were detected in IBD, especially in Crohn’s disease of the ileum. The α-defensin HD-5 is secreted in large quantities by Paneth cells, which are small epithelial cells at the bases of intestinal crypts. Variations in genes which show the highest linkage to Crohn’s disease affect proteins involved in Paneth cell degranulation. In addition to an outline of the strong associations between defective AMP secretion and ileal Crohn’s disease, defensin expression and function in colonic Crohn’s disease and ulcerative colitis will be covered in this chapter.

Antimicrobial Peptides and Inflammatory Bowel Disease

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Inflammatory bowel disease: an impaired barrier disease

Antimicrobial peptides in gastrointestinal inflammation.

Innate immunity includes defensins

Antimicrobial Peptides and Inflammatory Bowel Disease