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Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (15 May 2022) | Viewed by 35129

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Special Issue Editor

Dr. Laura Grasa

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Guest Editor

Unit of Physiology, Faculty of Veterinary Medicine, University of Zaragoza, 50013 Zaragoza, Spain
Interests: gastroenterology; intestine; intestinal microbiota; intestinal inflammation; TLR signaling; serotoninergic system; intestinal motility; colon cancer; metallodrugs; nanomolecules
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the intestine, involving complex interactions between host and microbiota.

The composition of the microbiota can be influenced by a variety of environmental factors, including diet, antibiotics, stress, etc. An intestinal dysbiosis may induce aberrant interactions between gut epithelium and microbiota and result in inflammatory responses to commensal microbes. Among the action mechanisms implicated in these inflammatory responses are those involved in intestinal barrier function, innate immune recognition of microbial ligands (TLR, NOD receptors), antigen presentation, T-cell immunity, autophagy, reactive oxygen generation, goblet cell/mucin production, antimicrobial peptides, Paneth cells or inflammatory mediator production.

In this Special Issue of Cells, I invite you to contribute original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “Molecular Mechanisms Involved in Chronic Intestinal Diseases in Response to Microbiota”. Expert articles describing mechanistic, functional, cellular, biochemical, or general aspects of intestinal inflammation in response to microbiota are highly welcome. Relevant topics include but are not limited to:

Microbiota;

Immunology in IBD;

Intestinal inflammation;

Cytokine signaling;

Pattern recognition receptors (TLR, NOD, RLR, CLR);

Oxidative stress;

Autophagy;

Antimicrobial peptides;

Mucin production;

Paneth cells;

Prebiotics;

Probiotics;

In vitro and in vivo models.

Dr. Laura Grasa
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 193 KiB

Open AccessEditorial

Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota

by Laura Grasa

Cells 2022, 11(23), 3722; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11233722 - 22 Nov 2022

Viewed by 729

Abstract

Chronic disorders of the intestine, such as inflammatory bowel diseases (IBDs) and irritable bowel syndrome (IBS), involve complex interactions between host and microbiota [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota)

Research

Jump to: Editorial, Review

17 pages, 2896 KiB

Open AccessArticle

Sympathetic Innervation Modulates Mucosal Immune Homeostasis and Epithelial Host Defense

by Shilpashree Mallesh, Anne S. Ten Hove, Reiner Schneider, Bianca Schneiker, Patrik Efferz, Jörg C. Kalff, Wouter J. de Jonge and Sven Wehner

Cells 2022, 11(16), 2606; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11162606 - 21 Aug 2022

Cited by 5 | Viewed by 2240

Abstract

Intestinal mucosal cells, such as resident macrophages and epithelial cells, express adrenergic receptors and are receptive to norepinephrine, the primary neurotransmitter of the sympathetic nervous system (SNS). It has been suggested that the SNS affects intestinal immune activity in conditions, such as inflammatory bowel disease; however, the underlying mechanisms remain ambiguous. Here, we investigated the effect of SNS on mucosal immune and epithelial cell functions. We employed 6-OHDA-induced sympathetic denervation (cSTX) to characterize muscularis-free mucosal transcriptomes by RNA-seq and qPCR, and quantified mucosal immune cells by flow cytometry. The role of norepinephrine and cytokines on epithelial functions was studied using small intestinal organoids. cSTX increased the presence of activated CD68⁺CD86⁺ macrophages and monocytes in the mucosa. In addition, through transcriptional profiling, the proinflammatory cytokines IL-1β, TNF-α, and IFN-γ were induced, while Arg-1 and CD163 expression was reduced. Further, cSTX increased intestinal permeability in vivo and induced genes involved in barrier integrity and antimicrobial defense. In intestinal organoids, similar alterations were observed after treatment with proinflammatory cytokines, but not norepinephrine. We conclude that a loss in sympathetic input induces a proinflammatory mucosal state, leading to reduced epithelial barrier functioning and enhanced antimicrobial defense. This implies that the SNS might be required to maintain intestinal immune functions during homeostasis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota)

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21 pages, 3686 KiB

Open AccessArticle

Tetragenococcus halophilus Alleviates Intestinal Inflammation in Mice by Altering Gut Microbiota and Regulating Dendritic Cell Activation via CD83

by S. M. Shamsul Islam, Hye-Myung Ryu and Seonghyang Sohn

Cells 2022, 11(12), 1903; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11121903 - 12 Jun 2022

Cited by 9 | Viewed by 2346

Abstract

Ulcerative colitis (UC) is one of the major subtypes of inflammatory bowel disease with unknown etiology. Probiotics have recently been introduced as a treatment for UC. Tetragenococcus halophilus (T. halophilus) is a lactic acid-producing bacterium that survives in environments with high salt concentrations, though little is known about its immunomodulatory function as a probiotic. The purpose of this study is to determine whether T. halophilus exerts an anti-inflammatory effect on intestinal inflammation in mice. Colitis was induced in C57BL/6J mice by feeding 4% DSS in drinking water for 7 days. T. halophilus was orally administered with DSS. Anti-inflammatory functions were subsequently evaluated by flow cytometry, qRT-PCT, and ELISA. Gut microbial composition was analyzed by 16S rRNA metagenomic analysis. DSS-induced colitis mice treated with T. halophilus showed less weight loss and significantly suppressed colonic shortening compared to DSS-induced colitis mice. T. halophilus significantly reduced the frequency of the dendritic cell activation molecule CD83 in peripheral blood leukocytes and intestinal epithelial lymphocytes. Frequencies of CD8+NK1.1+ cells decreased in mice with colitis after T. halophilus treatment and IL-1β levels were also reduced. Alteration of gut microbiota was observed in mice with colitis after administration of T. halophilus. These results suggest T. halophilus is effective in alleviating DSS-induced colitis in mice by altering immune regulation and gut microbiome compositions. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota)

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13 pages, 2585 KiB

Open AccessFeature PaperArticle

TLR2 and TLR4 Modulate Mouse Ileal Motility by the Interaction with Muscarinic and Nicotinic Receptors

by Elena Layunta, Raquel Forcén and Laura Grasa

Cells 2022, 11(11), 1791; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11111791 - 30 May 2022

Cited by 2 | Viewed by 1882

Abstract

Irritable bowel syndrome (IBS) is a chronic functional bowel disorder characterized by intestinal dysmotility. Changes in intestinal microbiota (dysbiosis) can lead to alterations in neuro-muscular functions in the gut. Toll-like receptors (TLRs) 2 and 4 recognize intestinal bacteria and are involved in the motor response induced by gastrointestinal (GI) neurotransmitters. Acetylcholine (ACh) is a well-known neurotransmitter involved in the regulation of GI motility. This study aimed to evaluate the role of TLR2 and TLR4 in the intestinal motor-response induced by ACh in the mouse ileum, as well as the expression and function of the muscarinic and nicotinic ACh receptors. Muscle contractility studies showed that the contractions induced by ACh were significantly lower in TLR2^−/− and TLR4^−/− with respect to WT mice. In WT mice, the contractions induced by ACh were reduced in the presence of AF-DX AF-DX 116 (a muscarinic ACh receptor (mAChR) M2 antagonist), 4-DAMP (a mAChR M3 antagonist), mecamylamine (a nicotinic AChR receptor (nAChR) α3β4 antagonist) and α-bungarotoxin (a nAChR α7 antagonist). In TLR2^−/− mice, the contractions induced by ACh were increased by AF-DX 116 and mecamylamine. In TLR4^−/− mice, the contractions induced by ACh were reduced by α-bungarotoxin and 4-DAMP. The mRNA and protein expressions of M3 and α3 receptors were diminished in the ileum from TLR2^−/− and TLR4^−/− with respect to WT mice. However, the levels of mRNA and protein of β4 were diminished only in TLR4^−/− but not in TLR2^−/− mice. In conclusion, our results show that TLR2 and TLR4 modulates the motor responses to ACh in the mouse ileum. TLR2 acts on muscarinic M2 and M3 and nicotinic α3β4 ACh receptors, while TLR4 acts on muscarinic M3 and nicotinic α3β4 and α7 ACh receptors. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota)

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Graphical abstract

24 pages, 5282 KiB

Open AccessArticle

Probiotics Function as Immunomodulators in the Intestine in C57Bl/6 Male Mice Exposed to Inhaled Diesel Exhaust Particles on a High-Fat Diet

by Danielle T. Phillippi, Sarah Daniel, Kayla N. Nguyen, Bea Angella Penaredondo and Amie K. Lund

Cells 2022, 11(9), 1445; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11091445 - 25 Apr 2022

Cited by 8 | Viewed by 2735

Abstract

Epidemiological studies reveal a correlation between air pollution exposure and gastrointestinal (GI) diseases, yet few studies have investigated the role of inhaled particulate matter on intestinal integrity in conjunction with a high-fat (HF) diet. Additionally, there is currently limited information on probiotics in mitigating air-pollutant responses in the intestines. Thus, we investigated the hypothesis that exposure to inhaled diesel exhaust particles (DEP) and a HF diet can alter intestinal integrity and inflammation, which can be attenuated with probiotics. 4–6-w-old male C57Bl/6 mice on a HF diet (45% kcal fat) were randomly assigned to be exposed via oropharyngeal aspiration to 35 µg of DEP suspended in 35 µL of 0.9% sterile saline or sterile saline (CON) only twice a week for 4 w. A subset of mice was treated with 0.3 g/day of Winclove Ecologic^® barrier probiotics (PRO) in drinking water throughout the duration of the study. Our results show that DEP exposure ± probiotics resulted in increased goblet cells and mucin (MUC)-2 expression, as determined by AB/PAS staining. Immunofluorescent quantification and/or RT-qPCR showed that DEP exposure increases claudin-3, occludin, zona occludens (ZO)-1, matrix metalloproteinase (MMP)-9, and toll-like receptor (TLR)-4, and decreases tumor necrosis factor (TNF)-α and interleukin (IL)-10 expression compared to CON. DEP exposure + probiotics increases expression of claudin-3, occludin, ZO-1, TNF-α, and IL-10 and decreases MMP-9 and TLR-4 compared to CON + PRO in the small intestine. Collectively, these results show that DEP exposure alters intestinal integrity and inflammation in conjunction with a HF diet. Probiotics proved fundamental in understanding the role of the microbiome in protecting and altering inflammatory responses in the intestines following exposure to inhaled DEP. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota)

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13 pages, 9125 KiB

Open AccessArticle

Next- and Third-Generation Sequencing Outperforms Culture-Based Methods in the Diagnosis of Ascitic Fluid Bacterial Infections of ICU Patients

by Hanna Goelz, Simon Wetzel, Negin Mehrbarzin, Stefan Utzolino, Georg Häcker and Mohamed Tarek Badr

Cells 2021, 10(11), 3226; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113226 - 18 Nov 2021

Cited by 11 | Viewed by 3273

Abstract

Objectives: Infections of the ascitic fluid are serious conditions that require rapid diagnosis and treatment. Ascites is often accompanied by other critical pathologies such as gastrointestinal bleeding and bowel perforation, and infection increases the risk of mortality in intensive care patients. Owing to a relatively low success rate of conventional culture methods in identifying the responsible pathogens, new methods may be helpful to guide antimicrobial therapy and to refine empirical regimens. Here, we aim to assess outcomes and to identify responsible pathogens in ascitic fluid infections, in order to improve patients’ care and to guide empirical therapy. Methods: Between October 2019 and March 2021, we prospectively collected 50 ascitic fluid samples from ICU patients with suspected infection. Beside standard culture-based microbiology methods, excess fluid underwent DNA isolation and was analyzed by next- and third-generation sequencing (NGS) methods. Results: NGS-based methods had higher sensitivity in detecting additional pathogenic bacteria such as E. faecalis and Klebsiella in 33 out of 50 (66%) ascitic fluid samples compared with culture-based methods (26%). Anaerobic bacteria were especially identified by sequencing-based methods in 28 samples (56%), in comparison with only three samples in culture. Analysis of clinical data showed a correlation between sequencing results and various clinical parameters such as peritonitis and hospitalization outcomes. Conclusions: Our results show that, in ascitic fluid infections, NGS-based methods have a higher sensitivity for the identification of clinically relevant pathogens than standard microbiological culture diagnostics, especially in detecting hard-to-culture anaerobic bacteria. Patients with such infections may benefit from the use of NGS methods by the possibility of earlier and better targeted antimicrobial therapy, which has the potential to lower the high morbidity and mortality in critically ill patients with ascitic bacterial infection. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota)

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21 pages, 3625 KiB

Open AccessFeature PaperArticle

Fecal Microbiome Changes and Specific Anti-Bacterial Response in Patients with IBD during Anti-TNF Therapy

by Dagmar Schierova, Radka Roubalova, Martin Kolar, Zuzana Stehlikova, Filip Rob, Zuzana Jackova, Stepan Coufal, Tomas Thon, Martin Mihula, Martin Modrak, Miloslav Kverka, Lukas Bajer, Klara Kostovcikova, Pavel Drastich, Jana Hercogova, Michaela Novakova, Martin Vasatko, Milan Lukas, Helena Tlaskalova-Hogenova and Zuzana Jiraskova Zakostelska

Cells 2021, 10(11), 3188; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113188 - 16 Nov 2021

Cited by 14 | Viewed by 3672

Abstract

Inflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract that have been linked to microbiome dysbiosis and immune system dysregulation. We investigated the longitudinal effect of anti-TNF therapy on gut microbiota composition and specific immune response to commensals in IBD patients. The study included 52 patients tracked over 38 weeks of therapy and 37 healthy controls (HC). To characterize the diversity and composition of the gut microbiota, we used amplicon sequencing of the V3V4 region of 16S rRNA for the bacterial community and of the ITS1 region for the fungal community. We measured total antibody levels as well as specific antibodies against assorted gut commensals by ELISA. We found diversity differences between HC, Crohn’s disease, and ulcerative colitis patients. The bacterial community of patients with IBD was more similar to HC at the study endpoint, suggesting a beneficial shift in the microbiome in response to treatment. We identified factors such as disease severity, localization, and surgical intervention that significantly contribute to the observed changes in the gut bacteriome. Furthermore, we revealed increased IgM levels against specific gut commensals after anti-TNF treatment. In summary, this study, with its longitudinal design, brings insights into the course of anti-TNF therapy in patients with IBD and correlates the bacterial diversity with disease severity in patients with ulcerative colitis (UC). Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota)

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16 pages, 1889 KiB

Open AccessArticle

Metagenomic Profiling of Fecal-Derived Bacterial Membrane Vesicles in Crohn’s Disease Patients

by Nader Kameli, Heike E. F. Becker, Tessa Welbers, Daisy M. A. E. Jonkers, John Penders, Paul Savelkoul and Frank R. Stassen

Cells 2021, 10(10), 2795; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102795 - 19 Oct 2021

Cited by 5 | Viewed by 2474

Abstract

Background: In the past, many studies suggested a crucial role for dysbiosis of the gut microbiota in the etiology of Crohn’s disease (CD). However, despite being important players in host–bacteria interaction, the role of bacterial membrane vesicles (MV) has been largely overlooked in the pathogenesis of CD. In this study, we addressed the composition of the bacterial and MV composition in fecal samples of CD patients and compared this to the composition in healthy individuals. Methods: Fecal samples from six healthy subjects (HC) in addition to twelve CD patients (six active, six remission) were analyzed in this study. Fecal bacterial membrane vesicles (fMVs) were isolated by a combination of ultrafiltration and size exclusion chromatography. DNA was obtained from the fMV fraction, the pellet of dissolved feces as bacterial DNA (bDNA), or directly from feces as fecal DNA (fDNA). The fMVs were characterized by nanoparticle tracking analysis and cryo-electron microscopy. Amplicon sequencing of 16s rRNA V4 hypervariable gene regions was conducted to assess microbial composition of all fractions. Results: Beta-diversity analysis showed that the microbial community structure of the fMVs was significantly different from the microbial profiles of the fDNA and bDNA. However, no differences were observed in microbial composition between fDNA and bDNA. The microbial richness of fMVs was significantly decreased in CD patients compared to HC, and even lower in active patients. Profiling of fDNA and bDNA demonstrated that Firmicutes was the most dominant phylum in these fractions, while in fMVs Bacteroidetes was dominant. In fMV, several families and genera belonging to Firmicutes and Proteobacteria were significantly altered in CD patients when compared to HC. Conclusion: The microbial alterations of MVs in CD patients particularly in Firmicutes and Proteobacteria suggest a possible role of MVs in host-microbe symbiosis and induction or progression of inflammation in CD pathogenesis. Yet, the exact role for these fMV in the pathogenesis of the disease needs to be elucidated in future studies. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota)

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Review

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17 pages, 1818 KiB

Open AccessReview

Colonic Fluid and Electrolyte Transport 2022: An Update

by Abel B. Negussie, Annika C. Dell, Bruce A. Davis and John P. Geibel

Cells 2022, 11(10), 1712; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101712 - 22 May 2022

Cited by 13 | Viewed by 5773

Abstract

Colonic epithelial cells are responsible for maintaining a delicate balance between luminal secretion and the absorption of fluids and ions. This review aims to discuss and update the model of colonic electrolyte secretion and absorption via the cystic fibrosis transmembrane regulator (CFTR), epithelial sodium channel (ENaC), Na-K-Cl cotransporters (NKCC1 and 2), Na-H exchangers (NHE1–4), colonic H,KATPase, and several other key components involved in multi-level transepithelial ion transport. Developments in our understanding of the activity, regulation, localization, and relationships of these ion transporters and their interactions have helped forge a more robust understanding of colonic ion movement that accounts for the colonic epithelium’s role in mucosal pH modulation, the setting of osmotic gradients pivotal for fluid retention and secretion, and cell death regulation. Deviations from homeostatic ion transport cause diarrhea, constipation, and epithelial cell death and contribute to cystic fibrosis, irritable bowel syndrome (IBS), ulcerative colitis, and cancer pathologies. Signal transduction pathways that regulate electrolyte movement and the regulatory relationships between various sensors and transporters (CFTR as a target of CaSR regulation and as a regulator of ENaC and DRA, for example) are imperative aspects of a dynamic and comprehensive model of colonic ion homeostasis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota)

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10 pages, 898 KiB

Open AccessReview

Bile Acids: Key Players in Inflammatory Bowel Diseases?

by Aicha Kriaa, Vincent Mariaule, Amin Jablaoui, Soufien Rhimi, Hela Mkaouar, Juan Hernandez, Brice Korkmaz, Adam Lesner, Emmanuelle Maguin, Ali Aghdassi and Moez Rhimi

Cells 2022, 11(5), 901; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11050901 - 05 Mar 2022

Cited by 19 | Viewed by 6180

Abstract

Inflammatory bowel diseases (IBDs) have emerged as a public health problem worldwide with a limited number of efficient therapeutic options despite advances in medical therapy. Although changes in the gut microbiota composition are recognized as key drivers of dysregulated intestinal immunity, alterations in bile acids (BAs) have been shown to influence gut homeostasis and contribute to the pathogenesis of the disease. In this review, we explore the interactions involving BAs and gut microbiota in IBDs, and discuss how the gut microbiota–BA–host axis may influence digestive inflammation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota)

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20 pages, 607 KiB

Open AccessReview

An Update on the Role of Extracellular Vesicles in the Pathogenesis of Necrotizing Enterocolitis and Inflammatory Bowel Diseases

by Rafał Filip

Cells 2021, 10(11), 3202; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113202 - 17 Nov 2021

Cited by 16 | Viewed by 2787

Abstract

Some of the most fundamental influences of microorganisms inhabiting the human intestinal tract are exerted during infant development and impact the maturation of intestinal mucosa and gut immune system. The impact of bacteria on the host gut immune system is partially mediated via released extracellular vesicles (EVs). The heterogeneity in EV content, size, and bacterial species origin can have an impact on intestinal cells, resulting in inflammation and an immune response, or facilitate pathogen entry into the gut wall. In mammals, maintaining the integrity of the gut barrier might also be an evolutionary function of maternal milk EVs. Recently, the usage of EVs has been explored as a novel therapeutic approach in several pathological conditions, including necrotizing enterocolitis (NEC) and inflammatory bowel disease (IBD). In this review, we attempt to summarize the current knowledge of EV biology, followed by a discussion of the role that EVs play in gut maturation and the pathogenesis of NEC and IBD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota)

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