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Immunological Reviews Jul 2014The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins... (Review)
Review
The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins MUC2 and MUC5AC are the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate-keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103(+) type. In addition to the gel-forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy.
Topics: Animals; Enterocytes; Gastrointestinal Tract; Goblet Cells; Humans; Immune System; Mucins; Mucous Membrane; Mucus; Peyer's Patches
PubMed: 24942678
DOI: 10.1111/imr.12182 -
Advanced Drug Delivery Reviews Dec 2021The gastrointestinal tract (GIT) affects not only local diseases in the GIT but also various systemic diseases. Factors that can affect the health and disease of both... (Review)
Review
The gastrointestinal tract (GIT) affects not only local diseases in the GIT but also various systemic diseases. Factors that can affect the health and disease of both GIT and the human body include 1) the mucosal immune system composed of the gut-associated lymphoid tissues and the lamina propria, 2) the intestinal barrier composed of mucus and intestinal epithelium, and 3) the gut microbiota. Selective delivery of drugs, including antigens, immune-modulators, intestinal barrier enhancers, and gut-microbiome manipulators, has shown promising results for oral vaccines, immune tolerance, treatment of inflammatory bowel diseases, and other systemic diseases, including cancer. However, physicochemical and biological barriers of the GIT present significant challenges for successful translation. With the advances of novel nanomaterials, oral nanomedicine has emerged as an attractive option to not only overcome these barriers but also to selectively deliver drugs to the target sites in GIT. In this review, we discuss the GIT factors and physicochemical and biological barriers in the GIT. Furthermore, we present the recent progress of oral nanomedicine for oral vaccines, immune tolerance, and anti-inflammation therapies. We also discuss recent advances in oral nanomedicine designed to fortify the intestinal barrier functions and modulate the gut microbiota and microbial metabolites. Finally, we opine about the future directions of oral nano-immunotherapy.
Topics: Administration, Oral; Anti-Inflammatory Agents; Gastrointestinal Microbiome; Humans; Immune Tolerance; Immunity, Mucosal; Intestinal Mucosa; Mucous Membrane; Nanoparticle Drug Delivery System; Vaccines
PubMed: 34710529
DOI: 10.1016/j.addr.2021.114021 -
Cell Jan 2016Proper adaptation to environmental perturbations is essential for tissue homeostasis. In the intestine, diverse environmental cues can be sensed by immune cells, which...
Proper adaptation to environmental perturbations is essential for tissue homeostasis. In the intestine, diverse environmental cues can be sensed by immune cells, which must balance resistance to microorganisms with tolerance, avoiding excess tissue damage. By applying imaging and transcriptional profiling tools, we interrogated how distinct microenvironments in the gut regulate resident macrophages. We discovered that macrophages exhibit a high degree of gene-expression specialization dependent on their proximity to the gut lumen. Lamina propria macrophages (LpMs) preferentially expressed a pro-inflammatory phenotype when compared to muscularis macrophages (MMs), which displayed a tissue-protective phenotype. Upon luminal bacterial infection, MMs further enhanced tissue-protective programs, and this was attributed to swift activation of extrinsic sympathetic neurons innervating the gut muscularis and norepinephrine signaling to β2 adrenergic receptors on MMs. Our results reveal unique intra-tissue macrophage specialization and identify neuro-immune communication between enteric neurons and macrophages that induces rapid tissue-protective responses to distal perturbations.
Topics: Animals; Cell Line; Intestinal Mucosa; Intestine, Small; Macrophages; Mice; Mucous Membrane; Neuroimmunomodulation; Neurons; Receptors, Adrenergic, beta-2; Salmonella Infections; Salmonella typhimurium; Specific Pathogen-Free Organisms
PubMed: 26777404
DOI: 10.1016/j.cell.2015.12.023 -
Annual Review of Immunology May 2016The immune system is responsible for defending an organism against the myriad of microbial invaders it constantly confronts. It has become increasingly clear that the... (Review)
Review
The immune system is responsible for defending an organism against the myriad of microbial invaders it constantly confronts. It has become increasingly clear that the immune system has a second major function: the maintenance of organismal homeostasis. Foxp3(+)CD4(+) regulatory T cells (Tregs) are important contributors to both of these critical activities, defense being the primary purview of Tregs circulating through lymphoid organs, and homeostasis ensured mainly by their counterparts residing in parenchymal tissues. This review focuses on so-called tissue Tregs. We first survey existing information on the phenotype, function, sustaining factors, and human equivalents of the three best-characterized tissue-Treg populations-those operating in visceral adipose tissue, skeletal muscle, and the colonic lamina propria. We then attempt to distill general principles from this body of work-as concerns the provenance, local adaptation, molecular sustenance, and targets of action of tissue Tregs, in particular.
Topics: Adipose Tissue; Animals; Colon; Forkhead Transcription Factors; Homeostasis; Humans; Mucous Membrane; Muscle, Skeletal; Organ Specificity; T-Lymphocytes, Regulatory
PubMed: 27168246
DOI: 10.1146/annurev-immunol-032712-095948 -
Cell Death and Differentiation Sep 2018The regeneration of intestinal epithelial are maintained by continuous differentiation and proliferation of intestinal stem cells (ISCs) under physiological and...
Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22.
The regeneration of intestinal epithelial are maintained by continuous differentiation and proliferation of intestinal stem cells (ISCs) under physiological and pathological conditions. However, little is known about the regulatory effect of intestinal microbiota on its recovery ability to repair damaged mucosal barrier. In this study, we established intestinal organoids and lamina propria lymphocytes (LPLs) co-cultured system, plus mice experiments, to explore the protective effect of Lactobacillus reuteri D8 on integrity of intestinal mucosa. We found that only live L. reuteri D8 was effective in protecting the morphology of intestinal organoids and normal proliferation of epithelial stained with EdU under TNF-α treatment, which was also further verified in mice experiments. L. reuteri D8 colonized in the intestinal mucosa and ameliorated intestinal mucosa damage caused by DSS treatment, including improvement of body weight, colon length, pathological change, and proliferation level. The repair process stimulated by L. reuteri D8 was also accompanied with increased numbers of Lgr5 and lysozyme cells both in intestinal organoids and mice intestine. Furthermore, we demonstrated that D8 metabolite indole-3-aldehyde stimulated LPLs to secret IL-22 through aryl hydrocarbon receptor (AhR) and then induced phosphorylation of STAT3 to accelerate proliferation of intestinal epithelial, thus recovering damaged intestinal mucosa. Our findings indicate L. reuteri protects intestinal barrier and activates intestinal epithelial proliferation, which sheds light on treatment approaches for intestinal inflammation based on ISCs with probiotics Lactobacillus and daily probiotic consumption in heath foods.
Topics: Animals; Coculture Techniques; Colitis; Dextran Sulfate; Indoles; Interleukins; Intestinal Mucosa; Lactobacillus; Lymphocytes; Mice; Mice, Inbred C57BL; Mucous Membrane; Muramidase; Phosphorylation; Receptors, Aryl Hydrocarbon; Receptors, G-Protein-Coupled; STAT3 Transcription Factor; Signal Transduction; Stem Cells; Tumor Necrosis Factor-alpha; Interleukin-22
PubMed: 29459771
DOI: 10.1038/s41418-018-0070-2 -
Cell Oct 2009The gastrointestinal tract of mammals is inhabited by hundreds of distinct species of commensal microorganisms that exist in a mutualistic relationship with the host....
The gastrointestinal tract of mammals is inhabited by hundreds of distinct species of commensal microorganisms that exist in a mutualistic relationship with the host. How commensal microbiota influence the host immune system is poorly understood. We show here that colonization of the small intestine of mice with a single commensal microbe, segmented filamentous bacterium (SFB), is sufficient to induce the appearance of CD4(+) T helper cells that produce IL-17 and IL-22 (Th17 cells) in the lamina propria. SFB adhere tightly to the surface of epithelial cells in the terminal ileum of mice with Th17 cells but are absent from mice that have few Th17 cells. Colonization with SFB was correlated with increased expression of genes associated with inflammation and antimicrobial defenses and resulted in enhanced resistance to the intestinal pathogen Citrobacter rodentium. Thus, manipulation of this commensal-regulated pathway may provide new opportunities for enhancing mucosal immunity and treating autoimmune disease.
Topics: Animals; Cell Differentiation; Citrobacter rodentium; Gram-Positive Bacteria; Immunity, Mucosal; Interleukin-17; Interleukins; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Mucous Membrane; Serum Amyloid A Protein; Specific Pathogen-Free Organisms; Symbiosis; T-Lymphocytes, Helper-Inducer; Interleukin-22
PubMed: 19836068
DOI: 10.1016/j.cell.2009.09.033 -
Nature Apr 2024The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens....
The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (T) cell development and function have been identified, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive T cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector T (eT) cell function. eT cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103SIRPα dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206 macrophages and eT cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies.
Topics: Animals; Female; Male; Mice; Antigens, CD; Dendritic Cells; Gene Expression Profiling; Helicobacter hepaticus; Helicobacter Infections; Immune Tolerance; Inflammation; Integrin alpha Chains; Intestinal Mucosa; Macrophages; Mice, Inbred C57BL; Mucous Membrane; Receptors, Immunologic; Single-Cell Gene Expression Analysis; T-Lymphocytes, Regulatory; Transcriptome
PubMed: 38570678
DOI: 10.1038/s41586-024-07251-0 -
Current Gastroenterology Reports Oct 2010The non-white blood cell mesenchymal elements of the intestinal lamina propria are the myofibroblasts, fibroblasts, pericytes, stromal stem cells, muscularis mucosae,... (Review)
Review
The non-white blood cell mesenchymal elements of the intestinal lamina propria are the myofibroblasts, fibroblasts, pericytes, stromal stem cells, muscularis mucosae, and the smooth muscle of the villus core associated with the lymphatic lacteal. We review the functional anatomy of these mesenchymal cells, what is known about their origin in the embryo and their replacement in adults, their putative role in intestinal mucosal morphogenesis, and the intestinal stem cell niche, and we consider new information about myofibroblasts as nonprofessional immune cells. Although our knowledge of the function of mesenchymal cells in intestinal disease is rudimentary, we briefly consider here their roles in cancer and intestinal inflammation.
Topics: Animals; Biomarkers; Cell Communication; Cell Transformation, Neoplastic; Endoderm; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibroblasts; Humans; Inflammation; Intestinal Mucosa; Mesenchymal Stem Cells; Mesoderm; Mice; Mucous Membrane; Muscle, Smooth; Myofibroblasts; Pericytes; Stromal Cells
PubMed: 20690004
DOI: 10.1007/s11894-010-0135-y -
Clinical and Translational... Jan 2022Microscopic colitis, a common cause of diarrhea, is characterized by a largely normal appearance of the mucosa but increased numbers of lymphocytes in the epithelium and...
INTRODUCTION
Microscopic colitis, a common cause of diarrhea, is characterized by a largely normal appearance of the mucosa but increased numbers of lymphocytes in the epithelium and lamina propria on microscopy. We sought to determine whether T-cell percentage was associated with exposures or symptoms.
METHODS
We conducted a case-control study that enrolled patients referred for colonoscopy for diarrhea. Patients were classified as microscopic colitis cases or controls by an experienced pathologist. Participants provided information on symptoms and exposures during a telephone or internet survey. Research biopsies from the ascending colon and descending colon were examined using immunofluorescence stains for CD3, CD8, and FOXP3 to determine percent T cells per total epithelial or lamina propria cells. Digital images were analyzed by regions of interest using Tissue Studio.
RESULTS
There were 97 microscopic colitis cases and 165 diarrhea controls. There was no association between demographic factors and percentage of intraepithelial or lamina propria T cells. In cases, the mean percent T cells were similar in the right colon and left colon. There was no association between mean percent T cells and stool frequency or consistency. There was no association with irritable bowel syndrome, abdominal pain, or medications purported to cause microscopic colitis.
DISCUSSION
The lack of association between the density of T cells and medications raises further doubts about their role in disease etiology. Loose and frequent stools in patients with microscopic colitis are not correlated with T-cell density.
Topics: Case-Control Studies; Colitis, Microscopic; Humans; Lymphocytes; Mucous Membrane
PubMed: 35166714
DOI: 10.14309/ctg.0000000000000467 -
Cellular and Molecular Gastroenterology... 2024Eosinophilic esophagitis (EoE) is an emerging form of food allergy that exerts a significant clinical and financial burden worldwide. EoE is clinically characterized by... (Review)
Review
Eosinophilic esophagitis (EoE) is an emerging form of food allergy that exerts a significant clinical and financial burden worldwide. EoE is clinically characterized by eosinophil-rich inflammatory infiltrates in esophageal mucosa and esophageal dysfunction. Remodeling events in esophageal epithelium and lamina propria also frequently occur in patients with EoE. Because subepithelial fibrosis is associated with esophageal stricture, the most severe consequence of EoE, there exists an urgent need for a deeper understanding of the molecular mechanisms mediating fibrosis in EoE. Here, we review emerging evidence from experimental model systems that implicates crosstalk between esophageal epithelial cells and underlying stromal cells in EoE fibrosis. We further discuss implications for epithelial-stromal interaction with regard to EoE patient care and propose future directions that may be pursued to further the understanding of epithelial-stromal crosstalk in EoE pathobiology.
Topics: Humans; Eosinophilic Esophagitis; Esophageal Mucosa; Mucous Membrane; Fibrosis
PubMed: 38316214
DOI: 10.1016/j.jcmgh.2024.01.020