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Cell Stem Cell Sep 2022Opposing roles have been proposed for IL-22 in intestinal pathophysiology. We have optimized human small intestinal organoid (hSIO) culturing, constitutively generating...
Opposing roles have been proposed for IL-22 in intestinal pathophysiology. We have optimized human small intestinal organoid (hSIO) culturing, constitutively generating all differentiated cell types while maintaining an active stem cell compartment. IL-22 does not promote the expansion of stem cells but rather slows the growth of hSIOs. In hSIOs, IL-22 is required for formation of Paneth cells, the prime producers of intestinal antimicrobial peptides (AMPs). Introduction of inflammatory bowel disease (IBD)-associated loss-of-function mutations in the IL-22 co-receptor gene IL10RB resulted in abolishment of Paneth cells in hSIOs. Moreover, IL-22 induced expression of host defense genes (such as REG1A, REG1B, and DMBT1) in enterocytes, goblet cells, Paneth cells, Tuft cells, and even stem cells. Thus, IL-22 does not directly control the regenerative capacity of crypt stem cells but rather boosts Paneth cell numbers, as well as the expression of AMPs in all cell types.
Topics: Calcium-Binding Proteins; DNA-Binding Proteins; Humans; Interleukins; Intestinal Mucosa; Intestine, Small; Organoids; Paneth Cells; Tumor Suppressor Proteins; Interleukin-22
PubMed: 36002022
DOI: 10.1016/j.stem.2022.08.002 -
Signal Transduction and Targeted Therapy Aug 2023As a family of cationic host defense peptides, defensins are mainly synthesized by Paneth cells, neutrophils, and epithelial cells, contributing to host defense. Their... (Review)
Review
As a family of cationic host defense peptides, defensins are mainly synthesized by Paneth cells, neutrophils, and epithelial cells, contributing to host defense. Their biological functions in innate immunity, as well as their structure and activity relationships, along with their mechanisms of action and therapeutic potential, have been of great interest in recent years. To highlight the key research into the role of defensins in human and animal health, we first describe their research history, structural features, evolution, and antimicrobial mechanisms. Next, we cover the role of defensins in immune homeostasis, chemotaxis, mucosal barrier function, gut microbiota regulation, intestinal development and regulation of cell death. Further, we discuss their clinical relevance and therapeutic potential in various diseases, including infectious disease, inflammatory bowel disease, diabetes and obesity, chronic inflammatory lung disease, periodontitis and cancer. Finally, we summarize the current knowledge regarding the nutrient-dependent regulation of defensins, including fatty acids, amino acids, microelements, plant extracts, and probiotics, while considering the clinical application of such regulation. Together, the review summarizes the various biological functions, mechanism of actions and potential clinical significance of defensins, along with the challenges in developing defensins-based therapy, thus providing crucial insights into their biology and potential clinical utility.
Topics: Animals; Humans; Paneth Cells; Inflammatory Bowel Diseases; Defensins
PubMed: 37574471
DOI: 10.1038/s41392-023-01553-x -
New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD.Autophagy Jan 2020One of the most significant challenges of inflammatory bowel disease (IBD) research is to understand how alterations in the symbiotic relationship between the genetic... (Review)
Review
One of the most significant challenges of inflammatory bowel disease (IBD) research is to understand how alterations in the symbiotic relationship between the genetic composition of the host and the intestinal microbiota, under impact of specific environmental factors, lead to chronic intestinal inflammation. Genome-wide association studies, followed by functional studies, have identified a role for numerous autophagy genes in IBD, especially in Crohn disease. Studies using and models, in addition to human clinical studies have revealed that autophagy is pivotal for intestinal homeostasis maintenance, gut ecology regulation, appropriate intestinal immune responses and anti-microbial protection. This review describes the latest researches on the mechanisms by which dysfunctional autophagy leads to disrupted intestinal epithelial function, gut dysbiosis, defect in anti-microbial peptide secretion by Paneth cells, endoplasmic reticulum stress response and aberrant immune responses to pathogenic bacteria. A better understanding of the role of autophagy in IBD pathogenesis may provide better sub-classification of IBD phenotypes and novel approaches for disease management. AIEC: adherent-invasive ; AMPK: AMP-activated protein kinase; ATF6: activating transcription factor 6; ATG: autophagy related; mice: mice with depletion specifically in intestinal epithelial cells; mice: mice hypomorphic for expression; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1, autophagy related; CALCOCO2: calcium binding and coiled-coil domain 2; CASP: caspase; CD: Crohn disease; CGAS: cyclic GMP-AMP synthase; CHUK/IKKA: conserved helix-loop-helix ubiquitous kinase; CLDN2: claudin 2; DAPK1: death associated protein kinase 1; DCs: dendritic cells; DSS: dextran sulfate sodium; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK: eukaryotic translation initiation factor 2 alpha kinase; ER: endoplasmic reticulum; ERBIN: Erbb2 interacting protein; ERN1/IRE1A: ER to nucleus signaling 1; FNBP1L: formin binding protein 1-like; FOXP3: forkhead box P3; GPR65: G-protein coupled receptor 65; GSK3B: glycogen synthase kinase 3 beta; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; IFN: interferon; IL: interleukin; IL10R: interleukin 10 receptor; IRGM: immunity related GTPase M; ISC: intestinal stem cell; LAMP1: lysosomal-associated membrane protein 1; LAP: LC3-associated phagocytosis; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; LPS: lipopolysaccharide; LRRK2: leucine-rich repeat kinase 2; MAPK: mitogen-activated protein kinase; MHC: major histocompatibility complex; MIF: macrophage migration inhibitory factor; MIR/miRNA: microRNA; MTMR3: myotubularin related protein 3; MTOR: mechanistic target of rapamycin kinase; MYD88: myeloid differentiation primary response gene 88; NLRP3: NLR family, pyrin domain containing 3; NOD2: nucleotide-binding oligomerization domain containing 2; NPC: Niemann-Pick disease type C; NPC1: NPC intracellular cholesterol transporter 1; OMVs: outer membrane vesicles; OPTN: optineurin; PI3K: phosphoinositide 3-kinase; PRR: pattern-recognition receptor; PTPN2: protein tyrosine phosphatase, non-receptor type 2; PTPN22: protein tyrosine phosphatase, non-receptor type 22 (lymphoid); PYCARD/ASC: PYD and CARD domain containing; RAB2A: RAB2A, member RAS oncogene family; RELA: v-rel reticuloendotheliosis viral oncogene homolog A (avian); RIPK2: receptor (TNFRSF)-interacting serine-threonine kinase 2; ROS: reactive oxygen species; SNPs: single nucleotide polymorphisms; SQSTM1: sequestosome 1; TAX1BP1: Tax1 binding protein 1; Th: T helper 1; TIRAP/TRIF: toll-interleukin 1 receptor (TIR) domain-containing adaptor protein; TLR: toll-like receptor; TMEM173/STING: transmembrane protein 173; TMEM59: transmembrane protein 59; TNF/TNFA: tumor necrosis factor; Treg: regulatory T; TREM1: triggering receptor expressed on myeloid cells 1; UC: ulcerative colitis; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type; XBP1: X-box binding protein 1; XIAP: X-linked inhibitor of apoptosis.
Topics: Animals; Apoptosis Regulatory Proteins; Autophagy; Endoplasmic Reticulum Stress; Gastrointestinal Microbiome; Humans; Inflammation; Intestines
PubMed: 31286804
DOI: 10.1080/15548627.2019.1635384 -
Science (New York, N.Y.) Jan 2022Epithelial organoids are stem cell–derived tissues that approximate aspects of real organs, and thus they have potential as powerful tools in basic and translational...
Epithelial organoids are stem cell–derived tissues that approximate aspects of real organs, and thus they have potential as powerful tools in basic and translational research. By definition, they self-organize, but the structures formed are often heterogeneous and irreproducible, which limits their use in the lab and clinic. We describe methodologies for spatially and temporally controlling organoid formation, thereby rendering a stochastic process more deterministic. Bioengineered stem cell microenvironments are used to specify the initial geometry of intestinal organoids, which in turn controls their patterning and crypt formation. We leveraged the reproducibility and predictability of the culture to identify the underlying mechanisms of epithelial patterning, which may contribute to reinforcing intestinal regionalization in vivo. By controlling organoid culture, we demonstrate how these structures can be used to answer questions not readily addressable with the standard, more variable, organoid models.
Topics: Animals; Cell Differentiation; Cell Shape; Epithelial Cells; Hydrogels; Intestinal Mucosa; Mice; Organogenesis; Organoids; Paneth Cells; Receptors, Notch; Signal Transduction; Stem Cells; Tissue Culture Techniques; Tissue Engineering; YAP-Signaling Proteins
PubMed: 34990240
DOI: 10.1126/science.aaw9021 -
Frontiers in Immunology 2020The mammalian intestine is the largest immune organ that contains the intestinal stem cells (ISC), differentiated epithelial cells (enterocytes, Paneth cells, goblet... (Review)
Review
The mammalian intestine is the largest immune organ that contains the intestinal stem cells (ISC), differentiated epithelial cells (enterocytes, Paneth cells, goblet cells, tuft cells, etc.), and gut resident-immune cells (T cells, B cells, dendritic cells, innate lymphoid cell, etc.). Inflammatory bowel disease (IBD), a chronic inflammatory disease characterized by mucosa damage and inflammation, threatens the integrity of the intestine. The continuous renewal and repair of intestinal mucosal epithelium after injury depend on ISCs. Inflamed mucosa healing could be a new target for the improvement of clinical symptoms, disease recurrence, and resection-free survival in IBD treated patients. The knowledge about the connections between ISC and immune cells is expanding with the development of intestinal organoid culture and single-cell RNA sequencing technology. Recent findings implicate that immune cells such as T cells, ILCs, dendritic cells, and macrophages and cytokines secreted by these cells are critical in the regeneration of ISCs and intestinal epithelium. Transplantation of ISC to the inflamed mucosa may be a new therapeutic approach to reconstruct the epithelial barrier in IBD. Considering the links between ISC and immune cells, we predict that the integration of biological agents and ISC transplantation will revolutionize the future therapy of IBD patients.
Topics: Animals; Dendritic Cells; Female; Immunity, Innate; Inflammatory Bowel Diseases; Intestinal Mucosa; Macrophages; Stem Cell Transplantation; Stem Cells; T-Lymphocytes
PubMed: 33584726
DOI: 10.3389/fimmu.2020.623691 -
The Journal of Experimental Medicine Feb 2020The intestine plays an important role in nutrient digestion and absorption, microbe defense, and hormone secretion. Although major cell types have been identified in the...
The intestine plays an important role in nutrient digestion and absorption, microbe defense, and hormone secretion. Although major cell types have been identified in the mouse intestinal epithelium, cell type-specific markers and functional assignments are largely unavailable for human intestine. Here, our single-cell RNA-seq analyses of 14,537 epithelial cells from human ileum, colon, and rectum reveal different nutrient absorption preferences in the small and large intestine, suggest the existence of Paneth-like cells in the large intestine, and identify potential new marker genes for human transient-amplifying cells and goblet cells. We have validated some of these insights by quantitative PCR, immunofluorescence, and functional analyses. Furthermore, we show both common and differential features of the cellular landscapes between the human and mouse ilea. Therefore, our data provide the basis for detailed characterization of human intestine cell constitution and functions, which would be helpful for a better understanding of human intestine disorders, such as inflammatory bowel disease and intestinal tumorigenesis.
Topics: Animals; Biomarkers; Cell Cycle; Cell Differentiation; Cell Proliferation; Cells, Cultured; Goblet Cells; Humans; Ileum; Intestinal Absorption; Mice; Mice, Inbred C57BL; Nutrients; Organoids; Paneth Cells; RNA-Seq; Signal Transduction; Single-Cell Analysis; Transcriptome
PubMed: 31753849
DOI: 10.1084/jem.20191130 -
International Journal of Molecular... Oct 2021Intestinal epithelial cells (IECs) are crucial for the digestive process and nutrient absorption. The intestinal epithelium is composed of the different cell types of... (Review)
Review
Intestinal epithelial cells (IECs) are crucial for the digestive process and nutrient absorption. The intestinal epithelium is composed of the different cell types of the small intestine (mainly, enterocytes, goblet cells, Paneth cells, enteroendocrine cells, and tuft cells). The small intestine is characterized by the presence of crypt-villus units that are in a state of homeostatic cell turnover. Organoid technology enables an efficient expansion of intestinal epithelial tissue in vitro. Thus, organoids hold great promise for use in medical research and in the development of new treatments. At present, the cholinergic system involved in IECs and intestinal stem cells (ISCs) are attracting a great deal of attention. Thus, understanding the biological processes triggered by epithelial cholinergic activation by acetylcholine (ACh), which is produced and released from neuronal and/or non-neuronal tissue, is of key importance. Cholinergic signaling via ACh receptors plays a pivotal role in IEC growth and differentiation. Here, we discuss current views on neuronal innervation and non-neuronal control of the small intestinal crypts and their impact on ISC proliferation, differentiation, and maintenance. Since technology using intestinal organoid culture systems is advancing, we also outline an organoid-based organ replacement approach for intestinal diseases.
Topics: Acetylcholine; Animals; Cell Culture Techniques; Cell Differentiation; Cell Proliferation; Intestinal Mucosa; Intestine, Small; Models, Biological; Organoids; Receptors, Cholinergic; Stem Cells
PubMed: 34681571
DOI: 10.3390/ijms222010912 -
Viruses Jan 2021Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a multifactorial disease in which dietary, genetic, immunological, and... (Review)
Review
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a multifactorial disease in which dietary, genetic, immunological, and microbial factors are at play. The role of enteric viruses in IBD remains only partially explored. To date, epidemiological studies have not fully described the role of enteric viruses in inflammatory flare-ups, especially that of human noroviruses and rotaviruses, which are the main causative agents of viral gastroenteritis. Genome-wide association studies have demonstrated the association between IBD, polymorphisms of the and genes (which drive the synthesis of histo-blood group antigens), and ligands for norovirus and rotavirus in the intestine. The role of autophagy in defensin-deficient Paneth cells and the perturbations of cytokine secretion in T-helper 1 and T-helper 17 inflammatory pathways following enteric virus infections have been demonstrated as well. Enteric virus interactions with commensal bacteria could play a significant role in the modulation of enteric virus infections in IBD. Based on the currently incomplete knowledge of the complex phenomena underlying IBD pathogenesis, future studies using multi-sampling and data integration combined with new techniques such as human intestinal enteroids could help to decipher the role of enteric viruses in IBD.
Topics: Animals; Autophagy; Biomarkers; Blood Group Antigens; Disease Management; Disease Susceptibility; Enterovirus; Enterovirus Infections; Gastrointestinal Microbiome; Host-Pathogen Interactions; Humans; Inflammatory Bowel Diseases; Microbial Interactions; Signal Transduction; Virome
PubMed: 33451106
DOI: 10.3390/v13010104 -
World Journal of Gastroenterology Jun 2023Crohn's disease (CD) is an inflammatory bowel disease characterized by immune-mediated flares affecting any region of the intestine alternating with remission periods.... (Review)
Review
Crohn's disease (CD) is an inflammatory bowel disease characterized by immune-mediated flares affecting any region of the intestine alternating with remission periods. In CD, the ileum is frequently affected and about one third of patients presents with a pure ileal type. Moreover, the ileal type of CD presents epidemiological specificities like a younger age at onset and often a strong link with smoking and genetic susceptibility genes. Most of these genes are associated with Paneth cell dysfunction, a cell type found in the intestinal crypts of the ileum. Besides, a Western-type diet is associated in epidemiological studies with CD onset and increasing evidence shows that diet can modulate the composition of bile acids and gut microbiota, which in turn modulates the susceptibility of the ileum to inflammation. Thus, the interplay between environmental factors and the histological and anatomical features of the ileum is thought to explain the specific transcriptome profile observed in CD ileitis. Indeed, both immune response and cellular healing processes harbour differences between ileal and non-ileal CD. Taken together, these findings advocate for a dedicated therapeutic approach to managing ileal CD. Currently, interventional pharmacological studies have failed to clearly demonstrate distinct response profiles according to disease site. However, the high rate of stricturing disease in ileal CD requires the identification of new therapeutic targets to significantly change the natural history of this debilitating disease.
Topics: Humans; Crohn Disease; Ileum; Ileitis; Inflammation; Paneth Cells; Ileal Diseases
PubMed: 37377591
DOI: 10.3748/wjg.v29.i21.3222 -
Immunity Dec 2022Intestinal stem cell maturation and development coincide with gut microbiota exposure after birth. Here, we investigated how early life microbial exposure, and...
Intestinal stem cell maturation and development coincide with gut microbiota exposure after birth. Here, we investigated how early life microbial exposure, and disruption of this process, impacts the intestinal stem cell niche and development. Single-cell transcriptional analysis revealed impaired stem cell differentiation into Paneth cells and macrophage specification upon antibiotic treatment in early life. Mouse genetic and organoid co-culture experiments demonstrated that a CD206 subset of intestinal macrophages secreted Wnt ligands, which maintained the mesenchymal niche cells important for Paneth cell differentiation. Antibiotics and reduced numbers of Paneth cells are associated with the deadly infant disease, necrotizing enterocolitis (NEC). We showed that colonization with Lactobacillus or transfer of CD206 macrophages promoted Paneth cell differentiation and reduced NEC severity. Together, our work defines the gut microbiota-mediated regulation of stem cell niches during early postnatal development.
Topics: Mice; Animals; Gastrointestinal Microbiome; Paneth Cells; Cell Differentiation; Enterocolitis, Necrotizing; Macrophages
PubMed: 36473468
DOI: 10.1016/j.immuni.2022.11.003