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Gastroenterology Jun 2018Diarrhea is common in infants (children less than 2 years of age), usually acute, and, if chronic, commonly caused by allergies and occasionally by infectious agents.... (Review)
Review
Diarrhea is common in infants (children less than 2 years of age), usually acute, and, if chronic, commonly caused by allergies and occasionally by infectious agents. Congenital diarrheas and enteropathies (CODEs) are rare causes of devastating chronic diarrhea in infants. Evaluation of CODEs is a lengthy process and infrequently leads to a clear diagnosis. However, genomic analyses and the development of model systems have increased our understanding of CODE pathogenesis. With these advances, a new diagnostic approach is needed. We propose a revised approach to determine causes of diarrhea in infants, including CODEs, based on stool analysis, histologic features, responses to dietary modifications, and genetic tests. After exclusion of common causes of diarrhea in infants, the evaluation proceeds through analyses of stool characteristics (watery, fatty, or bloody) and histologic features, such as the villus to crypt ratio in intestinal biopsies. Infants with CODEs resulting from defects in digestion, absorption, transport of nutrients and electrolytes, or enteroendocrine cell development or function have normal villi to crypt ratios; defects in enterocyte structure or immune-mediated conditions result in an abnormal villus to crypt ratios and morphology. Whole-exome and genome sequencing in the early stages of evaluation can reduce the time required for a definitive diagnosis of CODEs, or lead to identification of new variants associated with these enteropathies. The functional effects of gene mutations can be analyzed in model systems such as enteroids or induced pluripotent stem cells and are facilitated by recent advances in gene editing procedures. Characterization and investigation of new CODE disorders will improve management of patients and advance our understanding of epithelial cells and other cells in the intestinal mucosa.
Topics: Biopsy; Chronic Disease; Critical Pathways; Diarrhea, Infantile; Endoscopy, Digestive System; Enterocytes; Enteroendocrine Cells; Genetic Testing; Humans; Infant; Infant, Newborn; Intestinal Diseases; Mutation; Whole Genome Sequencing
PubMed: 29654747
DOI: 10.1053/j.gastro.2018.03.067 -
Nature Oct 2020The development of intestinal organoids from single adult intestinal stem cells in vitro recapitulates the regenerative capacity of the intestinal epithelium. Here we...
The development of intestinal organoids from single adult intestinal stem cells in vitro recapitulates the regenerative capacity of the intestinal epithelium. Here we unravel the mechanisms that orchestrate both organoid formation and the regeneration of intestinal tissue, using an image-based screen to assay an annotated library of compounds. We generate multivariate feature profiles for hundreds of thousands of organoids to quantitatively describe their phenotypic landscape. We then use these phenotypic fingerprints to infer regulatory genetic interactions, establishing a new approach to the mapping of genetic interactions in an emergent system. This allows us to identify genes that regulate cell-fate transitions and maintain the balance between regeneration and homeostasis, unravelling previously unknown roles for several pathways, among them retinoic acid signalling. We then characterize a crucial role for retinoic acid nuclear receptors in controlling exit from the regenerative state and driving enterocyte differentiation. By combining quantitative imaging with RNA sequencing, we show the role of endogenous retinoic acid metabolism in initiating transcriptional programs that guide the cell-fate transitions of intestinal epithelium, and we identify an inhibitor of the retinoid X receptor that improves intestinal regeneration in vivo.
Topics: Animals; Cell Differentiation; Enterocytes; Homeostasis; Intestinal Mucosa; Intestines; Male; Mice; Mice, Inbred C57BL; Organoids; Phenotype; Receptors, Retinoic Acid; Regeneration; Sequence Analysis, RNA; Signal Transduction; Transcription, Genetic; Tretinoin; Vitamin A
PubMed: 33029001
DOI: 10.1038/s41586-020-2776-9 -
Cell Dec 2015Microbial functions in the host physiology are a result of the microbiota-host co-evolution. We show that cold exposure leads to marked shift of the microbiota...
Microbial functions in the host physiology are a result of the microbiota-host co-evolution. We show that cold exposure leads to marked shift of the microbiota composition, referred to as cold microbiota. Transplantation of the cold microbiota to germ-free mice is sufficient to increase insulin sensitivity of the host and enable tolerance to cold partly by promoting the white fat browning, leading to increased energy expenditure and fat loss. During prolonged cold, however, the body weight loss is attenuated, caused by adaptive mechanisms maximizing caloric uptake and increasing intestinal, villi, and microvilli lengths. This increased absorptive surface is transferable with the cold microbiota, leading to altered intestinal gene expression promoting tissue remodeling and suppression of apoptosis-the effect diminished by co-transplanting the most cold-downregulated strain Akkermansia muciniphila during the cold microbiota transfer. Our results demonstrate the microbiota as a key factor orchestrating the overall energy homeostasis during increased demand.
Topics: Adipose Tissue, White; Animals; Apoptosis; Cold Temperature; Energy Metabolism; Enterocytes; Gastrointestinal Microbiome; Gastrointestinal Tract; Germ-Free Life; Homeostasis; Insulin Resistance; Intestinal Absorption; Mice; Verrucomicrobia
PubMed: 26638070
DOI: 10.1016/j.cell.2015.11.004 -
Cell Reports Mar 2022Intestinal epithelial cells derive from stem cells at the crypt base and travel along the crypt-villus axis to die at the villus tip. The two dominant villus epithelial...
Intestinal epithelial cells derive from stem cells at the crypt base and travel along the crypt-villus axis to die at the villus tip. The two dominant villus epithelial cell types, absorptive enterocytes and mucous-secreting goblet cells, are mature when they exit crypts. Murine enterocytes switch functional cell states during migration along the villus. Here, we ask whether this zonation is driven by the bone morphogenetic protein (BMP) gradient, which increases toward the villus. Using human intestinal organoids, we show that BMP signaling controls the expression of zonated genes in enterocytes. We find that goblet cells display similar zonation involving antimicrobial genes. Using an inducible Bmpr1a knockout mouse model, we confirm that BMP controls these zonated genes in vivo. Our findings imply that local manipulation of BMP signal strength may be used to reset the enterocyte "rheostat" of carbohydrate versus lipid uptake and to control the antimicrobial response through goblet cells.
Topics: Animals; Bone Morphogenetic Proteins; Cell Differentiation; Enterocytes; Goblet Cells; Intestinal Mucosa; Intestine, Small; Mice
PubMed: 35235783
DOI: 10.1016/j.celrep.2022.110438 -
Cell Nov 2018The intestinal epithelium is a highly structured tissue composed of repeating crypt-villus units. Enterocytes perform the diverse tasks of absorbing a wide range of...
The intestinal epithelium is a highly structured tissue composed of repeating crypt-villus units. Enterocytes perform the diverse tasks of absorbing a wide range of nutrients while protecting the body from the harsh bacterium-rich environment. It is unknown whether these tasks are spatially zonated along the villus axis. Here, we extracted a large panel of landmark genes characterized by transcriptomics of laser capture microdissected villus segments and utilized it for single-cell spatial reconstruction, uncovering broad zonation of enterocyte function along the villus. We found that enterocytes at villus bottoms express an anti-bacterial gene program in a microbiome-dependent manner. They next shift to sequential expression of carbohydrates, peptides, and fat absorption machineries in distinct villus compartments. Finally, they induce a Cd73 immune-modulatory program at the villus tips. Our approach can be used to uncover zonation patterns in other organs when prior knowledge of landmark genes is lacking.
Topics: Animals; Cell Differentiation; Cell Movement; Enterocytes; Male; Mice; Mice, Inbred C57BL; Single-Cell Analysis; Transcriptome
PubMed: 30270040
DOI: 10.1016/j.cell.2018.08.063 -
Journal of Lipid Research May 2023Conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA) by autotaxin, a secreted phospholipase D, is a major pathway for producing LPA. We previously...
Conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA) by autotaxin, a secreted phospholipase D, is a major pathway for producing LPA. We previously reported that feeding Ldlr mice standard mouse chow supplemented with unsaturated LPA or lysophosphatidylcholine qualitatively mimicked the dyslipidemia and atherosclerosis induced by feeding a Western diet (WD). Here, we report that adding unsaturated LPA to standard mouse chow also increased the content of reactive oxygen species and oxidized phospholipids (OxPLs) in jejunum mucus. To determine the role of intestinal autotaxin, enterocyte-specific Ldlr/Enpp2 KO (intestinal KO) mice were generated. In control mice, the WD increased enterocyte Enpp2 expression and raised autotaxin levels. Ex vivo, addition of OxPL to jejunum from Ldlr mice on a chow diet induced expression of Enpp2. In control mice, the WD raised OxPL levels in jejunum mucus and decreased gene expression in enterocytes for a number of peptides and proteins that affect antimicrobial activity. On the WD, the control mice developed elevated levels of lipopolysaccharide in jejunum mucus and plasma, with increased dyslipidemia and increased atherosclerosis. All these changes were reduced in the intestinal KO mice. We conclude that the WD increases the formation of intestinal OxPL, which i) induce enterocyte Enpp2 and autotaxin resulting in higher enterocyte LPA levels; that ii) contribute to the formation of reactive oxygen species that help to maintain the high OxPL levels; iii) decrease intestinal antimicrobial activity; and iv) raise plasma lipopolysaccharide levels that promote systemic inflammation and enhance atherosclerosis.
Topics: Mice; Animals; Lysophosphatidylcholines; Enterocytes; Lipopolysaccharides; Reactive Oxygen Species; Lysophospholipids; Phosphoric Diester Hydrolases; Diet, Western; Inflammation; Dyslipidemias; Atherosclerosis; Anti-Infective Agents
PubMed: 37059333
DOI: 10.1016/j.jlr.2023.100370 -
Methodist DeBakey Cardiovascular Journal 2019Besides the well-known hepatobiliary pathway of cholesterol excretion into the feces, transintestinal cholesterol excretion (TICE) is a second major pathway through... (Review)
Review
Besides the well-known hepatobiliary pathway of cholesterol excretion into the feces, transintestinal cholesterol excretion (TICE) is a second major pathway through which cholesterol is disposed from the body. In the process of TICE, cholesterol is taken up from lipoprotein particles at the basolateral side of the enterocyte and translocates towards the apical side of the enterocyte. At the apical side, the ATP-binding cassette transporters G5 and G8 form a heterodimer that transports cholesterol into the intestinal lumen. A substantial amount of the secreted cholesterol is likely reabsorbed by the cholesterol influx transporter Niemann-Pick C1-Like 1 (NPC1L1) since recent data indicate that inhibition of NPC1L1 increases the efficacy of TICE for disposal of cholesterol via the feces. The pathways and proteins involved in intracellular cholesterol trafficking in the enterocyte have not yet been identified. Therefore, in addition to discussing known mediators of TICE, this review will also examine potential candidates involved in cholesterol translocation in the enterocyte. Both the cholesterol reuptake and efflux pathways can be influenced by pharmaceutical means; thus, the TICE pathway is a very attractive target to increase cholesterol excretion from the body and prevent or mitigate atherosclerotic cardiovascular disease.
Topics: Animals; Anticholesteremic Agents; Biomarkers; Cardiovascular Diseases; Cholesterol; Down-Regulation; Dyslipidemias; Enterocytes; Feces; Humans; Intestinal Elimination; Membrane Transport Proteins
PubMed: 31049152
DOI: 10.14797/mdcj-15-1-70 -
Frontiers in Bioscience (Landmark... Mar 2018The main function of the porcine intestinal tract is nutrient digestion and absorption. This function is performed by the absorptive enterocytes, which are... (Review)
Review
The main function of the porcine intestinal tract is nutrient digestion and absorption. This function is performed by the absorptive enterocytes, which are differentiated from the intestinal stem cells residing at the bottom of the crypt. Nutrients such as glucose and amino acids are transported, absorbed by various transporters embedded on the membranes of these enterocytes. Metabolism occurs in each cell along the crypt-villus axis (CVA). Because the intestinal epithelial cells are the most vigorous, self-renewing cells, regenerating from the crypt bottom to the villus tip in only three to five days, the CVA is an appealing organ for studying cell maturation. In this review, we examine the glucose and amino acid transporters expressed in the apical membrane, basolateral membrane, or the inside of the absorptive enterocytes. We also discuss glucose and amino acid metabolism in small epithelial cells, and show how these nutrients influence the proliferation and differentiation of an intestinal stem cell into one specialized cell type when they migrate from the bottom of the crypt to the tip of the villus.
Topics: Amino Acid Transport Systems; Amino Acids; Animals; Cell Differentiation; Enterocytes; Glucose; Intestinal Absorption; Intestinal Mucosa; Monosaccharide Transport Proteins; Swine
PubMed: 29293459
DOI: 10.2741/4669 -
Small GTPases Apr 2016Recent human and mouse genetic studies have highlighted important contributions of several small GTPases, in particular Rab8a, (1) Cdc42, (2-4) and Rab11a, (5-8) to the... (Review)
Review
Recent human and mouse genetic studies have highlighted important contributions of several small GTPases, in particular Rab8a, (1) Cdc42, (2-4) and Rab11a, (5-8) to the proper morphogenesis and function of the mature intestinal epithelia. Additional insights about the involvement of these factors in maintaining intestinal stem cell homeostasis have also been obtained. (9,10) These studies suggest a conserved vesicular and membrane trafficking program utilized by the gastrointestinal tissue to support the rapid epithelial cell turnover and the highly sophisticated physiology of mature epithelial cells.
Topics: Animals; Enterocytes; Homeostasis; Humans; Intestinal Diseases; Stem Cell Niche; rab GTP-Binding Proteins; rho GTP-Binding Proteins
PubMed: 27142493
DOI: 10.1080/21541248.2016.1159274 -
Revista Espanola de Enfermedades... May 2020Although SARS-CoV-2 may primarily enter the cells of the lungs, the small bowel may also be an important entry or interaction site, as the enterocytes are rich in... (Review)
Review
Although SARS-CoV-2 may primarily enter the cells of the lungs, the small bowel may also be an important entry or interaction site, as the enterocytes are rich in angiotensin converting enzyme (ACE)-2 receptors. The initial gastrointestinal symptoms that appear early during the course of Covid-19 support this hypothesis. Furthermore, SARS-CoV virions are preferentially released apically and not at the basement of the airway cells. Thus, in the setting of a productive infection of conducting airway epithelia, the apically released SARS-CoV may be removed by mucociliary clearance and gain access to the GI tract via a luminal exposure. In addition, post-mortem studies of mice infected by SARS-CoV have demonstrated diffuse damage to the GI tract, with the small bowel showing signs of enterocyte desquamation, edema, small vessel dilation and lymphocyte infiltration, as well as mesenteric nodes with severe hemorrhage and necrosis. Finally, the small bowel is rich in furin, a serine protease which can separate the S-spike of the coronavirus into two "pinchers" (S1 and 2). The separation of the S-spike into S1 and S2 is essential for the attachment of the virion to both the ACE receptor and the cell membrane. In this special review, we describe the interaction of SARS-CoV-2 with the cell and enterocyte and its potential clinical implications.
Topics: Angiotensin-Converting Enzyme 2; Betacoronavirus; COVID-19; Coronavirus Infections; Enterocytes; Gastrointestinal Diseases; Humans; Intestine, Small; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Receptors, Angiotensin; Respiratory Mucosa; SARS-CoV-2
PubMed: 32343593
DOI: 10.17235/reed.2020.7137/2020