ABSTRACT
We assessed the hydrochemistry of 15 watersheds in the Halton Region, southern Ontario, in high resolution (n > 500 samples across n > 40 streams) to characterize water quality dynamics and governing controls on major and trace element concentrations in this rapidly urbanizing region. In 2022, major water quality parameters were generally in line with historic monitoring data yet significantly different across catchments, e.g., in specific conductance, turbidity, phosphate and chloride, and trace element concentrations. Distinct hydrochemical signatures were observed between urban and rural creeks, with urban stream sections and sites near the river mouths close to Lake Ontario having consistently higher chloride (up to 700 mg/L) and occasional enrichment in nutrients levels (up to 8 and 20 mg/L phosphate and nitrate, respectively). Particularly upper reaches exhibited hydrochemical signatures that were reflective of the catchment surface lithologies, for instance through higher dissolved Ca to Mg ratios. Unlike for chloride and phosphate, provincial water quality guidelines for trace elements and heavy metals were seldom surpassed (on < 10 occasions for copper, zinc, cadmium, and uranium). Concentrations of other trace elements (e.g., platinum group elements or rare earth elements) were expectedly low (< 0.3 µg/L) but showed spatiotemporal concentration patterns and concentration-discharge dynamics different from those of the major water quality parameters. Our results help improve the understanding of surface water conditions within Halton's regional Natural Heritage Systems and demonstrate how enhanced environmental monitoring can deliver actionable information for watershed decision-making.
Subject(s)
Environmental Monitoring , Rivers , Water Pollutants, Chemical , Water Quality , Environmental Monitoring/methods , Ontario , Water Pollutants, Chemical/analysis , Rivers/chemistry , Trace Elements/analysis , Metals, Heavy/analysis , Chlorides/analysis , Water Pollution, Chemical/statistics & numerical dataABSTRACT
The nuclear bile acid receptor, farnesoid X receptor (FXR), is an important regulator of intestinal and metabolic function. Previous studies suggest that pentacyclic triterpenes (PCTs), a class of plant-derived bioactive phytochemical, can modulate FXR activity and may therefore offer therapeutic benefits. Here, we investigated the effects of a prototypical PCT, hederagenin (HG), on FXR expression, activity, and antisecretory actions in colonic epithelial cells. T84 cells and murine enteroid-derived monolayers were employed to assess HG effects on FXR expression and activity in colonic epithelia. We measured mRNA levels by qRT-PCR and protein by ELISA and immunoblotting. Transepithelial Cl- secretion was assessed as changes in short circuit current in Ussing chambers. We determined HG treatment (5-10 µM) alone did not induce FXR activation but significantly increased expression of the receptor, both in T84 cells and murine enteroid-derived monolayers. This effect was accompanied by enhanced FXR activity, as assessed by FGF-15/19 induction in response to the synthetic, GW4064, or natural FXR agonist, chenodeoxycholic acid. Effects of HG on FXR expression and activity were mimicked by another PCT, oleanolic acid. Furthermore, we found FXR-induced downregulation of cystic fibrosis transmembrane conductance regulator Cl- channels and inhibition of transepithelial Cl- secretion were enhanced in HG-treated cells. These data demonstrate that dietary PCTs have the capacity to modulate FXR expression, activity, and antisecretory actions in colonic epithelial cells. Based on these data, we propose that plants rich in PCTs, or extracts thereof, have excellent potential for development as a new class of "FXR-targeted nutraceuticals".
Subject(s)
Chenodeoxycholic Acid , Colon , Mice , Animals , Pentacyclic Triterpenes/pharmacology , Pentacyclic Triterpenes/metabolism , Colon/metabolism , Chenodeoxycholic Acid/pharmacology , Epithelial Cells/metabolism , Intestinal Mucosa/metabolismABSTRACT
The COVID-19 pandemic has resulted in the infection of hundreds of millions of individuals over the past 3 years, coupled with millions of deaths. Along with these more acute impacts of infection, a large subset of patients has developed symptoms that collectively comprise "postacute sequelae of COVID-19" (PASC, also known as long COVID), which can persist for months and maybe even years. In this review, we outline the current knowledge on the role of impaired microbiota-gut-brain (MGB) axis signaling in the development of PASC and the potential mechanisms involved, which may lead to a better understanding of disease progression and treatment options in the future.
Subject(s)
Brain-Gut Axis , COVID-19 , Humans , Pandemics , Post-Acute COVID-19 Syndrome , Disease ProgressionABSTRACT
BACKGROUND: Antibacterial resistance is a growing concern worldwide, including in Mozambique. Diarrhea is an important cause of mortality in Mozambique, yet few local studies have reported on the resistance of bacterial pathogens in this context. Therefore, this study aims to characterize antibiotic susceptibility patterns of Salmonella, Shigella and Campylobacter spp. among patients with diarrhea, including those who are HIV-infected and-uninfected. METHODS: We conducted antibiotic susceptibility testing on 157 stool isolates recovered from 129 patients aged between 0 and 80 years with diarrhea, including HIV infected (n = 68) and-uninfected individuals (n = 61), assisted at two health centers in Maputo city. The isolates comprised of 99 Salmonella, 45 Shigella and 13 Campylobacter strains. The Kirby-Bauer disk diffusion method was used on Mueller-Hinton II agar for Salmonella and Shigella spp., while Mueller-Hinton II agar with 5% defibrinated sheep blood was used for Campylobacter spp. We tested six antibiotics listed on the national essential medicines list, including ciprofloxacin, erythromycin, azithromycin, trimethoprim-sulfamethoxazole, gentamicin, and tetracycline. RESULTS: All isolates were resistant to at least one antibiotic. A high percentage of Salmonella spp. isolates were found to be resistant to trimethoprim-sulfamethoxazole (89.9%, n = 89), erythromycin (88.9%, n = 88) and tetracycline (76.8%, n = 76). In addition, 86.6% (n = 39) and 68.9% (n = 31) of Shigella isolates were resistant to trimethoprim-sulfamethoxazole and tetracycline, respectively. The majority of Campylobacter isolates (92.3%, n = 12) were resistant to erythromycin, azithromycin and tetracycline. Multidrug resistance (MDR) was observed in 79.8% of Salmonella spp., 76.9% of Campylobacter spp., and 57.8% of Shigella spp. Drug susceptibility profiles for Salmonella spp. and Campylobacter were similar in both HIV-1 infected and uninfected patients. However, Shigella spp. isolates obtained from patients without HIV infection were significantly more likely to be resistant to erythromycin, azithromycin or to exhibit multidrug resistance than those obtained from patients with HIV-1 infection (p < 0.05). All Shigella spp. and Campylobacter spp. isolates were susceptible to gentamicin. CONCLUSION: Our study highlights concerning rates of antibiotic resistance and MDR among diarrheal bacterial pathogens in Mozambique. Further research is needed to understand the impact of HIV, ART therapy and immunosuppression on antibiotic resistance. Urgent interventions are essential to prevent the spread of resistant strains.
Subject(s)
Campylobacter , HIV Infections , Shigella , Animals , Sheep , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Azithromycin , HIV Infections/complications , HIV Infections/epidemiology , Trimethoprim, Sulfamethoxazole Drug Combination , Mozambique/epidemiology , Agar , Microbial Sensitivity Tests , Salmonella , Tetracycline , Diarrhea/epidemiology , Diarrhea/microbiology , Drug Resistance, Bacterial , Erythromycin , Bacteria , Drug Resistance, Multiple , Gentamicins/pharmacology , Gentamicins/therapeutic useABSTRACT
AIMS: At conception, the infant gut barrier is immature, gradually developing with regular intake of maternal milk. This study addressed whether the barrier-strengthening effect of breast feeding might be attributable, at least in part, to autochthonous beneficial human milk bacteria. METHODS AND RESULTS: Twelve bacterial strains from the breast milk of Pakistani mothers who underwent cesarean delivery (NPL-88, NPL-157, NPL-179, NPL-181, NPL-388 (Limosilactobacillus reuteri), NPL-76, NPL-495, NPL-504 (Limosilactobacillus fermentum), NPL-415 (Lactobacillus pentosus), NPL-412, NPL-416 (Lactiplantibacilllus plantarum) and NPL-374 (Bifidobacterium longum) were shortlisted based on their tolerance to acidic pH (2.8-4.2) and bile (0.1-0.3%). The effect of these bacteria on gut barrier function in the presence and absence of pathogens was assessed as changes in transepithelial electrical resistance (TEER) in the human T84 colonic epithelial cell line and in murine enteroid-derived monolayers (EDMs). The TEER of T84 cells monolayers rose in the presence of most of the human milk strains, being most pronounced in case of L. reuteri NPL-88 (34% within five h), exceeding the effect of the well-known probiotic L. acidophilus (20%). qRT-PCR, western blot and immunofluorescent staining associated the increase in TEER with enhanced expression of tight junction proteins. Pretreatment of murine EDMs with NPL-88 also largely prevented the ability of the pathogen, Salmonella, to decrease TEER (87 ± 1.50%; P < 0.0001, n = 4). CONCLUSIONS: Human milk lactic acid bacteria are potential probiotics that can strengthen gut barrier function and protect breastfed neonates against enteric infections.
Subject(s)
Limosilactobacillus fermentum , Limosilactobacillus reuteri , Probiotics , Infant , Female , Infant, Newborn , Mice , Humans , Animals , Milk, Human , Limosilactobacillus reuteri/genetics , Bacteria , Probiotics/metabolismABSTRACT
Infections with non-typhoidal Salmonella spp. represent the most burdensome foodborne illnesses worldwide, yet despite their prevalence, the mechanism through which Salmonella elicits diarrhoea is not entirely known. Intestinal ion transporters play important roles in fluid and electrolyte homeostasis in the intestine. We have previously shown that infection with Salmonella caused decreased colonic expression of the chloride/bicarbonate exchanger SLC26A3 (down-regulated in adenoma; DRA) in a mouse model. In this study, we focused on the mechanism of DRA downregulation during Salmonella infection, by using murine epithelial enteroid-derived monolayers (EDMs). The decrease in DRA expression caused by infection was recapitulated in EDMs and accompanied by increased expression of Atonal Homolog 1 (ATOH1), the goblet cell marker Muc2 and the enteroendocrine cell marker ChgA. This suggested biased epithelial differentiation towards the secretory, rather than absorptive phenotype. In addition, the downstream Notch effector, Notch intracellular domain (NICD) and Hes1 were decreased following Salmonella infection. The relevance of Notch signalling was further investigated using a γ-secretase inhibitor, which recapitulated the downregulation in Hes1 and DRA as well as upregulation in ATOH1 and Muc2 seen following infection. Our findings suggest that Salmonella infection may result in a shift from absorptive to secretory cell types through Notch inhibition, which explains why there is a decreased capacity for absorption and ultimately the accumulation of diarrhoeal fluid. Our work also shows the value of EDMs as a model to investigate mechanisms that might be targeted for therapy of diarrhoea caused by Salmonella infection. KEY POINTS: Salmonella is a leading foodborne pathogen known to cause high-chloride-content diarrhoea. Salmonella infection of murine enteroid-derived monolayers decreased DRA expression. Salmonella infection resulted in upregulation of the secretory epithelial marker ATOH1, the goblet cell marker Muc2 and the enteroendocrine cell marker ChgA. Downregulation of DRA may result from infection-induced Notch inhibition, as reflected by decreased expression of Notch intracellular domain and Hes1, as well as from decreased HNF1α signalling. The imbalance in intestinal epithelial differentiation favouring secretory over absorptive cell types is a possible mechanism by which Salmonella elicits diarrhoea and may be relevant therapeutically.
Subject(s)
Chlorides , Salmonella Infections , Animals , Antiporters/genetics , Antiporters/metabolism , Cell Differentiation , Chloride-Bicarbonate Antiporters/metabolism , Chlorides/metabolism , Diarrhea , Intestinal Mucosa/metabolism , Mice , Sulfate Transporters/genetics , Sulfate Transporters/metabolismABSTRACT
One of the primary functions of the intestinal epithelium is to transport fluid and electrolytes to and from the luminal contents. Under normal circumstances, absorptive and secretory processes are tightly regulated such that absorption predominates, thereby enabling conservation of the large volumes of water that pass through the intestine each day. However, in conditions of secretory diarrhea, this balance becomes dysregulated, so that fluid secretion, driven primarily by Cl- secretion, overwhelms absorptive capacity, leading to increased loss of water in the stool. Secretory diarrheas are common and include those induced by pathogenic bacteria and viruses, allergens, and disruptions to bile acid homeostasis, or as a side effect of many drugs. Here, we review the cellular and molecular mechanisms by which Cl- and fluid secretion in the intestine are regulated, how these mechanisms become dysregulated in conditions of secretory diarrhea, currently available and emerging therapeutic approaches, and how new strategies to exploit intestinal secretory mechanisms are successfully being used in the treatment of constipation.
Subject(s)
Diarrhea , Intestinal Secretions , Diarrhea/metabolism , Humans , Intestinal Absorption , Intestinal Mucosa/metabolism , Intestines , WaterABSTRACT
Human milk is a key source of promising probiotic lactic acid bacteria. The Enterococcus species, because of their dual commensal and pathogenic nature, demand critical safety analysis to establish them as probiotic candidates. In this study, eighteen E. faecalis strains from human milk of mothers living in Pakistan were typed at the strain level by riboprinting. The typed strains were then evaluated in vitro for physiological safety and the presence of transmissible antibiotic resistance genes, adhesion genes, biogenic amines, and virulence factors. Selected strains were then checked for tolerance to gastrointestinal acid and bile as criteria for probiotic efficacy. Molecular typing revealed that the strains fell into five distinct clusters or ribotypes. Testing revealed that they were non-hemolytic; however, all strains had gelatinase activity except NPL-493. The isolates were susceptible to most clinically important antibiotics except streptomycin. Molecular screening for antibiotic resistance genes, adhesion genes, biogenic amines, and virulence factors indicated that none of the strains possessed resistance genes for aminoglycosides, vancomycin, bacitracin, tetracycline, or clindamycin. Most virulence factors were absent except for the genes gelE and efaAs associated with gut adhesion and translocation, which were present in all except NPL-493. Strain NPL-493 was the most promising probiotic candidate demonstrating significant tolerance to the acid, bile, and digestive enzymes in the human GIT and antibacterial activity against multiple pathogens. The study concluded that E. faecalis NPL-493 from human milk was safe among all the strains and could be considered a potential probiotic.
Subject(s)
Enterococcus faecalis , Probiotics , Anti-Bacterial Agents/pharmacology , Drug Resistance, Microbial , Enterococcus faecalis/genetics , Humans , Milk, HumanABSTRACT
Function diagrams put the focus on physiology and physiological concepts rather than the associated anatomy. Function diagrams could potentially serve as an elaboration tool and memory aid (mnemonic) to improve learning and recall. The function diagram prototype of the gastrointestinal system can aid in the instruction of difficult gastrointestinal physiology topics using a sequential focus on fundamental gastrointestinal functions.
Subject(s)
Learning , Physiology , Bioengineering , Biomedical Engineering , Humans , Memory , Mental RecallABSTRACT
The transport of electrolytes and fluid by the intestinal epithelium is critical in health to maintain appropriate levels of fluidity of the intestinal contents. The transport mechanisms that underlie this physiological process are also subject to derangement in various digestive disease states, such as diarrheal illnesses. This article summarizes the 2019 Hans Ussing Lecture of the Epithelial Transport Group of the American Physiological Society and discusses some pathways by which intestinal transport is dysregulated, particularly in the setting of infection with the diarrheal pathogen, Salmonella, and in patients treated with small-molecule inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor (EGFr-TKI). The burdensome diarrhea in patients infected with Salmonella may be attributable to decreased expression of the chloride-bicarbonate exchanger downregulated in adenoma (DRA) that participates in electroneutral NaCl absorption. This outcome is possibly secondary to increased epithelial proliferation and/or decreased epithelial differentiation that occurs following infection. Conversely, the diarrheal side effects of cancer treatment with EGFr-TKI may be related to the known ability of EGFr-associated signaling to reduce calcium-dependent chloride secretion. Overall, the findings described may suggest targets for therapeutic intervention in a variety of diarrheal disease states.
Subject(s)
Antiporters/metabolism , Diarrhea/metabolism , Epithelial Cells/metabolism , Intestinal Absorption , Intestinal Mucosa/metabolism , Sulfate Transporters/metabolism , Animals , Antineoplastic Agents/toxicity , Cell Differentiation , Cell Proliferation , Diarrhea/chemically induced , Diarrhea/microbiology , Diarrhea/pathology , Epithelial Cells/drug effects , Epithelial Cells/microbiology , Epithelial Cells/pathology , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Intestinal Mucosa/drug effects , Intestinal Mucosa/microbiology , Intestinal Mucosa/pathology , Mice , Permeability , Protein Kinase Inhibitors/toxicity , Salmonella Infections, Animal/metabolism , Salmonella Infections, Animal/microbiology , Salmonella Infections, Animal/pathologyABSTRACT
Maternal milk is an important source of essential nutrients for the optimal growth of infants. Breastfeeding provides a continuous supply of beneficial bacteria to colonize the infant gastrointestinal tract (GIT) and offers health benefits for disease prevention and immunity. The purpose of this study was to isolate novel probiotic strains from the breast milk of native Pakistani mothers and to evaluate their probiotic potential. We isolated 21 strains of bacteria from the colostrum and mature milk of 20 healthy mothers, who had vaginal deliveries and were not taking antibiotics. After phenotypic and genotypic characterization, these isolates were tested for survival in the GIT using in vitro acid and bile tests. Nine strains showing good acid tolerance were assessed for their growth rate, bile resistance and ability to hydrolyze bile salts. Out of the four Lactobacillus isolates adjudged to be most promising as probiotics, three were Lactobacillus fermentum strains and one was a strain of Lactobacillus oris. This study demonstrates that human milk is a viable source of commensal bacteria beneficial to both adults and babies.
Subject(s)
Lactobacillus/physiology , Milk, Human/microbiology , Probiotics , Acids/metabolism , Adult , Bile Acids and Salts/metabolism , Colostrum/microbiology , Female , Gastrointestinal Tract/microbiology , Humans , Infant , Lactobacillus/classification , Lactobacillus/isolation & purification , Phylogeny , Pregnancy , Probiotics/classification , Probiotics/isolation & purification , Young AdultABSTRACT
While infectious agents have typical host preferences, the noninvasive enteric bacterium Vibrio cholerae is remarkable for its ability to survive in many environments, yet cause diarrheal disease (cholera) only in humans. One key V. cholerae virulence factor is its neuraminidase (VcN), which releases host intestinal epithelial sialic acids as a nutrition source and simultaneously remodels intestinal polysialylated gangliosides into monosialoganglioside GM1. GM1 is the optimal binding target for the B subunit of a second virulence factor, the AB5 cholera toxin (Ctx). This coordinated process delivers the CtxA subunit into host epithelia, triggering fluid loss via cAMP-mediated activation of anion secretion and inhibition of electroneutral NaCl absorption. We hypothesized that human-specific and human-universal evolutionary loss of the sialic acid N-glycolylneuraminic acid (Neu5Gc) and the consequent excess of N-acetylneuraminic acid (Neu5Ac) contributes to specificity at one or more steps in pathogenesis. Indeed, VcN was less efficient in releasing Neu5Gc than Neu5Ac. We show enhanced binding of Ctx to sections of small intestine and isolated polysialogangliosides from human-like Neu5Gc-deficient Cmah-/- mice compared to wild-type, suggesting that Neu5Gc impeded generation of the GM1 target. Human epithelial cells artificially expressing Neu5Gc were also less susceptible to Ctx binding and CtxA intoxication following VcN treatment. Finally, we found increased fluid secretion into loops of Cmah-/- mouse small intestine injected with Ctx, indicating an additional direct effect on ion transport. Thus, V. cholerae evolved into a human-specific pathogen partly by adapting to the human evolutionary loss of Neu5Gc, optimizing multiple steps in cholera pathogenesis.
Subject(s)
Biological Evolution , Cholera/microbiology , Disease Susceptibility , Epithelial Cells/metabolism , Mixed Function Oxygenases/physiology , Neuraminic Acids/metabolism , Vibrio cholerae/classification , Animals , Cholera/metabolism , Cholera/pathology , Epithelial Cells/pathology , Female , Humans , Intestine, Small/metabolism , Intestine, Small/microbiology , Intestine, Small/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Species Specificity , Vibrio cholerae/pathogenicityABSTRACT
KEY POINTS: â¢Nucleotide binding oligomerization domain (Nod)-like receptors regulate cognition, anxiety and hypothalamic-pituitary-adrenal axis activation. â¢Nod-like receptors regulate central and peripheral serotonergic biology. â¢Nod-like receptors are important for maintenance of gastrointestinal physiology. â¢Intestinal epithelial cell expression of Nod1 receptors regulate behaviour. ABSTRACT: Gut-brain axis signalling is critical for maintaining health and homeostasis. Stressful life events can impact gut-brain signalling, leading to altered mood, cognition and intestinal dysfunction. In the present study, we identified nucleotide binding oligomerization domain (Nod)-like receptors (NLR), Nod1 and Nod2, as novel regulators for gut-brain signalling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, and are important in the regulation of gastrointestinal physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress-induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic-pituitary-adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal cell proliferation and immature neurons, as well as reduced neural activation. In addition, NodDKO mice had increased gastrointestinal permeability and altered serotonin signalling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioural impairments and restored serotonin signalling. We also identified that intestinal epithelial cell-specific deletion of Nod1 (VilCre+ Nod1f/f ), but not Nod2, increased susceptibility to stress-induced anxiety-like behaviour and cognitive impairment following exposure to stress. Together, these data suggest that intestinal epithelial NLR are novel modulators of gut-brain communication and may serve as potential novel therapeutic targets for the treatment of gut-brain disorders.
Subject(s)
Brain/metabolism , Intestinal Mucosa/metabolism , Nod1 Signaling Adaptor Protein/metabolism , Nod2 Signaling Adaptor Protein/metabolism , Serotonin/metabolism , Synaptic Transmission , Animals , Anxiety/etiology , Anxiety/metabolism , Brain/physiology , Cells, Cultured , Cognition , Female , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/physiology , Intestinal Absorption , Intestinal Mucosa/physiology , Male , Mice , Mice, Inbred C57BL , Neurogenesis , Nod1 Signaling Adaptor Protein/genetics , Nod2 Signaling Adaptor Protein/genetics , Stress, Psychological/etiology , Stress, Psychological/metabolismABSTRACT
Congenital tufting enteropathy (CTE) is an autosomal recessive disease characterized by severe intestinal failure in infancy and mutations in the epithelial cell adhesion molecule (EPCAM) gene. Previous studies of CTE in mice expressing mutant EpCAM show neonatal lethality. Hence, to study the cellular, molecular, and physiological alterations that result from EpCAM mutation, a tamoxifen-inducible mutant EpCAM enteroid model has been generated. The presence of mutant EpCAM in the model was confirmed at both mRNA and protein levels. Immunofluorescence microscopy demonstrated the reduced expression of mutant EpCAM. Mutant enteroids had reduced budding potential as well as significantly decreased mRNA expression for epithelial lineage markers (Mucin 2, lysozyme, sucrase-isomaltase), proliferation marker Ki67, and secretory pathway transcription factors (Atoh1, Hnf1b). Significantly decreased numbers of Paneth and goblet cells were confirmed by staining. These findings were correlated with intestinal tissue from CTE patients and the mutant mice model that had significantly fewer Paneth and goblet cells than in healthy counterparts. FITC-dextran studies demonstrated significantly impaired barrier function in monolayers derived from mutant enteroids compared with control monolayers. In conclusion, we have established an ex vivo CTE model. The role of EpCAM in the budding potential, differentiation, and barrier function of enteroids is noted. Our study establishes new facets of EpCAM biology that will aid in understanding the pathophysiology of CTE and role of EpCAM in health and disease.NEW & NOTEWORTHY Here, we develop a novel ex vivo enteroid model for congenital tufting enteropathy (CTE) based on epithelial cell adhesion molecule (EPCAM) gene mutations found in patients. With this model we demonstrate the role of EpCAM in maintaining the functional homeostasis of the intestinal epithelium, including differentiation, proliferation, and barrier integrity. This study further establishes a new direction in EpCAM biology that will help in understanding the detailed pathophysiology of CTE and role of EpCAM.
Subject(s)
Diarrhea, Infantile/genetics , Epithelial Cell Adhesion Molecule/genetics , Intestinal Mucosa/cytology , Malabsorption Syndromes/genetics , Tissue Culture Techniques/methods , Animals , Cell Differentiation , Cell Proliferation , Cells, Cultured , Diarrhea, Infantile/pathology , Epithelial Cell Adhesion Molecule/metabolism , Female , Goblet Cells/cytology , Goblet Cells/metabolism , Goblet Cells/physiology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Malabsorption Syndromes/pathology , Male , Mice , Mice, Inbred C57BL , Paneth Cells/cytology , Paneth Cells/metabolism , Paneth Cells/physiologyABSTRACT
Crohn's disease (CD) is an inflammatory bowel disease that can involve any region of the gastrointestinal tract. First described in 1932 as terminal ileitis or regional enteritis, it predominately involves the ileum with or without colonic involvement. Isolated colonic CD was first described in 1960 and since then the phenotypic classification of CD has evolved to stratify patients into isolated ileal, ileocolonic, or isolated colonic involvement. In the current review we evaluate the published literature regarding differences in epidemiology, natural history, pathogenesis, response to therapy, and disease monitoring, when stratified by disease location. Based on the available evidence consideration could be given to a new classification for CD, which splits it into ileum dominant (isolated ileal and ileocolonic) and isolated colonic disease. This may allow for a more optimized approach to clinical care and scientific research for CD.
Subject(s)
Colitis/physiopathology , Crohn Disease/classification , Crohn Disease/physiopathology , Ileitis/physiopathology , Autophagy/physiology , Colitis/epidemiology , Colitis/immunology , Colitis/therapy , Crohn Disease/epidemiology , Crohn Disease/therapy , Cytokines/immunology , Disease Progression , Gastrointestinal Microbiome/physiology , Humans , Ileitis/epidemiology , Ileitis/immunology , Ileitis/therapy , Risk Factors , T-Lymphocytes/immunologyABSTRACT
BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic TH2-assocated inflammatory condition accompanied by substantial impairments in epithelial barrier function and increased numbers of interleukin 9 (IL-9) expressing inflammatory cells. While IL-9 is known to affect barrier function in the intestine, the functional effects of IL-9 on the esophagus are unclear. Herein we aimed to understand the expression of the IL-9 receptor and effects of IL-9 on the epithelium in EoE. METHODS: We used esophageal biopsies from pediatric EoE patients with active and inactive disease to analyze the expression of the IL-9 receptor, the adherens junction protein E-cadherin and the tight junction protein claudin-1. We treated primary human esophageal epithelial cells with IL-9 to understand its effects on E-cadherin expression and function. RESULTS: Active EoE subjects had increased epithelial expression of IL-9 receptor mRNA and protein (Pâ<â0.05) and decreased membrane bound E-cadherin (Pâ<â0.01) and claudin-1 (Pâ<â0.05) expression. IL-9 receptor expression and mislocalized claudin-1 positively correlated and while membrane bound E-cadherin expression negatively correlated with the degree of histologic epithelial remodeling (Pâ<â0.05). IL-9 decreased epithelial resistance in stratified primary human esophageal epithelial cells (Pâ<â0.01) and membrane bound E-cadherin in epithelial cell monolayers (Pâ<â0.01). CONCLUSIONS: These data suggest that IL-9, its receptor, and its effects on E-cadherin may be important mechanisms for epithelial barrier disruption in EoE.
Subject(s)
Antigens, CD/metabolism , Cadherins/metabolism , Eosinophilic Esophagitis/metabolism , Esophagus/metabolism , Interleukin-9/metabolism , Receptors, Interleukin-9/metabolism , Biopsy , Child , Eosinophilic Esophagitis/pathology , Epithelial Cells/metabolism , Epithelium/metabolism , Epithelium/pathology , Esophagus/pathology , Female , Humans , MaleABSTRACT
Chronic watery diarrhea poses a diagnostic and therapeutic challenge and is often a disabling condition for patients. Although acute diarrhea is likely to be caused by infection, the causes of chronic diarrhea (>4 weeks in duration) are more elusive. We review the pathophysiology, diagnosis, and treatment of chronic diarrhea. Drawing on recent insights into the molecular mechanisms of intestinal epithelial transport and barrier function, we discuss how diarrhea can result from a decrease in luminal solute absorption, an increase in secretion, or both, as well as derangements in barrier properties. We also describe the various extraepithelial factors that activate diarrheal mechanisms. Finally, clinical evaluation and tests used in the assessment of patients presenting with chronic diarrhea are reviewed, and an algorithm guiding therapeutic decisions and pharmacotherapy is presented.
Subject(s)
Diarrhea/metabolism , Intestinal Absorption , Intestinal Mucosa/metabolism , Intestinal Secretions , C-Reactive Protein/metabolism , Chromogranins/metabolism , Chronic Disease , Diarrhea/diagnosis , Diarrhea/physiopathology , Diarrhea/therapy , Feces/chemistry , Gastrointestinal Motility , Humans , Inflammation , Intestines/physiopathology , Irritable Bowel Syndrome/metabolism , Lactoferrin/metabolism , Leukocyte L1 Antigen Complex/metabolism , Osmolar Concentration , Permeability , Prostaglandins/metabolism , Serotonin/metabolism , Substance P/metabolismABSTRACT
Transport of fluid and electrolytes in the intestine allows for appropriate adjustments in luminal fluidity while reclaiming water used in digesting and absorbing a meal, and is closely regulated. This article discusses various endogenous and exogenous mechanisms whereby transport is controlled in the gut, placing these in the context of the ideas about the neurohumoral control of alimentary physiology that were promulgated by William Bayliss and Ernest Starling. The article considers three themes. First, mechanisms that intrinsically regulate chloride secretion, centred on the epidermal growth factor receptor (EGFr), are discussed. These may be important in ensuring that excessive chloride secretion, with the accompanying loss of fluid, is not normally stimulated by intestinal distension as the meal passes through the gastrointestinal tract. Second, mechanisms whereby probiotic microorganisms can impart beneficial effects on the gut are described, with a focus on targets at the level of the epithelium. These findings imply that the commensal microbiota exert important influences on the epithelium in health and disease. Finally, mechanisms that lead to diarrhoea in patients infected with an invasive pathogen, Salmonella, are considered, based on recent studies in a novel mouse model. Diarrhoea is most likely attributable to reduced expression of absorptive transporters and may not require the influx of neutrophils that accompanies infection. Overall, the goal of the article is to highlight the many ways in which critical functions of the intestinal epithelium are regulated under physiological and pathophysiological conditions, and to suggest possible targets for new therapies for digestive disease states.