Nutritional deficiency recapitulates intestinal injury associated with environmental enteric dysfunction in patient-derived Organ Chips

Environmental Enteric Dysfunction (EED) is a chronic inflammatory condition of the intestine characterized by villus blunting, compromised intestinal barrier function, and reduced nutrient absorption. Here, we show that key genotypic and phenotypic features of EED-associated intestinal injury can be reconstituted in a human intestine-on-a-chip (Intestine Chip) microfluidic culture device lined by organoid-derived intestinal epithelial cells from EED patients and cultured in niacinamide- and tryptophan-deficient (-N/-T) medium. Exposure of EED Intestine Chips to -N/-T deficiencies resulted in transcriptional changes similar to those seen in clinical EED patient samples including congruent changes in six of the top ten upregulated genes. Exposure of EED Intestine Chips or chips lined by healthy intestinal epithelium (healthy Intestine Chips) to -N/-T medium resulted in severe villus blunting and barrier dysfunction, as well as impairment of fatty acid uptake and amino acid transport. EED Intestine Chips exhibited reduced secretion of cytokines at baseline, but their production was significantly upregulated compared to healthy Intestine Chips when exposed to -N/-T deficiencies. The human Intestine Chip model of EED-associated intestinal injury may be useful for analyzing the molecular, genetic, and nutritional basis of this disease and can serve as a preclinical model for testing potential EED therapeutics.

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BAFF Blockade Attenuates Inflammatory Responses and Intestinal Barrier Dysfunction in a Murine Endotoxemia Model

Frontiers in Immunology ◽

10.3389/fimmu.2020.570920 ◽

2020 ◽

Vol 11 ◽

Author(s):

Runze Quan ◽

Chaoyue Chen ◽

Wei Yan ◽

Ying Zhang ◽

Xi Zhao ◽

...

Keyword(s):

Barrier Function ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Survival Rates ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Barrier Dysfunction ◽

Protein Levels ◽

Lps Challenge ◽

Endotoxemia Model

B cell-activating factor (BAFF) production is increased in septic patients. However, the specific role of BAFF in sepsis remains unknown. This study was designed to investigate the expression and function of BAFF in an experimental endotoxemia model and to identify the potential mechanisms. We established an endotoxemia mouse (6–8 weeks, 20–22 g) model by administering 30 mg/kg lipopolysaccharide (LPS). BAFF levels in the circulating system and organ tissues were measured 4 and 8 h after LPS injection. Survival rates in the endotoxemia mice were monitored for 72 h after BAFF blockade. The effects of BAFF blockade on systemic and local inflammation, organ injuries, and intestinal barrier function were also evaluated 4 h after LPS treatment. BAFF production was systemically and locally elevated after LPS challenge. BAFF blockade improved the survival rate, systemic inflammation, and multi-organ injuries. Moreover, BAFF blockade attenuated both intestinal inflammation and impaired intestinal permeability. BAFF blockade upregulated ZO-1 and occludin protein levels via the NF-κB/MLCK/MLC signaling pathway. These results suggested that BAFF blockade protects against lethal endotoxemia at least partially by alleviating inflammation, multi-organ injuries, and improving intestinal barrier function and provides a novel focus for further research on sepsis and experimental evidence for clinical therapy.

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STAT3 Signalling via the IL-6ST/gp130 Cytokine Receptor Promotes Epithelial Integrity and Intestinal Barrier Function during DSS-Induced Colitis

Biomedicines ◽

10.3390/biomedicines9020187 ◽

2021 ◽

Vol 9 (2) ◽

pp. 187

Author(s):

Lokman Pang ◽

Jennifer Huynh ◽

Mariah G. Alorro ◽

Xia Li ◽

Matthias Ernst ◽

...

Keyword(s):

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Intestinal Epithelial ◽

Barrier Dysfunction ◽

Epithelial Integrity ◽

Barrier Integrity ◽

Gp130 Receptor ◽

Stat3 Signalling

The intestinal epithelium provides a barrier against commensal and pathogenic microorganisms. Barrier dysfunction promotes chronic inflammation, which can drive the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although the Signal Transducer and Activator of Transcription-3 (STAT3) is overexpressed in both intestinal epithelial cells and immune cells in IBD patients, the role of the interleukin (IL)-6 family of cytokines through the shared IL-6ST/gp130 receptor and its associated STAT3 signalling in intestinal barrier integrity is unclear. We therefore investigated the role of STAT3 in retaining epithelial barrier integrity using dextran sulfate sodium (DSS)-induced colitis in two genetically modified mouse models, to either reduce STAT1/3 activation in response to IL-6 family cytokines with a truncated gp130∆STAT allele (GP130∆STAT/+), or by inducing short hairpin-mediated knockdown of Stat3 (shStat3). Here, we show that mice with reduced STAT3 activity are highly susceptible to DSS-induced colitis. Mechanistically, the IL-6/gp130/STAT3 signalling cascade orchestrates intestinal barrier function by modulating cytokine secretion and promoting epithelial integrity to maintain a defence against bacteria. Our study also identifies a crucial role of STAT3 in controlling intestinal permeability through tight junction proteins. Thus, therapeutically targeting the IL-6/gp130/STAT3 signalling axis to promote barrier function may serve as a treatment strategy for IBD patients.

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Anthocyanins and intestinal barrier function: a review

Journal of Food Bioactives ◽

10.31665/jfb.2019.5175 ◽

2019 ◽

Vol 5 ◽

pp. 18-30 ◽

Cited By ~ 4

Author(s):

Jonathan C. Valdez ◽

Bradley W. Bolling

Keyword(s):

Barrier Function ◽

Intestinal Inflammation ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Barrier Dysfunction ◽

Intestinal Barrier Dysfunction ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Berry Anthocyanins ◽

Chronic Intestinal Inflammation

Chronic intestinal inflammation, occurring in inflammatory bowel diseases (IBD), is associated with compromised intestinal barrier function. Inflammatory cytokines disrupt tight junctions and increase paracellular permeability of luminal antigens. Thus, chronic intestinal barrier dysfunction hinders the resolution of inflammation. Dietary approaches may help mitigate intestinal barrier dysfunction and chronic inflammation. A growing body of work in rodent models of colitis has demonstrated that berry consumption inhibits chronic intestinal inflammation. Berries are a rich dietary source of polyphenolic compounds, particularly anthocyanins. However, berry anthocyanins have limited bioavailability and are extensively metabolized by the gut microbiota and host tissue. This review summarizes the literature regarding the beneficial functions of anthocyanin-rich berries in treating and preventing IBD. Here, we will establish the role of barrier function in the pathogenesis of IBD and how dietary anthocyanins and their known microbial catabolites modulate intestinal barrier function.

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Impacts of Fructose on Intestinal Barrier Function, Inflammation and Microbiota in a Piglet Model

Nutrients ◽

10.3390/nu13103515 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3515

Author(s):

Pingting Guo ◽

Haichao Wang ◽

Linbao Ji ◽

Peixia Song ◽

Xi Ma

Keyword(s):

Inflammatory Response ◽

Tight Junction ◽

Growth Performance ◽

Oxidant Stress ◽

Intestinal Barrier ◽

Sensu Stricto ◽

Intestinal Barrier Function ◽

Human Beings ◽

Barrier Dysfunction ◽

Gene Expressions

The metabolic disorder caused by excessive fructose intake was reported extensively and often accompanied by intestinal barrier dysfunction. And the rising dietary fructose was consumed at an early age of human. However, related researches were almost conducted in rodent models, while in the anatomy and physiology of gastrointestinal tract, pig is more similar to human beings than rodents. Hence, weaned piglets were chosen as the model animals in our study to investigate the fructose’s impacts on intestinal tight junction, inflammation response and microbiota structure of piglets. Herein, growth performance, inflammatory response, oxidation resistance and ileal and colonic microbiota of piglet were detected after 35-day fructose supplementation. Our results showed decreased tight junction gene expressions in piglets after fructose addition, with no obvious changes in the growth performance, antioxidant resistance and inflammatory response. Moreover, fructose supplementation differently modified the microbiota structures in ileum and colon. In ileum, the proportions of Streptococcus and Faecalibacterium were higher in Fru group (fructose supplementation). In colon, the proportions of Blautia and Clostridium sensu stricto 1 were higher in Fru group. All the results suggested that tight junction dysfunction might be an earlier fructose-induced event than inflammatory response and oxidant stress and that altered microbes in ileum and colon might be the potential candidates to alleviate fructose-induced intestinal permeability alteration.

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Intestinal Barrier Function in Gluten-Related Disorders

Nutrients ◽

10.3390/nu11102325 ◽

2019 ◽

Vol 11 (10) ◽

pp. 2325 ◽

Cited By ~ 13

Author(s):

Danielle Cardoso-Silva ◽

Deborah Delbue ◽

Alice Itzlinger ◽

Renée Moerkens ◽

Sebo Withoff ◽

...

Keyword(s):

Immune Response ◽

Celiac Disease ◽

Immunoglobulin E ◽

Intestinal Barrier ◽

Causative Factor ◽

Mucosal Barrier ◽

Intestinal Barrier Function ◽

Epithelial Barrier ◽

Barrier Dysfunction ◽

Wheat Sensitivity

Gluten-related disorders include distinct disease entities, namely celiac disease, wheat-associated allergy and non-celiac gluten/wheat sensitivity. Despite having in common the contact of the gastrointestinal mucosa with components of wheat and other cereals as a causative factor, these clinical entities have distinct pathophysiological pathways. In celiac disease, a T-cell mediate immune reaction triggered by gluten ingestion is central in the pathogenesis of the enteropathy, while wheat allergy develops as a rapid immunoglobulin E- or non-immunoglobulin E-mediated immune response. In non-celiac wheat sensitivity, classical adaptive immune responses are not involved. Instead, recent research has revealed that an innate immune response to a yet-to-be-defined antigen, as well as the gut microbiota, are pivotal in the development in this disorder. Although impairment of the epithelial barrier has been described in all three clinical conditions, its role as a potential pathogenetic co-factor, specifically in celiac disease and non-celiac wheat sensitivity, is still a matter of investigation. This article gives a short overview of the mucosal barrier of the small intestine, summarizes the aspects of barrier dysfunction observed in all three gluten-related disorders and reviews literature data in favor of a primary involvement of the epithelial barrier in the development of celiac disease and non-celiac wheat sensitivity.

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CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP) Deficiency Attenuates Heatstroke-Induced Intestinal Injury

Inflammation ◽

10.1007/s10753-021-01577-x ◽

2021 ◽

Author(s):

Yan Cao ◽

Maiying Fan ◽

Yanfang Pei ◽

Lei Su ◽

Weiwei Xiao ◽

...

Keyword(s):

Protein Expression ◽

Er Stress ◽

Intestinal Barrier ◽

Intestinal Injury ◽

Intestinal Epithelial ◽

Barrier Dysfunction ◽

Homologous Protein

Abstract The intestine is one of the main target organs involved in the pathological process of heatstroke. CCAAT/enhancer-binding protein homologous protein (CHOP) is involved in endoplasmic reticulum (ER) stress-induced apoptosis. This study aimed to explore the role of CHOP in heatstroke-induced intestinal injury and potential therapy. An in vitro heat stress (HS) model using Caco-2 cells was employed. We observed the role of CHOP in apoptosis-mediated intestinal epithelial cell injury secondary to HS by evaluating cell viability, lactate dehydrogenase release, apoptosis levels, and GRP78, PERK, ATF4, CHOP, Bcl-2, and BAX mRNA and protein expression. To further study the role of CHOP in HS-induced intestinal barrier dysfunction, we assessed transepithelial electrical resistance, paracellular tracer flux, ultrastructure of tight junctions, and protein expression of ZO-1 and occludin. Male wild-type mice and CHOP knockout mice were used for in vivo experiments. We evaluated serum d-lactate and diamine oxidase levels, histopathological changes, intestinal ultrastructure, and ZO-1 and occludin protein expression. HS activated the PERK-CHOP pathway and promoted apoptosis by upregulating BAX and downregulating Bcl-2; these effects were prevented by CHOP silencing. Intestinal epithelial barrier function was disrupted by HS in vitro and in vivo. CHOP silencing prevented intestinal barrier dysfunction in Caco-2 cells, whereas CHOP knockout mice exhibited decreased intestinal mucosal injury. The ER stress inhibitor 4-phenylbutyrate (4-PBA) prevented HS-induced intestinal injury in vitro and in vivo. This study indicated that CHOP deficiency attenuates heatstroke-induced intestinal injury and may contribute to the identification of a novel therapy against heatstroke associated with the ER stress pathway.

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Lactobacillus rhamnosus GG Attenuates Lipopolysaccharide-Induced Inflammation and Barrier Dysfunction by Regulating MAPK/NF-κB Signaling and Modulating Metabolome in the Piglet Intestine

Journal of Nutrition ◽

10.1093/jn/nxaa009 ◽

2020 ◽

Vol 150 (5) ◽

pp. 1313-1323 ◽

Cited By ~ 4

Author(s):

Jiangdi Mao ◽

Siri Qi ◽

Yanjun Cui ◽

Xiaoxiao Dou ◽

Xin M Luo ◽

...

Keyword(s):

P38 Mapk ◽

Intraperitoneal Injection ◽

Intestinal Barrier ◽

Mitogen Activated Protein Kinase ◽

Intestinal Barrier Function ◽

Saline Control ◽

Barrier Dysfunction ◽

Large White ◽

Oral Inoculation ◽

Tnf Α

ABSTRACT Background Probiotic Lactobacillius rhamnosus GG (LGG) shows beneficial immunomodulation on cultured cell lines in vitro and in mouse models. Objective The aim was to investigate the effects of LGG on intestinal injury and the underlying mechanisms by elucidating inflammatory signaling pathways and metabolomic response to LPS stimulation in the piglet intestine. Methods Piglets (Duroc × Landrace × Large White, including males and female; 8.6 ± 1.1 kg) aged 28 d were assigned to 3 groups (n = 6/group): oral inoculation with PBS for 2 wk before intraperitoneal injection of physiological saline [control (CON)] or LPS (25 μg/kg body weight; LPS) or oral inoculation with LGG for 2 wk before intraperitoneal injection of LPS (LGG+LPS). Piglets were killed 4 h after LPS injection. Systemic inflammation, intestinal integrity, inflammation signals, and metabolomic characteristics in the intestine were determined. Results Compared with CON, LPS stimulation significantly decreased ileal zonula occludens 1 (ZO-1; 44%), claudin-3 (44%), and occludin (41%) expression; increased serum diamineoxidase (73%), D-xylose (19%), TNF-α (43%), and IL-6 (55%) concentrations; induced p38 mitogen-activated protein kinase (p38 MAPK; 85%), extracellular signal-regulated kinase (ERK; 96%), and NF-κB p65 phosphorylation (37%) (P < 0.05). Compared with LPS stimulation alone, LGG pretreatment significantly enhanced the intestinal barrier by upregulating expressions of tight junction proteins (ZO-1, 73%; claudin-3, 55%; occludin, 67%), thereby decreasing serum diamineoxidase (26%) and D-xylose (28%) concentrations, and also reduced serum TNF-α expression (16%) and ileal p38 MAPK (79%), ERK (43%) and NF-κB p65 (37%) phosphorylation levels (P < 0.05). Metabolomic analysis showed clear separation between each group. The concentrations of caprylic acid [fold-change (FC) = 2.39], 1-mono-olein (FC = 2.68), erythritol (FC = 4.62), and ethanolamine (FC = 4.47) significantly increased in the intestine of LGG + LPS piglets compared with the LPS group (P < 0.05). Conclusions These data suggest that LGG alleviates gut inflammation, improves intestinal barrier function, and modulates the metabolite profile of piglets challenged with LPS. This trial was registered at the Zhejiang University (http://www.lac.zju.edu.cn) as ZJU20170529.

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Oleanolic acid ameliorates intestinal alterations associated with EAE

Journal of Neuroinflammation ◽

10.1186/s12974-020-02042-6 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Beatriz Gutierrez ◽

Isabel Gallardo ◽

Lorena Ruiz ◽

Yolanda Alvarez ◽

Victoria Cachofeiro ◽

...

Keyword(s):

Oleanolic Acid ◽

Inflammatory Responses ◽

Intestinal Barrier ◽

Serum Levels ◽

Short Chain Fatty Acids ◽

Preclinical Model ◽

Gastrointestinal Hormone ◽

Barrier Dysfunction ◽

Anti Inflammatory

Abstract Background Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease affecting the CNS. Recent studies have indicated that intestinal alterations play key pathogenic roles in the development of autoimmune diseases, including MS. The triterpene oleanolic acid (OA), due to its anti-inflammatory properties, has shown to beneficially influence the severity of the experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS. We herein investigate EAE-associated gut intestinal dysfunction and the effect of OA treatment. Methods Mice with MOG35–55-induced EAE were treated with OA or vehicle from immunization day and were daily analyzed for clinical deficit. We performed molecular and histological analysis in serum and intestinal tissues to measure oxidative and inflammatory responses. We used Caco-2 and HT29-MTX-E12 cells to elucidate OA in vitro effects. Results We found that OA protected from EAE-induced changes in intestinal permeability and preserved the mucin-containing goblet cells along the intestinal tract. Serum levels of the markers for intestinal barrier damage iFABP and monocyte activation sCD14 were consistently and significantly reduced in OA-treated EAE mice. Beneficial OA effects also included a decrease of pro-inflammatory mediators both in serum and colonic tissue of treated-EAE mice. Moreover, the levels of some immunoregulatory cytokines, the neurotrophic factor GDNF, and the gastrointestinal hormone motilin were preserved in OA-treated EAE mice. Regarding oxidative stress, OA treatment prevented lipid peroxidation and superoxide anion accumulation in intestinal tissue, while inducing the expression of the ROS scavenger Sestrin-3. Furthermore, short-chain fatty acids (SCFA) quantification in the cecal content showed that OA reduced the high iso-valeric acid concentrations detected in EAE-mice. Lastly, using in vitro cell models which mimic the intestinal epithelium, we verified that OA protected against intestinal barrier dysfunction induced by injurious agents produced in both EAE and MS. Conclusion These findings reveal that OA ameliorates the gut dysfunction found in EAE mice. OA normalizes the levels of gut mucosal dysfunction markers, as well as the pro- and anti-inflammatory immune bias during EAE, thus reinforcing the idea that OA is a beneficial compound for treating EAE and suggesting that OA may be an interesting candidate to be explored for the treatment of human MS.

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Intestinal Barrier Dysfunction, LPS Translocation, and Disease Development

Journal of the Endocrine Society ◽

10.1210/jendso/bvz039 ◽

2020 ◽

Vol 4 (2) ◽

Cited By ~ 20

Author(s):

Siddhartha S Ghosh ◽

Jing Wang ◽

Paul J Yannie ◽

Shobha Ghosh

Keyword(s):

Barrier Function ◽

Current Knowledge ◽

Intestinal Barrier ◽

Systemic Circulation ◽

Intestinal Barrier Function ◽

Disease Development ◽

Barrier Dysfunction ◽

Intestinal Alkaline Phosphatase ◽

Targeted Interventions ◽

Associated Diseases

Abstract The intestinal barrier is complex and consists of multiple layers, and it provides a physical and functional barrier to the transport of luminal contents to systemic circulation. While the epithelial cell layer and the outer/inner mucin layer constitute the physical barrier and are often referred to as the intestinal barrier, intestinal alkaline phosphatase (IAP) produced by epithelial cells and antibacterial proteins secreted by Panneth cells represent the functional barrier. While antibacterial proteins play an important role in the host defense against gut microbes, IAP detoxifies bacterial endotoxin lipopolysaccharide (LPS) by catalyzing the dephosphorylation of the active/toxic Lipid A moiety, preventing local inflammation as well as the translocation of active LPS into systemic circulation. The causal relationship between circulating LPS levels and the development of multiple diseases underscores the importance of detailed examination of changes in the “layers” of the intestinal barrier associated with disease development and how this dysfunction can be attenuated by targeted interventions. To develop targeted therapies for improving intestinal barrier function, it is imperative to have a deeper understanding of the intestinal barrier itself, the mechanisms underlying the development of diseases due to barrier dysfunction (eg, high circulating LPS levels), the assessment of intestinal barrier function under diseased conditions, and of how individual layers of the intestinal barrier can be beneficially modulated to potentially attenuate the development of associated diseases. This review summarizes the current knowledge of the composition of the intestinal barrier and its assessment and modulation for the development of potential therapies for barrier dysfunction-associated diseases.

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DSS-induced colitis is associated with adipose tissue dysfunction and disrupted hepatic lipid metabolism leading to hepatosteatosis and dyslipidemia in mice

Scientific Reports ◽

10.1038/s41598-021-84761-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jeonghyeon Kwon ◽

Chungho Lee ◽

Sungbaek Heo ◽

Bobae Kim ◽

Chang-Kee Hyun

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Activity Index ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Acid Oxidation ◽

Barrier Dysfunction ◽

Alcoholic Fatty Liver ◽

Brown Adipose

AbstractConsidering high prevalence of non-alcoholic fatty liver diseases (NAFLD) in patients with inflammatory bowel disease (IBD), this study aimed to elucidate molecular mechanisms for how intestinal inflammatory conditions are causally linked to hepatic steatosis and dyslipidemia. Both younger and older mice treated with acute or chronic dextran sodium sulfate (DSS) developed colitis, which was evidenced by weight loss, colon length shortening, and elevated disease activity index and inflammation score. They also showed decreased expression of intestinal barrier function-related proteins and elevated plasma lipopolysaccharide level, indicating DSS-induced barrier dysfunction and thereby increased permeability. Interestingly, they displayed phenotypes of hepatic fat accumulation and abnormal blood lipid profiles. This DSS-induced colitis-associated lipid metabolic dysfunction was due to overall disruption of metabolic processes including fatty acid oxidation, lipogenesis, lipolysis, reverse cholesterol transport, bile acid synthesis, and white adipose tissue browning and brown adipose tissue thermogenesis, most of which are mediated by key regulators of energy homeostasis such as FGF21, adiponectin, and irisin, via SIRT1/PGC-1α- and LXRα-dependent pathways. Our study suggests a potential molecular mechanism underlying the comorbidity of NAFLD and IBD, which could provide a key to understanding how the two diseases are pathogenically linked and discovering critical therapeutic targets for their treatment.

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