Prebiotic inulin and sodium butyrate attenuate barrier dysfunction by induction of antimicrobial peptides in diet-induced obese mice

Defects in the mucosal barrier have been associated with metabolic diseases such as obesity and non-alcoholic fatty liver disease (NAFLD). Mice fed a Western-style diet (WSD) develop obesity and are characterized by a diet-induced intestinal barrier dysfunction, bacterial endotoxin translocation and subsequent liver steatosis. To examine whether inulin or sodium butyrate could improve gut barrier dysfunction, C57BL/6 mice were fed a control diet or a WSD ± fructose supplemented with either 10% inulin or 5% sodium butyrate for 12 weeks respectively. Inulin and sodium butyrate attenuated hepatosteatitis in the WSD-induced obesity mouse model by reducing weight gain, liver weight, plasma and hepatic triglyceride level. Furthermore, supplementation with inulin or sodium butyrate induced expression of Paneth cell α-defensins and matrix metalloproteinase-7 (MMP7), which was impaired by the WSD and particularly the fructose-added WSD. Effects on antimicrobial peptide function in the ileum were accompanied by induction of β-defensin-1 and tight junction genes in the colon resulting in improved intestinal permeability and endotoxemia. Organoid culture of small intestinal crypts revealed that the short chain fatty acids (SCFA) butyrate, propionate and acetate, fermentation products of inulin, induce Paneth cell α-defensin expression in vitro, and that histone deacetylation and STAT3 might play a role in butyrate-mediated induction of α-defensins. In summary, inulin and sodium butyrate attenuate diet-induced barrier dysfunction and induce expression of Paneth cell antimicrobials. The administration of prebiotic fiber or sodium butyrate could be an interesting therapeutic approach to improve diet-induced obesity.

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Genetically obese mice do not show increased gut permeability or faecal bile acid hydrophobicity

British Journal Of Nutrition ◽

10.1017/s000711451300024x ◽

2013 ◽

Vol 110 (6) ◽

pp. 1157-1164 ◽

Cited By ~ 18

Author(s):

Lotta K. Stenman ◽

Reetta Holma ◽

Helena Gylling ◽

Riitta Korpela

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Intestinal Permeability ◽

Low Grade ◽

Obese Mice ◽

Gut Permeability ◽

Barrier Dysfunction ◽

Gut Barrier ◽

Genetic Obesity ◽

Gut Barrier Function

Gut barrier dysfunction may lead to metabolic endotoxaemia and low-grade inflammation. Recent publications have demonstrated gut barrier dysfunction in obesity induced by a diet high in fat, and a pathogenetic role for luminal bile acids has been proposed. We aimed to investigate whether genetically obese mice develop increased gut permeability and alterations in luminal bile acids on a diet with a regular fat content. We used seven obese male ob/ob mice of C57BL/6J background and ten male wild-type (WT) mice of the same strain. Faeces were collected for bile acid analysis. Intestinal permeability was measured in an Ussing chamber upon euthanasia, using 4 kDa fluorescein isothiocyanate dextran, as per mille (‰, 1/1000) of translocated dextran. We analysed the liver expression of lipopolysaccharide-binding protein (LBP), as well as serum LBP (ELISA). Intestinal permeability was not affected by genetic obesity (jejunum: 0·234 (sem 0·04) ‰ for obese v. 0·225 (sem 0·03) ‰ for WT, P= 0·93; colon: 0·222 (sem 0·06) ‰ for obese v. 0·184 (sem 0·03) ‰ for WT, P= 0·86), nor was liver LBP expression (relative expression: 0·55 (sem 0·08) for obese v. 0·55 (sem 0·13) for WT, P= 0·70). Serum LBP was 2·5-fold higher in obese than in WT mice (P= 0·001). Obese mice had increased daily excretion of total bile acids, but their faecal bile acid hydrophobicity was unchanged. In conclusion, genetic obesity did not impair gut barrier function in mice on a regular chow diet, nor was faecal bile acid hydrophobicity affected.

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Antihypertensive agents do not prevent blood–brain barrier dysfunction and cognitive deficits in dietary-induced obese mice

International Journal of Obesity ◽

10.1038/ijo.2017.57 ◽

2017 ◽

Vol 41 (6) ◽

pp. 926-934 ◽

Cited By ~ 12

Author(s):

J C L Mamo ◽

V Lam ◽

C Giles ◽

S H Coulson ◽

N Fimognari ◽

...

Keyword(s):

Blood Brain Barrier ◽

Cognitive Deficits ◽

Antihypertensive Agents ◽

Brain Barrier ◽

Obese Mice ◽

Barrier Dysfunction ◽

Blood Brain

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Obesity Attenuates Ventilator-Induced Lung Injury by Modulating the STAT3–SOCS3 Pathway

Frontiers in Immunology ◽

10.3389/fimmu.2021.720844 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shih-Wei Wu ◽

Chung-Kan Peng ◽

Shu-Yu Wu ◽

Yu Wang ◽

Sung-Sen Yang ◽

...

Keyword(s):

Lung Injury ◽

Lung Injury Score ◽

Protective Mechanism ◽

Free Access ◽

Obese Mice ◽

Wild Type ◽

Barrier Dysfunction ◽

Ventilator Induced Lung Injury ◽

Nfκb Pathway ◽

Set Up

BackgroundVentilator-induced lung injury (VILI) is characterized by vascular barrier dysfunction and suppression of alveolar fluid clearance (AFC). Obesity itself leads to chronic inflammation, which may initiate an injurious cascade to the lungs and simultaneously induce a protective feedback. In this study, we investigated the protective mechanism of obesity on VILI in a mouse model.MethodsThe VILI model was set up via 6-h mechanical ventilation with a high tidal volume. Parameters including lung injury score, STAT3/NFκB pathway, and AFC were assessed. Mice with diet-induced obesity were obtained by allowing free access to a high-fat diet since the age of 3 weeks. After a 9-week diet intervention, these mice were sacrificed at the age of 12 weeks. The manipulation of SOCS3 protein was achieved by siRNA knockdown and pharmaceutical stimulation using hesperetin. WNK4 knockin and knockout obese mice were used to clarify the pathway of AFC modulation.ResultsObesity itself attenuated VILI. Knockdown of SOCS3 in obese mice offset the protection against VILI afforded by obesity. Hesperetin stimulated SOCS3 upregulation in nonobese mice and provided protection against VILI. In obese mice, the WNK4 axis was upregulated at the baseline, but was significantly attenuated after VILI compared with nonobese mice. At the baseline, the manipulation of SOCS3 by siRNA and hesperetin also led to the corresponding alteration of WNK4, albeit to a lesser extent. After VILI, WNK4 expression correlated with STAT3/NFκB activation, regardless of SOCS3 status. Obese mice carrying WNK4 knockout had VILI with a severity similar to that of wild-type obese mice. The severity of VILI in WNK4-knockin obese mice was counteracted by obesity, similar to that of wild-type nonobese mice only.ConclusionsObesity protects lungs from VILI by upregulating SOCS3, thus suppressing the STAT3/NFκB inflammatory pathway and enhancing WNK4-related AFC. However, WNK4 activation is mainly from direct NFκB downstreaming, and less from SOCS3 upregulation. Moreover, JAK2–STAT3/NFκB signaling predominates the pathogenesis of VILI. Nevertheless, the interaction between SOCS3 and WNK4 in modulating VILI in obesity warrants further investigation.

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Alterations of Gut Microbiota Prior to Changes of Paneth Cell‐antimicrobial Peptides in High Fat‐induced Obese Mice

The FASEB Journal ◽

10.1096/fasebj.30.1_supplement.1166.5 ◽

2016 ◽

Vol 30 (S1) ◽

Author(s):

Xiulan Guo ◽

Jinchao Li ◽

Renyong Tang ◽

Wei Liu ◽

Zhenhua Liu

Keyword(s):

Gut Microbiota ◽

Antimicrobial Peptides ◽

Paneth Cell ◽

Obese Mice ◽

High Fat

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Deletion of the Casp8 gene in mice results in ileocolitis, gut barrier dysfunction, and malassimilation, which can be partially attenuated by inulin or sodium butyrate

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00297.2018 ◽

2019 ◽

Vol 317 (4) ◽

pp. G493-G507 ◽

Cited By ~ 3

Author(s):

Valentina Kaden-Volynets ◽

Claudia Günther ◽

Julia Zimmermann ◽

Julia Beisner ◽

Christoph Becker ◽

...

Keyword(s):

Body Weight ◽

Sodium Butyrate ◽

Barrier Function ◽

Liver Steatosis ◽

Caspase 8 ◽

Free Access ◽

Barrier Dysfunction ◽

Gut Barrier ◽

Inflammatory Bowel ◽

The Impact

Genetically modified mice have been successfully used as models for inflammatory bowel diseases; however, dietary effects were poorly examined. Here, we studied the impact of particular nutrients and supplements on gut functions related to the knockout of the epithelial caspase-8 gene. Caspase-8 knockout (Casp8∆IEC) and control (Casp8fl) mice were fed for 4 wk a control diet (CD) enriched with 10% inulin (CD-Inu) or 5% sodium butyrate (CD-But) while having free access to plain water or water supplemented with 30% fructose (+F). Body weight changes, intestinal inflammation, and selected markers for barrier function and of liver steatosis were assessed. Casp8∆IEC mice developed ileocolitis accompanied by changes in intestinal barrier morphology and reduced expression of barrier-related genes such as mucin-2 ( Muc2) and defensins in the ileum and Muc2 in the colon. Casp8∆IEC mice fed a CD also showed impaired body weight gain compared with Casp8fl mice, which was even more pronounced in mice receiving water supplemented with fructose. Furthermore, we observed a marked liver steatosis and inflammation in some but not all Casp8∆IEC mice under a CD, which was on average similar to that observed in control mice under a fructose-rich diet. Hepatic lipid accumulation, as well as markers of ileal barrier function, but not intestinal pathohistology or body weight loss, were attenuated by diets enriched with inulin or butyrate, especially in the absence of fructose supplementation. Our data show that ileocolitis, barrier dysfunction, and malassimilation in Caspase-8 knockout mice can be partially attenuated by oral inulin or butyrate supplementation. NEW & NOTEWORTHY Genetic mouse models for ileocolitis are important to understand inflammatory bowel disease in humans. We examined dietetic factors that might aggravate or attenuate ileocolitis and related pathologies in such a model. Deletion of the caspase-8 gene results not only in ileocolitis but also in gut barrier dysfunction, liver steatosis, and malassimilation, which can be partially attenuated by oral inulin or sodium butyrate. Our data indicate that diet modifications can contribute to disease variability and therapy.

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