Glutamate attenuates lipopolysaccharide induced intestinal barrier injury by regulating corticotropin-releasing factor pathway in weaned pigs

Guo, Junjie; Liang, Tianzeng; Chen, Huifu; Li, Xiangen; Ren, Xiaorui; Wang, Xiuying; Xiao, Kan; Zhao, Jiangchao; Zhu, Huiling; Liu, Yulan

doi:10.5713/ab.21.0476

Cited by 7 publications

(8 citation statements)

References 44 publications

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“…Glutamate has been reported to be elevated in the plasma of active CeD patients (53). It has been also shown to enhance intestinal barrier integrity and antioxidant functions, and to help reduce injury to the intestine caused by inflammation (56).…”

Section: Resultsmentioning

confidence: 99%

Investigating intestinal epithelium metabolic dysfunction in Celiac Disease using personalized genome-scale models

McCreery,

Alessi,

Mollo

et al. 2024

Preprint

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Celiac Disease (CeD) is an autoimmune condition characterized by an aberrant immune response triggered by the ingestion of gluten, which damages epithelial cells lining the small intestine. Small intestinal epithelial cells (sIECs) play a key role in various metabolic processes, including the enzymatic digestion and absorption of nutrients. Although nutritional malabsorption is widely recognized in CeD, the underlying disrupted metabolic processes remain largely undefined. To address this knowledge gap, we constructed personalized gender-specific genome-scale models of sIEC metabolism using transcriptional data from 42 subjects with active CeD, remission CeD, and healthy controls. We computationally simulated these models under a relevant diet for each group of subjects to assess the activity of 59 metabolic tasks essential for sIEC function and to profile metabolite secretion into the bloodstream and intestinal lumen. These investigations revealed significant variations in the activity of 25 metabolic tasks in active and remission CeD models. These tasks impact critical processes integral to sIEC function such as amino acid metabolism, nucleotide synthesis and DNA repair, ATP generation, and oxidative stress regulation. Additionally, we identified 54 metabolites with altered secretion profiles in CeD, encompassing amino acids, vitamins, antioxidants, and fatty acids. Furthermore, we pinpointed 22 FDA-approved drugs that target the genes associated with differentially active metabolic functions whose altered activities adversely affect sIEC in CeD, potentially helping to restore their normal activity. Our study unveils new insights into the metabolic reprogramming of sIEC in CeD, paving the way for therapeutic interventions targeting dysregulated metabolic processes.

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Section: Resultsmentioning

confidence: 99%

Investigating intestinal epithelium metabolic dysfunction in Celiac Disease using personalized genome-scale models

McCreery,

Alessi,

Mollo

et al. 2024

Preprint

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“…Proinflammatory and regulatory mediators are released along with MC activation, and many of them have an effect on the intestinal barrier as well as modulating immune response [ 5 , 22 ]. With zona occludens 1 protein (ZO-1) as an indicator of the intercellular TJ between intestinal epithelial cells, we observed that TJ was markedly damaged on Caco2 cells by the culture medium of HMC-1 pre-treated with CRH, and JM25-1 restored the TJ ( Figure 3 A,D,E).…”

Section: Resultsmentioning

confidence: 99%

A Novel Mast Cell Stabilizer JM25-1 Rehabilitates Impaired Gut Barrier by Targeting the Corticotropin-Releasing Hormone Receptors

Sun

Liu

et al. 2022

Pharmaceuticals

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Mast cell (MC) plays a central role in intestinal permeability; however, few MC-targeting drugs are currently available for protection of the intestinal barrier in clinical practice. A nonfluorinated Lidocaine analog 2-diethylamino-N-2,5-dimethylphenyl acetamide (JM25-1) displays anti-allergic effect, but its impact on MC remains elusive. In this study, we explored whether JM25-1 has therapeutic potential on intestinal barrier defect through stabilizing MC. JM25-1 alleviated release of β-hexosaminidase and cytokine production of MC. The paracellular permeability was redressed by JM25-1 in intestinal epithelial cell monolayers co-cultured with activated MC. In vivo, JM25-1 diminished intestinal mucosal MC amount and cytokine production, especially downregulating the expression of CRHR1, accompanied by an increase of CRHR2. Protective effects appeared in JM25-1-treated stress rats with a recovery of weight and intestinal barrier integrity. Through network pharmacology analysis, JM25-1 showed a therapeutic possibility for irritable bowel syndrome (IBS) with predictive targeting on PI3K/AKT/mTOR signaling. As expected, JM25-1 reinforced p-PI3K, p-AKT, p-mTOR signaling in MC, while the mTOR inhibitor Rapamycin reversed the action of JM25-1 on the expression of CRHR1 and CRHR2. Moreover, JM25-1 successfully remedied intestinal defect and declined MC and CRHR1 expression in rat colon caused by colonic mucus of IBS patients. Our data implied that JM25-1 possessed therapeutic capacity against intestinal barrier defects by targeting the CRH receptors of MC through PI3K/AKT/mTOR signaling.

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“…Numerous studies have shown that LPS can disrupt intestinal barrier integrity and reduce intestinal tight junction mRNA expression and protein levels [5,33]. Wang H et al found that the expression level of CLDN-1 mRNA in the jejunal mucosa was signi cantly down-regulated4 h after intraperitoneal injection of 100 µg/kg BW LPS in weaned piglets, while the mRNA expression level of OCLN was not signi cantly affected [34].…”

Section: Discussionmentioning

confidence: 99%

“…Intactness of intestinal barrier function is pivotal for the growth performance, health and welfare of animals. Numerous scienti c evidences showed that bacterial infection, endotoxin challenge can impair barrier function and integrity of the small intestine in animals [4,5]. In fact, nursery piglets with immature gut are commonly subjected to weaning stress resulting physiological, environmental, and social stressors in the modern swine farm [6].…”

Section: Introductionmentioning

confidence: 99%

The synbiotic mixture of lactulose and Bacillus coagulans protect intestinal barrier dysfunction and apoptosis in weaned piglets challenged with lipopolysaccharide

Zheng

Zhao

Yan

et al. 2023

Preprint

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Background Lactulose has been considered to be an effective prebiotic protect intestinal mucosal injury in pigs. Bacillus coagulans (B. coagulans) is known as ‘the king of probiotics’ due to its high stability in the gastrointestinal tract, non-toxic effects, as well as high pharmacological activity. Our previous in vitro study indicating that the combination of lactulose and B. coagulans may be a good candidate as alternative of antibiotic growth promoters. However, the in vivo effects of lactulose and B. coagulans on growth and intestinal health under immune challenge in piglets remains unclear. The objective of this study is to explore the possibility of symbiotic containing lactulose and B. coagulans as alternative of antibiotic growth promoter in piglets and its effects on the intestinal mucosal injury and barrier dysfunction under immune challenge. Methods A total of 24 weaned male piglets were randomly assigned to 4 groups: CTR-saline, LPS-LPS, ANT-LPS and SYN-LPS groups, respectively. Piglets in the CTR-saline and LPS-LPS group were fed basal diet, while other piglets were fed either with 75 mg/kg chlortetracycline (CTC) or synbiotic mixture of 10 g/kg lactulose and 2×109 CFU/kg B. coagulans for 32 days before intraperitoneal injection of saline or lipopolysaccharide (LPS) (100 µg/kg BW), respectively. Piglets were sacrificed 4 h after LPS injection to collect samples for determining intestinal morphology, integrity and barrier functions as well as relative genes and protein expression analysis. Results Our data shown that dietary supplementation of synbiotic mixture of lactulose and B. coagulans had higher feed efficiency than CTC and CON. Under acute immune stress, LPS injection induced higher serum diamine oxidase activities, D-lactic acid levels, and endotoxin status, lower villus height and ratio of villus height to crypt depth, greater mRNA and lower protein expression related tight junction in both jejunum and ileum. Moreover, higher apoptosis index and higher protein expression of Bax and caspase-3 were also observed in LPS challenge group. Surprisingly, dietary synbiotic mixture with lactulose and B. coagulans remarkably protected against LPS-induced intestinal damage, barrier dysfunction and higher apoptosis progress as well as CTC. Conclusions Our in vivo data suggest that dietary supplementation of synbiotic mixture with lactulose and B. coagulans resulted in higher feed efficiency, and show greater resilience to LPS-induced intestinal morphology damage, barrier dysfunction and aggressive apoptosis in piglets as well as the protective effects of CTC. Those results indicating that synbiotic mixture of lactulose and B. coagulans as novel synbiotic shown beneficial effects on the performance and resilience to acute immune stress in piglets.

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Glutamate attenuates lipopolysaccharide induced intestinal barrier injury by regulating corticotropin-releasing factor pathway in weaned pigs

Cited by 7 publications

References 44 publications

Investigating intestinal epithelium metabolic dysfunction in Celiac Disease using personalized genome-scale models

Investigating intestinal epithelium metabolic dysfunction in Celiac Disease using personalized genome-scale models

A Novel Mast Cell Stabilizer JM25-1 Rehabilitates Impaired Gut Barrier by Targeting the Corticotropin-Releasing Hormone Receptors

The synbiotic mixture of lactulose and Bacillus coagulans protect intestinal barrier dysfunction and apoptosis in weaned piglets challenged with lipopolysaccharide

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