Absence of neurotensin attenuates intestinal dysbiosis and inflammation by maintaining Mmp7/α‐defensin axis in diet‐induced obese mice
Jing LiXian LiJun SongBaoxiang YanStephanie A. RockJianhang JiaJinpeng LiuChi WangTodd WeissHeidi L. WeissTianyan GaoAshfaqul AlamB. Mark Evers
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We previously reported that high levels of plasma neurotensin (NT), a gut hormone released from enteroendocrine cells of the small bowel, contribute to obesity and comorbid conditions. Gut microbiota has been implicated in the obesity development. Paneth cells are critical in maintaining gut microbiota composition and homeostasis by releasing antimicrobial proteins including α-defensins. The purpose of our current study was to determine the possible role of NT in gut microbiota composition and α-defensin gene expression associated with obesity. Here we show that the ratio of Firmicutes/Bacteroidetes (F/B ratio) and intestinal proinflammatory cytokines is significantly increased in NT+/+ mice fed with a high-fat diet (HFD) which were improved in NT-deficient mice. HFD disrupted the intestinal Mmp7/α-defensin axis, which was completely prevented in NT-/- mice. In addition, NT treatment inhibited DEFA5 expression and concurrent NF-κB activity, which was blocked by a pan PKC inhibitor (Gö6983) or an inhibitor for atypical PKCs (CRT0066854). More importantly, the shRNA-mediated knockdown of atypical PKCτ reversed NT-attenuated DEFA5 expression and increased NF-κB activity. NT contributes to the HFD-induced disruption of gut microbiota composition and α-defensin expression. PKCτ/λ plays a central role in NT-mediated α-defensin gene expression which might be mediated through the inhibition of NF-κB signaling pathways in Paneth cells.Keywords:
Proinflammatory cytokine
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Abstract Objective There is growing evidence supporting that the gut microbiota is a major driver of human health and disease. While gut microbiota transfer (GMT) is commonly used as an approach to restore "eubiosis", there is a surprising lack of data on whether the transferred microbiota efficiently and durably repopulate the gut of the transplanted subject. Moreover, little is known on the effects of GMT on non-alcoholic fatty liver disease (NAFLD). Methods Chronic dysbiosis and NAFLD-like liver injury were induced by feeding C57Bl/6j mice for 16 weeks with a high-fat diet. For GMT, dysbiotic mice underwent preliminary gut cleansing, followed by oral gavage with a suspension of fresh fecal matter procured from a pool of lean mice (1 dose, or 10 doses). We next characterized microbiota composition and we measured the relative abundance of specific pathobionts in recipient mice, using high-throughput shotgun analysis in a dynamic manner, over time. All experiments took place in a specific germ-free environment. Results After 4 months on a high-fat diet, mice displayed fatty liver infiltration with moderate parenchymal inflammatory changes. Dysbiosis was evidenced by a reduced bacterial diversity, as well as a dramatically increased abundance of Firmicutes, and lower Verrucomicrobia and Actinobacteria. Gut microbiota transfer was associated with a transitory reduction in NAFLD-induced hepatocellular injury. While dysbiotic mice displayed a shift in their microbiota composition towards that of lean donors after GMT, this effect rapidly faded after one week, and mice recovered their initial, dysbiotic microbiota. Conclusion The current study indicates that, when used in mice with chronically established dysbiosis, GMT is merely associated with transitory changes in gut microbiota composition, as well as significant but moderate reduction in hepatocellular injury.
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Increasing application of antibiotics changes the gut microbiota composition, leading to dysbiosis of the gut microbiota. Although growing evidence suggests the potential role of gut dysbiosis as the cause of neurodevelopmental disorders and behavioral defects, a broad gap of knowledge remains to be narrowed to better understand the exact mechanisms by which maternal gut dysbiosis alters microbiota development and social interactions of offspring. Here, we showed that maternal gut dysbiosis during gestation is a critical determinant of gut microbiota and social interactions off mouse offspring. Gut microbiota of 2-week-old offspring showed significant changes in response to maternal antibiotic treatment. We even detected distinct effects of maternal oral antibiotics on gut microbiota of 14-week-old offspring. Compared to controls, offspring born to antibiotics-treated mothers displayed reduction in sociability and preference for social novelty, suggesting that the altered offspring social behavior was closely linked to dysbiosis of maternal gut microbiota. Our study opens the possibility to better understand the mechanism of how maternal gut microbiota vertically impairs social interactions of offspring in animal models, providing support to the maternal gut microbiota as a potential mediator between offspring microbiota and behaviors.
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It is well known that there is an imbalance of gut microbiota in liver diseases, our previous study has proved that Aronia melanocarpa polyphenols (AMPs) can modulate the gut microbiota and affect the progression of liver diseases. Here, we analyzed the gut microbiota by 16S rRNA sequencing and bioinformatic analysis to explored the changes of gut microbiota composition and functions after LPS and AMPs intervention. Our results showed that there were significant differences in the gut microbiota structure between different treatment groups, such as increasing the abundance of Lactobacillaceae and Muribaculaceae, decreasing the abundance of Ruminococcaceae and Acidaminococcaceae. Furthermore, PICRUSt prediction showed that 29 functional pathways have changed significantly which may promote the treatment of liver diseases. This study could help to supplement the information about the community of gut microbiota in liver diseases and provide a new strategy for the treatment of liver diseases.
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Diversity and activity of gut microbiota residing in humans and animals are significantly influenced by the diet. A quercetin containing diet is effective in recovering gut microbiota in mice after antibiotic treatment and may act as a prebiotic in combating gut dysbiosis.
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Previous studies suggested a possible gut microbiota dysbiosis in chronic heart failure (CHF). However, direct evidence was lacking. In this study, we investigated the composition and metabolic patterns of gut microbiota in CHF patients to provide direct evidence and comprehensive understanding of gut microbiota dysbiosis in CHF. We enrolled 53 CHF patients and 41 controls. Metagenomic analyses of faecal samples and metabolomic analyses of faecal and plasma samples were then performed. We found that the composition of gut microbiota in CHF was significantly different from controls. Faecalibacterium prausnitzii decrease and Ruminococcus gnavus increase were the essential characteristics in CHF patients' gut microbiota. We also observed an imbalance of gut microbes involved in the metabolism of protective metabolites such as butyrate and harmful metabolites such as trimethylamine N-oxide in CHF patients. Metabolic features of both faecal and plasma samples from CHF patients also significantly changed. Moreover, alterations in faecal and plasma metabolic patterns correlated with gut microbiota dysbiosis in CHF. Taken together, we found that CHF was associated with distinct gut microbiota dysbiosis and pinpointed the specific core bacteria imbalance in CHF, along with correlations between changes in certain metabolites and gut microbes.
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Antibiotic therapy through short-term or repeated long-term prescriptions can have several damaging effects on the normal microbiota of the gastrointestinal tract. Changes in microbiota could be multiple including decreased diversity of species in gut microbiota, changed metabolic activity, and the occurrence of antibiotic-resistant strains. Antibiotic-induced gut dysbiosis in turn can induce antibiotic-associated diarrhoea and recurrent infections caused by Clostridioides difficile. There is also evidence that the use of different chemical classes of antibiotics for the treatment of a variety of ailments can lead to several health issues including gastrointestinal, immunologic, and neurocognitive conditions. This review discusses gut dysbiosis, its symptoms and one important cause, which is antibiotic therapy for the induction of gut dysbiosis. Since the maintenance of good gut health is important for the well-being and functioning of physiological and cognitive activities through the normal gut-microbiota-brain relationship, the condition of dysbiosis is not desirable. Specific therapies are prescribed by medical practitioners for the cure of a variety of ailments, and, if the prescription of antibiotics becomes unavoidable, there is a possibility of the onset of gut dysbiosis as the side or after effects. Therefore, the restoration of imbalanced gut microbiota to its balanced condition becomes necessary. A healthy relationship between gut microbiota and the brain can be achieved with the introduction of probiotic strains into the gut in a practical and consumer-friendly way, such as consumption of food and beverages prepared with the use of characterised probiotic species, fermented foods as the potential biotics, or synbiotic supplements.
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ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Frej-MÄ drzak M, Jeziorek M, Sarowska J, Jama-Kmiecik A, Choroszy-Król I. The role of probiotics and prebiotics in the proper functioning of gut microbiota and the treatment of diseases caused by gut microbiota dysbiosis. Nutrition, Obesity & Metabolic Surgery. 2020;7(1):9-15. doi:10.5114/noms.2020.94667. APA Frej-MÄ drzak, M., Jeziorek, M., Sarowska, J., Jama-Kmiecik, A., & Choroszy-Król, I. (2020). The role of probiotics and prebiotics in the proper functioning of gut microbiota and the treatment of diseases caused by gut microbiota dysbiosis. Nutrition, Obesity & Metabolic Surgery, 7(1), 9-15. https://doi.org/10.5114/noms.2020.94667 Chicago Frej-MÄ drzak, Magdalena, MaÅgorzata Jeziorek, Jolanta Sarowska, Agnieszka Jama-Kmiecik, and Irena Choroszy-Król. 2020. "The role of probiotics and prebiotics in the proper functioning of gut microbiota and the treatment of diseases caused by gut microbiota dysbiosis". Nutrition, Obesity & Metabolic Surgery 7 (1): 9-15. doi:10.5114/noms.2020.94667. Harvard Frej-MÄ drzak, M., Jeziorek, M., Sarowska, J., Jama-Kmiecik, A., and Choroszy-Król, I. (2020). The role of probiotics and prebiotics in the proper functioning of gut microbiota and the treatment of diseases caused by gut microbiota dysbiosis. Nutrition, Obesity & Metabolic Surgery, 7(1), pp.9-15. https://doi.org/10.5114/noms.2020.94667 MLA Frej-MÄ drzak, Magdalena et al. "The role of probiotics and prebiotics in the proper functioning of gut microbiota and the treatment of diseases caused by gut microbiota dysbiosis." Nutrition, Obesity & Metabolic Surgery, vol. 7, no. 1, 2020, pp. 9-15. doi:10.5114/noms.2020.94667. Vancouver Frej-MÄ drzak M, Jeziorek M, Sarowska J, Jama-Kmiecik A, Choroszy-Król I. The role of probiotics and prebiotics in the proper functioning of gut microbiota and the treatment of diseases caused by gut microbiota dysbiosis. Nutrition, Obesity & Metabolic Surgery. 2020;7(1):9-15. doi:10.5114/noms.2020.94667.
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Alcoholic liver disease (ALD) is a major health issue globally due to the consumption of alcoholic beverages. Thymus quinquecostatus Celak is a food additive and an edible herb that is widely used in Asia and possesses hepatoprotective activity, but the underlying mechanisms behind this protective activity are not completely understood. The purpose of this study was to investigate the hepatoprotective effects of Thymus quinquecostatus Celak extract (TQE) against ALD as well as the underlying mechanism based on gut microbiota and the gut-liver axis. TQE supplementation markedly alleviated chronic alcohol-induced liver injury in C57 mice. TQE also ameliorated gut barrier dysfunction induced by alcohol. Consequently, the activation of the lipopolysaccharide (LPS) translocation-mediated TLR4 pathway and the subsequent inflammatory response and ROS overproduction in the liver were suppressed. Meanwhile, alcohol-induced gut microbiota dysbiosis was also corrected by TQE. To further investigate the contribution of gut dysbiosis correction to the beneficial effects of TQE on ALD, a fecal microbiota transplantation study was conducted. TQE-manipulated gut microbiota transplantation markedly counteracted the alcohol-induced gut dysbiosis in the recipient mice. In parallel with gut dysbiosis correction, liver damage was partly ameliorated in the recipient mice. Gut barrier dysfunction, endotoxemia, TLR4 pathway induction as well as downstream inflammatory response and ROS overproduction were also partly suppressed due to gut dysbiosis correction in alcohol-fed recipient mice. In summary, these results suggest that gut dysbiosis correction contributes to the hepatoprotective effects of TQE against alcohol through the gut-liver axis.
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Gastrointestinal dysfunction is a common peripheral organ complication after traumatic brain injury (TBI), yet the underlying mechanism remains unknown. TBI has been demonstrated to cause gut microbiota dysbiosis in animal models, although the impacts of gut microbiota dysbiosis on gastrointestinal dysfunction were not examined. Bile acids are key metabolites between gut microbiota and host interactions. Therefore, the aim of this study was to investigate the mechanistic links between them by detecting the alterations of gut microbiota and bile acid profile after TBI. For that, we established TBI in mice using a lateral fluid percussion injury model. Gut microbiota was examined by 16S rRNA sequencing, and bile acids were profiled by ultra-performance liquid chromatography-tandem mass spectrometry. Our results showed that TBI caused intestinal inflammation and gut barrier impairment. Alterations of gut microbiota and bile acid profile were observed. The diversity of gut microbiota experienced a time dependent change from 1 h to 7 days post-injury. Levels of bile acids in feces and plasma were decreased after TBI, and the decrease was more significant in secondary bile acids, which may contribute to intestinal inflammation. Specific bacterial taxa such as Staphylococcus and Lachnospiraceae that may contribute to the bile acid metabolic changes were identifed. In conclusion, our study suggested that TBI-induced gut microbiota dysbiosis may contribute to gastrointestinal dysfunction via altering bile acid profile. Gut microbiota may be a potential treatment target for TBI-induced gastrointestinal dysfunction.
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