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Milk-derived extracellular vesicles alleviate ulcerative colitis by regulating the gut immunity and reshaping the gut microbiota

Rationale: Bovine milk constitutes an essential part of human diet, especially for children, due to its enrichment of various nutrients. We recently developed an effective protocol for the isolation of extracellular vesicles from milk (mEVs) and discovered that mEVs contained large amounts of immune...

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Autores principales: Tong, Lingjun, Hao, Haining, Zhang, Zhe, Lv, Youyou, Liang, Xi, Liu, Qiqi, Liu, Tongjie, Gong, Pimin, Zhang, Lanwei, Cao, Fangfang, Pastorin, Giorgia, Lee, Chuen Neng, Chen, Xiaoyuan, Wang, Jiong-Wei, Yi, Huaxi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344018/
https://www.ncbi.nlm.nih.gov/pubmed/34373759
http://dx.doi.org/10.7150/thno.62046
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author Tong, Lingjun
Hao, Haining
Zhang, Zhe
Lv, Youyou
Liang, Xi
Liu, Qiqi
Liu, Tongjie
Gong, Pimin
Zhang, Lanwei
Cao, Fangfang
Pastorin, Giorgia
Lee, Chuen Neng
Chen, Xiaoyuan
Wang, Jiong-Wei
Yi, Huaxi
author_facet Tong, Lingjun
Hao, Haining
Zhang, Zhe
Lv, Youyou
Liang, Xi
Liu, Qiqi
Liu, Tongjie
Gong, Pimin
Zhang, Lanwei
Cao, Fangfang
Pastorin, Giorgia
Lee, Chuen Neng
Chen, Xiaoyuan
Wang, Jiong-Wei
Yi, Huaxi
author_sort Tong, Lingjun
collection PubMed
description Rationale: Bovine milk constitutes an essential part of human diet, especially for children, due to its enrichment of various nutrients. We recently developed an effective protocol for the isolation of extracellular vesicles from milk (mEVs) and discovered that mEVs contained large amounts of immune-active proteins and modulated the gut immunity and microbiota in healthy mice. Here, we aimed to explore the therapeutic effects of mEVs on inflammatory bowel disease. Methods: MicroRNAs and protein content in mEVs were analyzed by RNA sequencing and proteomics, respectively, followed by functional annotation. Ulcerative colitis (UC) was induced by feeding mice with dextran sulfate sodium. Intestinal immune cell populations were phenotyped by flow cytometry, and the gut microbiota was analyzed via 16S rRNA sequencing. Results: We showed that abundant proteins and microRNAs in mEVs were involved in the regulation of immune and inflammatory pathways and that oral administration of mEVs prevented colon shortening, reduced intestinal epithelium disruption, inhibited infiltration of inflammatory cells and tissue fibrosis in a mouse UC model. Mechanistically, mEVs attenuated inflammatory response via inhibiting TLR4-NF-κB signaling pathway and NLRP3 inflammasome activation. Furthermore, mEVs were able to correct cytokine production disorder and restore the balance between T helper type 17 (Th17) cells and interleukin-10(+)Foxp3(+) regulatory T (Treg) cells in the inflamed colon. The disturbed gut microbiota in UC was also partially recovered upon treatment with mEVs. The correlation between the gut microbiota and cytokines suggests that mEVs may modulate intestinal immunity via influencing the gut microbiota. Conclusions: These findings reveal that mEVs alleviate colitis by regulating intestinal immune homeostasis via inhibiting TLR4-NF-κB and NLRP3 signaling pathways, restoring Treg/Th17 cell balance, and reshaping the gut microbiota.
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spelling pubmed-83440182021-08-08 Milk-derived extracellular vesicles alleviate ulcerative colitis by regulating the gut immunity and reshaping the gut microbiota Tong, Lingjun Hao, Haining Zhang, Zhe Lv, Youyou Liang, Xi Liu, Qiqi Liu, Tongjie Gong, Pimin Zhang, Lanwei Cao, Fangfang Pastorin, Giorgia Lee, Chuen Neng Chen, Xiaoyuan Wang, Jiong-Wei Yi, Huaxi Theranostics Research Paper Rationale: Bovine milk constitutes an essential part of human diet, especially for children, due to its enrichment of various nutrients. We recently developed an effective protocol for the isolation of extracellular vesicles from milk (mEVs) and discovered that mEVs contained large amounts of immune-active proteins and modulated the gut immunity and microbiota in healthy mice. Here, we aimed to explore the therapeutic effects of mEVs on inflammatory bowel disease. Methods: MicroRNAs and protein content in mEVs were analyzed by RNA sequencing and proteomics, respectively, followed by functional annotation. Ulcerative colitis (UC) was induced by feeding mice with dextran sulfate sodium. Intestinal immune cell populations were phenotyped by flow cytometry, and the gut microbiota was analyzed via 16S rRNA sequencing. Results: We showed that abundant proteins and microRNAs in mEVs were involved in the regulation of immune and inflammatory pathways and that oral administration of mEVs prevented colon shortening, reduced intestinal epithelium disruption, inhibited infiltration of inflammatory cells and tissue fibrosis in a mouse UC model. Mechanistically, mEVs attenuated inflammatory response via inhibiting TLR4-NF-κB signaling pathway and NLRP3 inflammasome activation. Furthermore, mEVs were able to correct cytokine production disorder and restore the balance between T helper type 17 (Th17) cells and interleukin-10(+)Foxp3(+) regulatory T (Treg) cells in the inflamed colon. The disturbed gut microbiota in UC was also partially recovered upon treatment with mEVs. The correlation between the gut microbiota and cytokines suggests that mEVs may modulate intestinal immunity via influencing the gut microbiota. Conclusions: These findings reveal that mEVs alleviate colitis by regulating intestinal immune homeostasis via inhibiting TLR4-NF-κB and NLRP3 signaling pathways, restoring Treg/Th17 cell balance, and reshaping the gut microbiota. Ivyspring International Publisher 2021-07-25 /pmc/articles/PMC8344018/ /pubmed/34373759 http://dx.doi.org/10.7150/thno.62046 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Tong, Lingjun
Hao, Haining
Zhang, Zhe
Lv, Youyou
Liang, Xi
Liu, Qiqi
Liu, Tongjie
Gong, Pimin
Zhang, Lanwei
Cao, Fangfang
Pastorin, Giorgia
Lee, Chuen Neng
Chen, Xiaoyuan
Wang, Jiong-Wei
Yi, Huaxi
Milk-derived extracellular vesicles alleviate ulcerative colitis by regulating the gut immunity and reshaping the gut microbiota
title Milk-derived extracellular vesicles alleviate ulcerative colitis by regulating the gut immunity and reshaping the gut microbiota
title_full Milk-derived extracellular vesicles alleviate ulcerative colitis by regulating the gut immunity and reshaping the gut microbiota
title_fullStr Milk-derived extracellular vesicles alleviate ulcerative colitis by regulating the gut immunity and reshaping the gut microbiota
title_full_unstemmed Milk-derived extracellular vesicles alleviate ulcerative colitis by regulating the gut immunity and reshaping the gut microbiota
title_short Milk-derived extracellular vesicles alleviate ulcerative colitis by regulating the gut immunity and reshaping the gut microbiota
title_sort milk-derived extracellular vesicles alleviate ulcerative colitis by regulating the gut immunity and reshaping the gut microbiota
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344018/
https://www.ncbi.nlm.nih.gov/pubmed/34373759
http://dx.doi.org/10.7150/thno.62046
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