PMID- 37900940 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231031 IS - 1948-0210 (Print) IS - 1948-0210 (Electronic) IS - 1948-0210 (Linking) VI - 15 IP - 9 DP - 2023 Sep 26 TI - Multiomics reveal human umbilical cord mesenchymal stem cells improving acute lung injury via the lung-gut axis. PG - 908-930 LID - 10.4252/wjsc.v15.i9.908 [doi] AB - BACKGROUND: Acute lung injury (ALI) and its final severe stage, acute respiratory distress syndrome, are associated with high morbidity and mortality rates in patients due to the lack of effective specific treatments. Gut microbiota homeostasis, including that in ALI, is important for human health. Evidence suggests that the gut microbiota improves lung injury through the lung-gut axis. Human umbilical cord mesenchymal cells (HUC-MSCs) have attractive prospects for ALI treatment. This study hypothesized that HUC-MSCs improve ALI via the lung-gut microflora. AIM: To explore the effects of HUC-MSCs on lipopolysaccharide (LPS)-induced ALI in mice and the involvement of the lung-gut axis in this process. METHODS: C57BL/6 mice were randomly divided into four groups (18 rats per group): Sham, sham + HUC-MSCs, LPS, and LPS + HUC-MSCs. ALI was induced in mice by intraperitoneal injections of LPS (10 mg/kg). After 6 h, mice were intervened with 0.5 mL phosphate buffered saline (PBS) containing 1 x 10(6) HUC-MSCs by intraperitoneal injections. For the negative control, 100 mL 0.9% NaCl and 0.5 mL PBS were used. Bronchoalveolar lavage fluid (BALF) was obtained from anesthetized mice, and their blood, lungs, ileum, and feces were obtained by an aseptic technique following CO(2) euthanasia. Wright's staining, enzyme-linked immunosorbent assay, hematoxylin-eosin staining, Evans blue dye leakage assay, immunohistochemistry, fluorescence in situ hybridization, western blot, 16S rDNA sequencing, and non-targeted metabolomics were used to observe the effect of HUC-MSCs on ALI mice, and the involvement of the lung-gut axis in this process was explored. One-way analysis of variance with post-hoc Tukey's test, independent-sample Student's t-test, Wilcoxon rank-sum test, and Pearson correlation analysis were used for statistical analyses. RESULTS: HUC-MSCs were observed to improve pulmonary edema and lung and ileal injury, and decrease mononuclear cell and neutrophil counts, protein concentrations in BALF and inflammatory cytokine levels in the serum, lung, and ileum of ALI mice. Especially, HUC-MSCs decreased Evans blue concentration and Toll-like receptor 4, myeloid differentiation factor 88, p-nuclear factor kappa-B (NF-kappaB)/NF-kappaB, and p-inhibitor alpha of NF-kappaB (p-IkappaBalpha)/IkappaBalpha expression levels in the lung, and raised the pulmonary vascular endothelial-cadherin, zonula occludens-1 (ZO-1), and occludin levels and ileal ZO-1, claudin-1, and occludin expression levels. HUC-MSCs improved gut and BALF microbial homeostases. The number of pathogenic bacteria decreased in the BALF of ALI mice treated with HUC-MSCs. Concurrently, the abundances of Oscillospira and Coprococcus in the feces of HUS-MSC-treated ALI mice were significantly increased. In addition, Lactobacillus, Bacteroides, and unidentified_Rikenellaceae genera appeared in both feces and BALF. Moreover, this study performed metabolomic analysis on the lung tissue and identified five upregulated metabolites and 11 downregulated metabolites in the LPS + MSC group compared to the LPS group, which were related to the purine metabolism and the taste transduction signaling pathways. Therefore, an intrinsic link between lung metabolite levels and BALF flora homeostasis was established. CONCLUSION: This study suggests that HUM-MSCs attenuate ALI by redefining the gut and lung microbiota. CI - (c)The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved. FAU - Lv, Lu AU - Lv L AD - Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou 313000, Zhejiang Province, China. FAU - Cui, En-Hai AU - Cui EH AD - Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou 313000, Zhejiang Province, China. kjkceh@126.com. FAU - Wang, Bin AU - Wang B AD - Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou 313000, Zhejiang Province, China. FAU - Li, Li-Qin AU - Li LQ AD - Traditional Chinese Medicine Key Laboratory Cultivation Base of Zhejiang Province for the Development and Clinical Transformation of Immunomodulatory Drugs, Huzhou 313000, Zhejiang Province, China. FAU - Hua, Feng AU - Hua F AD - Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou 313000, Zhejiang Province, China. FAU - Lu, Hua-Dong AU - Lu HD AD - Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou 313000, Zhejiang Province, China. FAU - Chen, Na AU - Chen N AD - Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou 313000, Zhejiang Province, China. FAU - Chen, Wen-Yan AU - Chen WY AD - Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou 313000, Zhejiang Province, China. LA - eng PT - Journal Article PL - United States TA - World J Stem Cells JT - World journal of stem cells JID - 101535826 PMC - PMC10600741 OTO - NOTNLM OT - Acute lung injury OT - Human umbilical cord mesenchymal cells OT - Lipopolysaccharide OT - Microflora OT - Toll-like receptor 4/nuclear factor kappa-B signaling pathway OT - Untargeted metabolomics COIS- Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article. EDAT- 2023/10/30 06:47 MHDA- 2023/10/30 06:48 PMCR- 2023/09/26 CRDT- 2023/10/30 04:42 PHST- 2023/05/12 00:00 [received] PHST- 2023/07/23 00:00 [revised] PHST- 2023/09/06 00:00 [accepted] PHST- 2023/10/30 06:48 [medline] PHST- 2023/10/30 06:47 [pubmed] PHST- 2023/10/30 04:42 [entrez] PHST- 2023/09/26 00:00 [pmc-release] AID - 10.4252/wjsc.v15.i9.908 [doi] PST - ppublish SO - World J Stem Cells. 2023 Sep 26;15(9):908-930. doi: 10.4252/wjsc.v15.i9.908.