Author:
Pi Yu,Wu Yujun,Zhang Xiangyu,Lu Dongdong,Han Dandan,Zhao Jiangchao,Zheng Xiaojiao,Zhang Shiyi,Ye Hao,Lian Shuai,Bai Yu,Wang Zhenyu,Tao Shiyu,Ni Dongjiao,Zou Xinhua,Jia Wei,Zhang Guolong,Li Defa,Wang Junjun
Abstract
Abstract
Background
Low birth weight (LBW) is associated with intestinal inflammation and dysbiosis after birth. However, the underlying mechanism remains largely unknown.
Objective
In the present study, we aimed to investigate the metabolism, therapeutic potential, and mechanisms of action of bile acids (BAs) in LBW-induced intestinal inflammation in a piglet model.
Methods
The fecal microbiome and BA profile between LBW and normal birth weight (NBW) neonatal piglets were compared. Fecal microbiota transplantation (FMT) was employed to further confirm the linkage between microbial BA metabolism and intestinal inflammation. The therapeutic potential of ursodeoxycholic acid (UDCA), a highly differentially abundant BA between LBW and NBW piglets, in alleviating colonic inflammation was evaluated in both LBW piglets, an LBW-FMT mice model, and a DSS-induced colitis mouse model. The underlying cellular and molecular mechanisms by which UDCA suppresses intestinal inflammation were also investigated in both DSS-treated mice and a macrophage cell line. Microbiomes were analyzed by using 16S ribosomal RNA sequencing. Fecal and intestinal BA profiles were measured by using targeted BA metabolomics. Levels of farnesoid X receptor (FXR) were knocked down in J774A.1 cells with small interfering RNAs.
Results
We show a significant difference in both the fecal microbiome and BA profiles between LBW and normal birth weight animals in a piglet model. Transplantation of the microbiota of LBW piglets to antibiotic-treated mice leads to intestinal inflammation. Importantly, oral administration of UDCA, a major BA diminished in the intestinal tract of LBW piglets, markedly alleviates intestinal inflammation in LBW piglets, an LBW-FMT mice model, and a mouse model of colitis by inducing M2 macrophage polarization. Mechanistically, UDCA reduces inflammatory cytokine production by engaging BA receptor FXR while suppressing NF-κB activation in macrophages.
Conclusions
These findings establish a causal relationship between LBW-associated intestinal abnormalities and dysbiosis, suggesting that restoring intestinal health and postnatal maldevelopment of LBW infants may be achieved by targeting intestinal microbiota and BA metabolism.
Funder
National Natural Science Foundation of China
China Postdoctoral Science Foundation
Key Area Research and Development Program of Guangdong Province
National Outstanding Youth Science Fund Project of National Natural Science Foundation of China
Beijing Municipal Natural Science Foundation
Publisher
Springer Science and Business Media LLC
Subject
Microbiology (medical),Microbiology
Reference72 articles.
1. McIntire DD, Bloom SL, Casey BM, Leveno KJ. Birth weight in relation to morbidity and mortality among newborn infants. New Engl J Med. 1999;340(16):1234–8.
2. Zhu YH, Wang W, Yuan TL, Fu LL, Zhou LA, Lin G, et al. MicroRNA-29a mediates the impairment of intestinal epithelial integrity induced by intrauterine growth restriction in pig. Am J Physiol-Gastr L. 2017;312(5):G434–42.
3. Wu G, Bazer FW, Wallace JM, Spencer TE. Board-invited review: intrauterine growth retardation: implications for the animal sciences. J Anim Sci. 2006;84(9):2316–37.
4. Jain V, Singhal A. Catch up growth in low birth weight infants: striking a healthy balance. Rev Endocr Metab Disord. 2012;13(2):141–7.
5. Guilloteau P, Zabielski R, Hammon HM, Metges CC. Nutritional programming of gastrointestinal tract development. Is the pig a good model for man? Nutr Res Rev. 2010;23(1):4–22.
Cited by
17 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献