Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in VSports app下载. gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. V体育官网.

. 2020 Jun;8(12):e14456.
doi: 10.14814/phy2.14456.

The secondary bile acids, ursodeoxycholic acid and lithocholic acid, protect against intestinal inflammation by inhibition of epithelial apoptosis

Natalia K Lajczak-McGinley  1 , Emanule Porru  2 , Ciara M Fallon  1 , Jessica Smyth  1 , Caitriona Curley  1 , Paul A McCarron  3 , Murtaza M Tambuwala  3 , Aldo Roda  2   4 , Stephen J Keely  1
Affiliations

"V体育官网入口" The secondary bile acids, ursodeoxycholic acid and lithocholic acid, protect against intestinal inflammation by inhibition of epithelial apoptosis

"VSports最新版本" Natalia K Lajczak-McGinley et al. Physiol Rep. 2020 Jun.

Abstract

Increased epithelial permeability is a key feature of IBD pathogenesis and it has been proposed that agents which promote barrier function may be of therapeutic benefit. We have previously reported the secondary bile acid, ursodeoxycholic acid (UDCA), to be protective in a mouse model of colonic inflammation and that its bacterial metabolism is required for its beneficial effects. The current study aimed to compare the effects of UDCA, LCA, and a non-metabolizable analog of UDCA, 6-methyl-UDCA (6-MUDCA), on colonic barrier function and mucosal inflammation in a mouse model of colonic inflammation. Bile acids were administered daily to C57Bl6 mice by intraperitoneal injection. Colonic inflammation, induced by addition of DSS (2. 5%) to the drinking water, was measured as disease activity index (DAI) and histological score. Epithelial permeability and apoptosis were assessed by measuring FITC-dextran uptake and caspase-3 cleavage, respectively. Cecal bile acids were measured by HPLC-MS/MS. UDCA and LCA, but not 6-MUDCA, were protective against DSS-induced increases in epithelial permeability and colonic inflammation. Furthermore, UDCA and LCA inhibited colonic epithelial caspase-3 cleavage both in DSS-treated mice and in an in vitro model of cytokine-induced epithelial injury. HPLC-MS/MS analysis revealed UDCA administration to increase colonic LCA levels, whereas LCA administration did not alter UDCA levels. UDCA, and its primary metabolite, LCA, protect against intestinal inflammation in vivo, at least in part, by inhibition of epithelial apoptosis and promotion of barrier function. These data suggest that clinical trials of UDCA in IBD patients are warranted VSports手机版. .

Keywords: apoptosis; bile acid; colitis; epithelial barrier function. V体育安卓版.

PubMed Disclaimer

Conflict of interest statement

None declared.

Figures

FIGURE 1
FIGURE 1
Analysis of cecal bile acids in mice administered UDCA, LCA, or 6‐MUDCA. Starting 24 hr prior to administration of DSS (2.5% in the drinking water), and daily thereafter, separate groups of male C57BL6 mice received endotoxin‐free PBS or Na+‐UDCA (30 mg/kg), Na+‐LCA (30 mg/kg), or Na+‐6α‐MUDCA (30 mg/kg) dissolved in PBS by IP injection. On the 7th day, mice were sacrificed and the cecal content was collected and analyzed for levels of (a) UDCA, (b) LCA, and (c) CDCA, as described in Materials and Methods. Data are expressed as mean ± sem. n = 12; **p < .01, *** p < .001 compared to untreated controls
FIGURE 2
FIGURE 2
Effects of UDCA, LCA, and 6‐MUDCA on disease activity in DSS‐treated mice. Starting 24 hr prior to administration of DSS (2.5% in the drinking water), and daily thereafter, separate groups of male C57BL6 mice received either endotoxin‐free PBS or Na+‐UDCA (30 mg/kg), Na+‐LCA (30 mg/kg), or Na+‐6α‐MUDCA (30 mg/kg) dissolved in PBS by IP injection. (a) Disease activity index (DAI) was assessed daily (n = 12). For clarity, the inset depicts DAI at the end of the treatment period on Day 7. (b) Body weight was assessed daily to monitor disease progression. (c) Mice were sacrificed on day 7 and their colons were removed and measured (n = 5–6). ***p < .001 compared to controls (no DSS treatment); ## p < .001 compared to DSS‐treated mice
FIGURE 3
FIGURE 3
Effects of UDCA, LCA, and 6‐MUDCA mucosal inflammation in DSS‐treated mice. Starting 24 hr prior to administration of DSS (2.5% in the drinking water), and daily thereafter, separate groups of male C57BL6 mice received endotoxin‐free PBS or Na+‐UDCA (30 mg/kg), Na+‐LCA (30 mg/kg), or Na+‐6α‐MUDCA (30 mg/kg) dissolved in PBS by IP injection. (a) Sections of colon from control, DSS‐treated and bile acid‐treated C57BL6 mice were taken and processed for H&E staining. (b) Inflammation score was assessed as described in Materials and Methods (n = 3). (c) Sections of distal colon were stripped of their muscle layers and MPO activity was assessed (n = 5–6); **p < .01,***p < .001 compared to controls (no DSS treatment); # p < 005, ## p < .01, ### p < .001 compared to DSS‐treated mice
FIGURE 4
FIGURE 4
Effects of UDCA, LCA, and 6‐MUDCA on barrier function and epithelial caspase‐3 cleavage in DSS‐treated mice. Starting 24 hr prior to administration of DSS (2.5% in the drinking water), and daily thereafter, separate groups of male C57BL6 mice received endotoxin‐free PBS, Na+‐UDCA (30 mg/kg), Na+‐LCA (30 mg/kg), or Na+‐6α‐MUDCA (30 mg/kg) by IP injection. On the 6th day, mice were administered FITC‐dextran (6 mg/kg) by oral gavage and after a further 24 hr mice were sacrificed. (a) Levels of FITC‐dextran in serum samples were measured (n = 12). (b) Sections of colon from control, DSS‐treated and DSS + bile acid‐treated C57BL6 mice were taken and processed for immunohistochemical staining with Cleaved Caspase‐3 antibody (n = 3) *p < .05, ***p < .001 compared between indicated groups
FIGURE 5
FIGURE 5
Effects of UDCA, LCA, and 6‐MUDCA on colonic epithelial barrier function in vitro. Monolayers of T84 cells grown on permeable supports were treated with IFN‐γ (40 ng/ml) 24 hr prior adding TNF (20 ng/ml) alone or in combination with Na+‐UDCA (100 µM), Na+‐LCA (10 µM) or Na+‐6α‐MUDCA (100 µM). FITC‐dextran (10 mg/ml) was then added to the apical side. (a) After 24 hr, the basolateral media was collected and FITC‐dextran levels were measured (n = 4). (b) Lysates from cells treated with IFNγ and TNF in the absence or presence of UDCA, LCA, or 6‐MUDCA were analyzed for levels of the p89 fragment of cleaved PARP by western blotting. Panel c shows densitometric analysis of 5 similar experiments. ***p < .05 compared to untreated cells; ### p < .001 compared to TNF/IFNγ‐treated cells.
See this image and copyright information in PMC

References (VSports在线直播)

    1. Alemi, F. , Poole, D. P. , Chiu, J. , Schoonjans, K. , Cattaruzza, F. , Grider, J. R. , … Corvera, C. U. (2013). The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology, 144, 145–154. 10.1053/j.gastro.2012.09.055 - V体育ios版 - DOI - PMC - PubMed
    1. Amaral, J. D. , Viana, R. J. , Ramalho, R. M. , Steer, C. J. , & Rodrigues, C. M. (2009). Bile acids: Regulation of apoptosis by ursodeoxycholic acid. Journal of Lipid Research, 50, 1721–1734. - PMC - PubMed
    1. Araki, Y. , Andoh, A. , Tsujikawa, T. , Fujiyama, Y. , & Bamba, T. (2001). Alterations in intestinal microflora, faecal bile acids and short chain fatty acids in dextran sulphate sodium‐induced experimental acute colitis in rats. European Journal of Gastroenterology & Hepatology, 13(2), 107–112. 10.1097/00042737-200102000-00004 - DOI - PubMed
    1. Beuers, U. (2006). Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nature Clinical Practice Gastroenterology & Hepatology, 3, 318–328. - "VSports最新版本" PubMed
    1. Cabrera, D. , Arab, J. P. , & Arrese, M. (2019). UDCA, NorUDCA, and TUDCA in liver diseases: A review of their mechanisms of action and clinical applications. Handbook of Experimental Pharmacology, 256, 237–264. - PubMed

Publication types

MeSH terms

"V体育官网入口" Substances

"V体育2025版" LinkOut - more resources