title: Effect of artesunate supplementation on bacterial translocation and dysbiosis of gut microbiota in rats with liver cirrhosis.
abstract: OBJECTIVE
  To evaluate the effect of artesunate (AS) supplementation on bacterial translocation (BT) and gut microbiota in a rat model of liver cirrhosis.
  
  
  METHODS
  Fifty-four male Sprague-Dawley rats were randomly divided into a normal control group (N), a liver cirrhosis group (M) and a liver cirrhosis group intervened with AS (MA). Each group was sampled at 4, 6 and 8 wk. Liver cirrhosis was induced by injection of carbon tetrachloride (CCl4), intragastric administration of 10% ethanol, and feeding a high fat diet. Rats in the MA group were intragastrically administered with AS (25 mg/kg body weight, once daily). Injuries of the liver and intestinal mucosa were assessed by hematoxylin-eosin or Masson's trichrome staining. Liver index was calculated as a ratio of the organ weight (g) to body weight (g). The gut microbiota was examined by automated ribosomal intergenic-spacer analysis of fecal DNA. BT was assessed by standard microbiological techniques in the blood, mesenteric lymph nodes (MLNs), liver, spleen, and kidney.
  
  
  RESULTS
  Compared to group N, the body weight was reduced significantly in groups M and MA due to the development of liver cirrhosis over the period of 8 wk. The body weight was higher in group MA than in group M. The liver indices were significantly elevated at 4, 6 and 8 wk in groups M and MA compared to group N. AS supplementation partially decreased the liver indices in group MA. Marked histopathologic changes in the liver and small intestinal mucosa in group M were observed, which were alleviated in group MA. Levels of pro-inflammatory interleukin-6 and tumor necrosis factor-α were significantly elevated at 8 wk in ileal homogenates in group M compared to group N, which were decreased after AS supplementation in group MA. The dysbiosis of gut microbiota indicated by the mean diversity (Shannon index) and mean similarity (Sorenson index) was severe as the liver cirrhosis developed, and AS supplementation had an apparent intervention effect on the dysbiosis of gut microbiota at 4 wk. The occurrence of BT was increased in the liver of group M compared to that of group N. AS supplementation reduced BT in group MA at 8 wk. BT also occurred in the MLNs, spleen, and kidney, which was reduced by AS supplementation. BT was not detected in the blood in any group.
  
  
  CONCLUSIONS
  Dysbiosis of gut microbiota, injury of intestinal mucosal barrier and BT occurred as liver cirrhosis progressed, which might enhance inflammation and aggravate liver injury. AS may have other non-antimalarial effects that modulate gut microbiota, inhibit BT and alleviate inflammation, resulting in a reduction in CCl4, alcohol and high fat-caused damages to the liver and intestine.
authors.affiliation: Yun-Xia Chen, Li Meng, Department of Microbiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China.
authors.forename: Yun-Xia
authors.initials: YX
authors.lastname: Chen
authors.affiliation: Yun-Xia Chen, Li Meng, Department of Microbiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Lai
authors.affiliation: Yun-Xia Chen, Li Meng, Department of Microbiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China.
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Zhang
authors.affiliation: Yun-Xia Chen, Li Meng, Department of Microbiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China.
authors.forename: Yang-Hui
authors.initials: YH
authors.lastname: Bi
authors.affiliation: Yun-Xia Chen, Li Meng, Department of Microbiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Meng
authors.affiliation: Yun-Xia Chen, Li Meng, Department of Microbiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China.
authors.forename: Xu-Jiong
authors.initials: XJ
authors.lastname: Li
authors.affiliation: Yun-Xia Chen, Li Meng, Department of Microbiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China.
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Tian
authors.affiliation: Yun-Xia Chen, Li Meng, Department of Microbiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China.
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Wang
authors.affiliation: Yun-Xia Chen, Li Meng, Department of Microbiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China.
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Fan
authors.affiliation: Yun-Xia Chen, Li Meng, Department of Microbiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China.
authors.forename: Zhong-Fu
authors.initials: ZF
authors.lastname: Zhao
authors.affiliation: Yun-Xia Chen, Li Meng, Department of Microbiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China.
authors.forename: De-Wu
authors.initials: DW
authors.lastname: Han
authors.affiliation: Yun-Xia Chen, Li Meng, Department of Microbiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Ji
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D001419:Bacteria / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018988:Bacterial Translocation / Q000187:drug effects*; D002251:Carbon Tetrachloride; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D018450:Disease Progression; D064806:Dysbiosis; D005243:Feces / Q000382:microbiology; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D008297:Male; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D037621:Artemisinins; D016207:Cytokines; D018836:Inflammation Mediators; D000077332:Artesunate; D002251:Carbon Tetrachloride
keywords: Artesunate; Bacterial translocation; Gut microbiota; Hepatic cirrhosis; Intervention