镉（Cadmium, Cd）是一种广泛存在于环境中的有害金属，严重威胁动物和人类健康。镉的主要靶器官是肝脏，可引起肝脏组织损伤和肝脏炎症。已有研究表明，肠道菌群的稳态与肝脏疾病的发生与否关系紧密，但其在镉诱发的肝脏损伤中是否发挥作用以及如何发挥作用尚未研究。肠FXR（farnesoid X receptor）/FGF15（fibroblast growth factor 15）信号通路在胆汁酸的负反馈调节中发挥到了关键作用，肠道中的FXR在与胆汁酸结合后激活，通过调节转录因子的活性影响FGF15的表达和释放。该信号通路通过对胆汁酸合成代谢和肠道菌群稳态的调控来联系肠道和肝脏，但目前尚无研究显示镉导致的肝脏损伤与FXR/FGF15信号通路表达之间的联系。因此，本文旨在探究肠道菌群及FXR/FGF15信号通路在镉暴露引起的小鼠肝损伤的作用机制。首先，本试验使用C57BL/6小鼠镉中毒模型，研究镉暴露对小鼠肝脏以及肠道的毒性作用，以及镉暴露对小鼠肠道菌群稳态的影响；而后通过抗生素清除小鼠肠道菌群实验和粪菌移植实验，探讨肠道菌群在镉致肝损伤中的作用与影响；最后使用FXR肠道特异性激动剂Fexaramine对镉暴露小鼠进行处理，探究FXR/FGF15信号通路在镉致肝损伤中的作用与影响。

试验一：镉暴露诱导小鼠肝脏损伤和肠道菌群失调

有毒重金属镉一般通过食源性渠道进入到畜禽体内，经由肠道吸收后转移至肝脏当中。本试验使用浓度为6mg/kg B.W.的氯化镉溶液对小鼠进行灌胃处理，研究镉暴露对小鼠肝脏和肠道的影响。结果表明，小鼠在摄入镉后，血清中的肝功能指标(ALP、ALT、AST)水平显著上升，肝脏组织出现明显的空泡变性和炎性细胞浸润，血清和肝脏组织内的炎症因子(TNF-α、IL-6、IL-1β、F4/80)表达量明显增加，肝脏还出现了胆管增生以及纤维化的现象，纤维化相关基因(CK19、α-SMA、TGFβ1)的表达水平呈明显上升趋势，而体内包括血清、肝脏以及肠道内的胆汁酸含量均有上升，肠道中胆汁酸的代谢组分T-βMCA含量明显提高。同时，经镉处理后，小鼠小肠的长度明显缩短，肠绒毛出现损伤，长度变短，肠道组织中的炎症因子(TNF-α、IL-6、IL-1β)表达量上升，肠道屏障受损。进一步对小鼠肠道菌群进行16s rRNA测序，分析对照组小鼠和镉暴露组小鼠肠道菌群的组成和多样性。结果显示，镉处理组的小鼠肠道内的菌群组成和多样性均发生了明显的改变，特别是某些致病性菌群的丰度显著增加，而粪便中的BSH含量则明显下降。

试验二：镉暴露通过诱导小鼠肠道菌群失调进而导致肝脏损伤

肠道菌群在许多生理功能中发挥重要作用，而肠道菌群失调可以影响动物机体的代谢和免疫，从而导致肝脏损伤。本研究旨在探究肠道菌群在镉致肝脏损伤中的作用。为了验证肠道菌群可以作为镉致肝损伤的靶点，在进行镉处理前，清除小鼠肠道菌群，结果表明抗生素处理后，小鼠肝脏损伤得到显著缓解；血清中的肝功能指标(ALP、ALT、AST)相较于镉暴露组，有了明显下降；肝脏组织中的肝索排列也变得较为规则，肝细胞坏死和出血的情况都有所减少，空泡化变性也趋于降低。进一步研究发现，小鼠肝脏组织中的胆管增生也得到了抑制，CK19的表达量显著下降，体内包括血清、肝脏和肠道的胆汁酸含量也显著下降。进一步通过粪菌移植实验，将原两组小鼠的肠道菌群移植至使用抗生素清除了肠道菌群的小鼠体内，结果表明，接收了镉暴露组粪便的小鼠相较于接收了对照组粪便的小鼠，肝脏则出现明显损伤，血清中的肝功能指标(ALP、ALT、AST)水平显著上升，肝脏组织发生空泡变性和炎性细胞浸润显著增加，肝脏胆管增生相关基因CK19的表达量显著上升，粪便内BSH含量明显上升，体内包括血清、肝脏以及肠道内的胆汁酸含量显著提高。

试验三：镉暴露通过肠道菌群-FXR/FGF15信号轴诱导小鼠肝脏损伤

FXR/FGF15信号通路可通过调节胆汁酸合成、转运和肠道对胆汁酸的吸收，来维持代谢平衡。近年来肠道与肝脏的相互作用被越来越多地研究，FXR/FGF15信号通路作为重要的胆汁酸-肝-肠轴信号通路，通过调节肝脏和肠道之间的相互作用，维持机体胆汁酸代谢的平衡。本研究旨在探究FXR/FGF15信号通路在镉暴露引起的肝损伤中的作用。试验结果显示，经镉处理后，小鼠肠道中FXR/FGF15信号通路的表达下降，而在镉暴露前使用抗生素进行处理后，小鼠肠道FXR/FGF15信号通路表达的下调得以缓解，移植了镉暴露组肠道菌群的小鼠，也下调了肠道FXR/FGF15信号通路，而后使用FXR肠道特异性激动剂Fexaramine处理镉暴露组小鼠，Fexaramine处理后肠道组织中FXR和FGF15 mRNA的表达水平均得到显著提高，而Fexaramine处理后镉暴露小鼠的肝脏组织损伤程度明显减轻，肝脏功能也得到恢复，血清中的肝功能指标(ALP、ALT、AST)水平相较于镉暴露组出现明显下降，肝脏组织内的炎症因子(TNF-α、IL-6、IL-1β)含量呈明显下降趋势，镉暴露诱导发生的肝脏胆管增生现象得到缓解，CK19表达量明显下降，体内包括血清、肝脏以及肠道内的胆汁酸含量均降低。进一步试验后显示，经Fexaramine处理后，镉暴露小鼠的肠道损伤和炎性反应得到缓解，受损的肠道屏障获得恢复，肠道紧密连接蛋白(Occludin、Claudin-1、ZO-1)表达较单独镉暴露组小鼠显著提升，同时经破损肠道屏障转移至肝脏的肠道细菌数量也成下降趋势。

综上所述，镉可导致肝脏受损和炎症反应，同时导致肠道菌群组成和丰度的改变；清除肠道菌群和激活FXR/FGF15信号轴可改善镉所导致的肝脏损伤；此外，FXR/FGF15信号轴可以通过降低肝脏胆汁酸合成，改善受损的肠道屏障等方式来保护肝脏免受镉引起的损害。本研究结果可为通过靶向调节肠道菌群或肠FXR改善镉引起的肝损伤提供理论依据，为兽医临床上动物镉中毒的防治提供新的靶点和策略。

Cadmium (Cd) is a hazardous metal widely present in the environment and poses a serious threat to animal and human health. The main target organ of Cd is the liver, which can cause liver tissue damage and liver inflammation. It has been shown that gut microbiota homeostasis is closely related to the development of liver disease, but whether and how gut microbiota plays a role in Cd-induced liver injury has not been investigated. The intestinal FXR (farnesoid X receptor)/FGF15 (fibroblast growth factor 15) signaling pathway plays a key role in the negative feedback regulation of bile acids. FXR in the intestine is activated upon binding to bile acids and affects the expression and release of FGF15 by regulating the activity of transcription factors. This signaling pathway links the intestine and liver through the regulation of bile acid anabolism and gut microbiota homeostasis, but no studies have yet shown a link between Cd-induced liver injury and FXR/FGF15 signaling pathway expression. Therefore, the aim of this paper was to investigate the mechanism of the role of gut microbiota and FXR/FGF15 signaling pathway in liver injury induced by Cd exposure in mice. Firstly, we used C57BL/6 mouse cadmium poisoning model to investigate the toxic effects of cadmium exposure on mouse liver and intestine, and the effects of cadmium exposure on the homeostasis of mouse gut microbiota; then we investigated the role and effects of gut microbiota in cadmium-induced liver injury by antibiotic clearance of mouse gut microbiota and fecal bacteria transplantation experiment; finally, we used FXR intestinal specific agonist ( Fexaramine was used to treat cadmium-exposed mice to investigate the role and effect of FXR/FGF15 signaling pathway in cadmium-induced liver injury.

Experiment 1: Cadmium exposure induced liver injury and gut microbiota disorder in mice

Toxic heavy metal cadmium generally enters the body of livestock and poultry through food-borne channels and is absorbed through the intestinal tract and transferred to the liver. In this experiment, the effects of cadmium exposure on the liver and intestine of mice were investigated by gavage treatment with cadmium chloride solution at a concentration of 6 mg/kg B.W. The results showed that the levels of liver function indicators (ALP, ALT, AST) in the serum of mice were significantly increased after cadmium ingestion, liver tissues showed significant vacuolar degeneration and inflammatory cell infiltration, the expression of inflammatory factors (TNF-α, IL-6, IL-1β, F4/80) in the serum and liver tissues was significantly increased, and the liver also showed bile duct hyperplasia as well as fibrosis, and fibrosis The expression levels of fibrosis-related genes (CK19, α-SMA, TGFβ1) were significantly increased, while the bile acid content in the body including serum, liver and intestine were increased, and the content of T-βMCA, a metabolic component of bile acid in the intestine, was significantly increased. Meanwhile, after cadmium treatment, the length of small intestine of mice was significantly shortened, the intestinal villi were damaged and shortened, the expression of inflammatory factors (TNF-α, IL-6, IL-1β) in intestinal tissues was increased, and the intestinal barrier was damaged. Further, 16s rRNA sequencing was performed to analyze the composition and diversity of gut microbiota in control mice and cadmium-exposed mice. The results showed that the composition and diversity of the gut microbiota in the cadmium-treated group of mice were significantly altered, especially the abundance of certain pathogenic microbiota was significantly increased, while the bile salt hydrolase content in the feces was significantly decreased.

Experiment 2: Cadmium exposure induced liver injury in mice by dysregulating gut microbiota

Gut microbiota plays an important role in many physiological functions, and dysbiosis of gut microbiota can affect the metabolism and immunity of the animal organism, which can lead to liver injury. The aim of this study was to investigate the role of gut microbiota in cadmium-induced liver injury. In order to verify that gut microbiota can be used as a target of cadmium-induced liver injury, gut microbiota were removed before cadmium treatment, and the results showed that liver injury in mice was significantly alleviated after antibiotic treatment; liver function indexes (ALP, ALT, AST) in serum were significantly decreased compared with the cadmium-exposed group; the arrangement of liver cords in liver tissue also became more regular, and hepatocyte necrosis and hemorrhage were The hepatic cords in the liver tissues also became more regular, the necrosis and hemorrhage of hepatocytes were reduced, and the vacuolation degeneration tended to decrease. Further study revealed that bile duct proliferation in mouse liver tissues was also inhibited, the expression of CK19 was significantly decreased, and the bile acid content in the body including serum, liver and intestine was also significantly decreased. The results showed that mice that received feces from the cadmium-exposed group showed significant liver damage, a significant increase in serum levels of liver function indicators (ALP, ALT, AST), significant vacuolar degeneration and inflammatory cell infiltration in liver tissues compared with those of the cadmium-exposed group. The expression of the gene CK19 increased significantly, and the level of bile salt hydrolase in the feces elevated greatly, the bile acid content in the body, including the serum, liver and intestine, had a great increase.

Experiment 3: Cadmium exposure induced liver damage in mice via the gut microbiota -FXR/FGF15 signaling axis

The FXR/FGF15 signaling pathway can maintain metabolic homeostasis by regulating bile acid synthesis, transport, and intestinal absorption of bile acids. The interaction between the intestine and the liver has been increasingly studied in recent years, and the FXR/FGF15 signaling pathway, as an important bile acid-hepatic-intestinal axis signaling pathway, maintains the balance of bile acid metabolism in the body by regulating the interaction between the liver and the intestine. The aim of this study was to investigate the role of FXR/FGF15 signaling pathway in liver injury induced by cadmium exposure. The test results showed that the expression of FXR/FGF15 signaling pathway in the intestine of mice treated with cadmium decreased, while the downregulation of intestinal FXR/FGF15 signaling pathway expression was alleviated after treatment with antibiotics prior to cadmium exposure, and mice transplanted with gut microbiota from the cadmium-exposed group also downregulated intestinal FXR/FGF15 signaling pathway after treatment with FXR intestine-specific The expression levels of both FXR and FGF15 mRNA in intestinal tissues were significantly increased after Fexaramine treatment, while liver tissue damage was significantly reduced and liver function was restored in cadmium-exposed mice after Fexaramine treatment, and serum liver function indexes (ALP, ALT. The levels of liver function indicators (ALP, ALT, AST) in serum decreased significantly compared with those in the cadmium-exposed group, the levels of inflammatory factors (TNF-α, IL-6, IL-1β) in liver tissues decreased significantly, the bile duct hyperplasia in liver induced by cadmium exposure was alleviated, the expression of CK19 decreased significantly, and the bile acid content in the body, including serum, liver and intestine, was reduced. Further tests showed that after Fexaramine treatment, intestinal damage and inflammatory response in cadmium-exposed mice were alleviated, the damaged intestinal barrier was restored, and the expression of intestinal tight junction protein (Occludin, Claudin-1, ZO-1) was significantly increased compared with that in cadmium-exposed mice alone, while the number of intestinal bacteria transferred to the liver via the broken intestinal barrier was also decreased The number of intestinal bacteria transferred to the liver through the broken intestinal barrier also decreased.

In conclusion, Cd can cause liver damage and inflammatory response, as well as alteration of gut microbiota composition and abundance; removal of gut microbiota and activation of FXR/FGF15 signaling axis can improve the liver damage caused by Cd; in addition, FXR/FGF15 signaling axis can protect the liver from Cd-induced damage by reducing hepatic bile acid synthesis and improving the damaged intestinal barrier. The results of this study may provide a theoretical basis for improving Cd-induced liver injury by targeting the regulation of gut microbiota or intestinal FXR, and provide new targets and strategies for the prevention and treatment of Cd poisoning in veterinary clinical animals.

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