现代集约化养殖中潮湿、噪声等各种刺激因素易使鸡长期处于应激环境，对鸡的生产性能产生不利影响。慢性应激下会导致肉鸡体重下降、采食量增加、外周脂肪沉积。胆汁酸的从头合成是调节肝脏脂质代谢的重要途径之一，胆汁酸的疏水性能抑制特定的肠道微生物的生长，其中含有胆盐水解酶的肠道微生物能够将初级胆汁酸代谢为次级胆汁酸，改变胆汁酸池的胆汁酸组成。为了探究皮质酮暴露诱导的慢性应激是否影响肝脏胆汁酸的合成与转运，总胆汁酸的改变是否影响盲肠内容物中微生物的菌群结构，菌群结构的改变是否与脂肪肝的产生有关联？这些问题均尚不清楚，研究主要分为以下两部分。

1.慢性应激对鸡肝脏胆汁酸合成转运影响的探究

本研究以1日龄雪山草鸡为研究对象，正常饲喂至30日龄，随机挑选24只大小体重相近的鸡，分为两组，每组12只生物学重复。处理组每天于皮下注射等体积的2 mg/kg的皮质酮溶液（每天注射两次，上午8:00~9:00；下午17:00~18:00），对照组按体重注射对应体积的酒精溶剂（15%的乙醇生理盐水），连续处理14天建立慢性应激模型，在实验期间鸡自由采食和饮水。45日龄鸡过夜进食后宰杀，收集血浆，采集肝脏冰冻组织及分子样。油红染色结果表明：慢性应激皮质酮暴露导致鸡肝脏脂肪肝，肝细胞内出现大量脂肪变性。肝脏中TG 含量与形态学观察一致，慢性皮质酮暴露增加了肝脏的TG含量（P < 0.01）血液生化结果显示慢性皮质酮暴露极显著降低了血清中碱性磷酸酶水平的酶活性（P < 0.001），血浆中的谷草转氨酶和谷丙转氨酶活性并无显著差异。

此外，慢性皮质酮暴露极显著增加了血浆中Tch（P < 0.001）、LDL（P < 0.001）和VLDL（P < 0.01）的含量。我们还检测了总胆汁酸在肝肠循环中的含量。结果表明：慢性皮质酮暴露显著（P < 0.01）降低了肝脏中总胆汁酸含量，盲肠内容物中总胆汁酸的含量显著（P < 0.01）增加，但是不影响血清中总胆汁酸的含量。采用荧光实时定量RT-PCR 检测肝脏中与胆汁酸合成、转运相关基因表达的结果显示：慢性皮质酮暴露显著增加（P < 0.05）了肝脏中FXR和OATP1B1 mRNA的水平，但显著（P < 0.05）降低了CYP8B1的mRNA表达。Western blot 结果显示 ：慢性皮质酮暴露显著（P < 0.05）降低了肝脏CYP27A1的蛋白表达水平。

2．对慢性应激下对盲肠中微生物的组成变化的探究

屠宰后，收集鸡两侧盲肠内容物。每组随机选取8个生物学重复，提取微生物DNA。针对微生物基因组V3-V4区进行特异性引物扩增，PCR产物采用illumina MiSeq测序平台进行16S rDNA测序。结果表明：慢性皮质酮暴露对盲肠微生物α多样性中Simpson指数和Shannon指数没有明显影响，对反映微生物丰富度的指数Ace和Chao也均无显著影响。从β多样性分析结果来看：慢性皮质酮暴露显著(P < 0.05)增加了弯曲菌门（Campilobacterota）的相对含量。PcoA主成分分析显示：慢性皮质酮暴露显著(P < 0.05)改变了鸡盲肠微生物的群落组成。采用LEFSe分析进行组间差异物种比较，结果显示：慢性皮质酮暴露显著(P < 0.05)降低梭状芽胞杆菌（Clostridia）、颤螺菌属（Oscillospiraceae）、毛螺旋菌属（Lachnospiraceae）和艾森伯格氏菌（Eisenbergiella）等在盲肠的富集程度，显著增加巴恩斯氏菌科（Barnesiellaceae）、乳杆菌科（Lactobacillaceae）、弯曲菌科（Campilobacterota）和螺杆菌科（Helicobacteraceae）等在盲肠的富集程度。通过肠道微生物与环境因子的互作分析，结果表明：粪便总胆汁酸与乳酸菌属（Lactobacillus）的丰度呈显著（P < 0.05）正相关；而肝脏总胆汁酸与优杆菌属（Eubacterium）呈显著（P < 0.05）正相关，与螺杆菌属（Helicobacter）呈显著(P < 0.05)负相关；血浆胆固醇与乳酸菌属（Lactobacillus）、巴恩斯氏菌（Barnesiella）呈显著（P < 0.05）正相关，与布劳特氏菌属（blautia）、优杆菌属（Eubacterium）呈显著负相关。

综上所述，慢性皮质酮暴露诱导鸡脂肪肝，破坏了肝脏胆汁酸转运与合成，导致肝脏内总胆汁酸含量下降。此外，盲肠内容物中滞留的总胆汁酸改变了鸡肠道微生物菌群结构，乳酸菌属（Lactobacillus）的显著变化与粪便胆汁酸、甘油三酯、胆固醇相关，优杆菌属（Eubacterium）的变化与肝脏胆汁酸相关。

Moisture, noise and other stimulating factors in modern intensive breeding industry tend to make chickens live in a stressful environment in the long run , which will cause negative effects on the performance of chickens. Broilers under chronic stress can lead to weight loss, increased food intake and peripheral fat deposition. Synthesis of the bile acids from the very beginning is one of the most important ways to regulate the lipid metabolism in the liver. The hydrophobic property of bile acids will inhibit the growth of specific group of  intestinal microorganisms. Among them, the intestinal microorganisms which contains  the bile hydrolytic enzyme can metabolize the primary bile acids into secondary and change the composition of bile acids pool. To explore whether the chronic stress induced by corticosterone exposure affects the synthesis and transport of liver bile acid. Whether the change of total bile acid affects the microbial community structure in cecal contents? Whether the change of microbial community structure is associated with the production of fatty liver? These questions remain unresolved. The research is mainly carried out from two aspects.

1. The effect of chronic stress on bile acid synthesis and transport in chicken liver

In this study, one-day-old Xueshan Grass chickens were used as the research subjects. Twenty-four chickens of similar size and weight were randomly selected, normally fed to 30 days’ age. They were divided into two groups with 12 biological replicates in each group. Treatment group was subcutaneously injected with the same volume of 2 mg/kg corticosterone solution every day (twice daily, 8:00A.M~9:00 A.M.; 17:00 PM ~18:00 PM), the control group was injected with the corresponding volume of alcoholic solvent (15% ethanol normal saline) ,according to body weight. The chronic stress model was established after continuous treatment for 14 days. During this experiment, chickens were free to eat and drink. The 45-day-old chickens were fed at night and slaughtered to collect their plasma ,frozen liver tissue and molecular samples. The results of oil-red staining showed that chronic stress exposure to corticosterone resulted in fatty liver and a large amount of steatosis in liver cells. TG content in liver is consistent with the morphological observation ; chronic corticosterone exposure has increased liver TG content (P < 0.01); blood biochemical results showed that chronic corticosterone exposure significantly reduced the activity of serum alkaline phosphatase enzyme (P < 0.001),whereas plasma aspertate aminotransferase and third transaminase activity has no significant difference.

In addition, chronic corticosterone exposure significantly increased the plasma contents of Tch (P < 0.05), LDL (P < 0.05) and VLDL (P < 0.05). We also measured the total bile acid levels in the hepatointestinal circulation. The results showed that chronic corticosterone exposure significantly decreased the content of total bile acid in liver (P < 0.01), and significantly increased the content of total bile acid in cecum contents (P < 0.01), but did not affect the content of total bile acid in serum. Fluorescence real-time quantitative RT-PCR was used to detect the expression of genes related to bile acid synthesis and transport in the liver. The results showed that: Chronic corticosterone exposure significantly increased the mRNA levels of FXR (P < 0.05) and OATP1B1 (P < 0.05) in liver, but significantly decreased the mRNA expression of CYP8B1 (P < 0.01). Western blot results showed that chronic corticosterone exposure significantly decreased the protein expression level of CYP27A1 in liver(P < 0.05).

2. The study on the changes of the composition of cecal microbial under chronic stress

After the slaughter, the cecal contents on both sides of the chicken were collected. Eight biological replicates were randomly selected from each group to extract microbial DNA. Specific primers were amplified for the V3-V4 region of the microbial genome, and 16S rDNA sequencing of the PCR products was performed using Illumina MiSeq sequencing platform. The results showed that chronic corticosterone exposure had no significant effect on the Simpson index and Shannon index of α diversity of cecal microorganisms. It has no effect on the ACE and Chao indices of microbial richness, either. According to the results of β-diversity analysis, chronic corticosterone exposure significantly increased the relative content of Bacteroidota (P < 0.05). PCOA principal component analysis showed that chronic corticosterone exposure significantly changed the composition of microbial community in the cecum of chickens (P < 0.05). LEFSE analysis was used to compare different species between groups, and the results showed that: Chronic corticosterone exposure significantly reduced the enrichment degree of Clostridia, Oscillospiraceae, Lachnospiraceae and Eisenbergiella in cecum. Significantly increased the enrichment degree of Barnesiellaceae, Lactobacillaceae, Campilobacterota and Helicobacteraceae in cecum. Through interaction analysis of intestinal microorganism and environmental factors, the results showed that fecal total bile acid was positively correlated with the abundance of Lactobacillus (P < 0.05). The total bile acid of liver was significantly (P < 0.05) positively correlated with Eubacterium, and negatively correlated with Helicobacter. Plasma cholesterol was positively correlated with Lactobacillus and Barnesiella (P < 0.05), and negatively correlated with Blautia and Eubacterium (P < 0.05).

In conclusion, chronic corticosterone-induced fatty liver in chickens destroys liver’s total bile acid, and its transport and synthesis, thus leading to a decrease in liver’s total bile acid content. In addition, the retention of total bile acids in cecum contents changed the structure of intestinal microflora. Significant changes in Lactobacillus were associated with fecal bile acid, triglyceride and cholesterol, while changes in Eubacterium were associated with liver bile acid.

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