【目的】果糖过量摄入可增加营养代谢疾病患病风险。果糖与代谢性疾病的关系，目前已成为全球关注的公共卫生问题。有研究指出，果糖可引发结肠微环境改变，增加循环系统中内毒素、炎症因子，同时改变结肠菌群结构及其代谢产物，从而导致非酒精性脂肪肝的发生。但是，果糖改变结肠微环境，影响结肠功能的机制尚不明确。

结肠微环境（Colonic microenvironment）指的是结肠内的生物屏障、化学和物理屏障、免疫屏障等所有参与维持结肠健康稳态的因子。芳香烃受体（Aryl hydrocarbon receptor，AhR）是一种重要的核受体蛋白，参与调节和组织稳态高度相关的生物学过程。有研究表明AhR的适度活化可以保护肠道屏障，但果糖和AhR的关系尚未被报道。因此，本课题通过体内和体外模型，采用微生物组和代谢组方法结合，应用分子生物学技术，研究果糖对结肠微环境的影响机制。

【方法】（1）不同剂量果糖对正常大鼠结肠微环境的影响评价：实验周期20周，将健康SD大鼠随机分为4组（n=10），周期内灌胃不同剂量果糖0（Con），2.6 （Fru-L，按照等效剂量换算约为60kg成年人每天果糖摄入量25g），5.3（Fru-M，按照等效剂量换算约为60kg成年人每天果糖摄入量50g）and 10.5（Fru-H，按照等效剂量换算约为60kg成年人每天果糖摄入量120g）g/kg/day 20周后，对体重，空腹血糖、促炎症因子白介素-6（IL-6）、白介素-8（IL-8），抗炎因子白介素-10（IL-10）和巨噬细胞炎性蛋白-2（MIP-2）、结肠紧密连接蛋白闭锁小带（ZO-1），闭锁蛋白（Occludin）表达；结肠菌群进行检测分析。

（2）果糖、葡萄糖和蔗糖对正常大鼠结肠微环境的差异化影响：实验周期20周，将健康SD大鼠随机分为4组（n=10），周期内灌胃相同剂量（5.3g/kg/day，按照等效剂量换算约为60kg成年人每天果糖摄入量50g）的果糖（Fru），葡萄糖（Glu），蔗糖（Sac）20周后，对其体重，空腹血糖、糖耐量、炎症因子白介素-6（IL-6）、白介素-8（IL-8）、结肠紧密连接蛋白ZO-1、Occludin、脂滴聚集蛋白Perlipin-1、ADRP和Tip-47表达进行测定，并对结肠菌群进行检测分析。

（3）高果糖饮食对大鼠结肠微环境的影响机制：将SD大鼠随机分为4组（n=12），其中2组使用2%葡聚糖硫酸钠（Dextran sodium，DSS）对大鼠进行造模，自由采食含35%果糖饲料8周，通过对组织切片，血清和结肠黏膜中炎症因子IL-1β、IL-6，IL-8和TNF-α、血清中脂多糖（Lipopolysaccharide，LPS）和二胺氧化酶（DAO）、免疫球蛋白sIgA、IgA和IgG；紧密连接蛋白（ZO-1、Occludin、Claudin-1和Claudin-4），黏液蛋白（Muc2、TFF3和Relm-β）和抗凋亡蛋白Bcl-2，促凋亡蛋白Bax等进行分析；利用多组学分析技术筛选导致结肠微环境失衡的生物标志物：色氨酸代谢中产物吲哚丙烯酸（Indoleacrylic acid，IAA）和吲哚-3-甲醛（Indole-3-carboxaldehyde，I3A），以HT-29人结肠癌细胞作为结肠上皮细胞模型，炎症上述两种生物标志物在屏障功能方面的作用，使用10mM果糖，10ng/ml LPS，0.1mM IAA和I3A处理细胞48h， 收集细胞全RNA和蛋白，检测紧密连接蛋白ZO-1、Occludin和Claudin-4蛋白表达变化，并进行核质分离检测AhR入核情况，验证代谢物生物标志物色氨酸代谢中产物吲哚丙烯酸（IAA）和吲哚-3-甲醛（I3A）对芳烃受体（AhR）激活情况。

（4）果糖对结肠炎大鼠结肠微环境的影响：将SD大鼠随机分为4组（n=12），其中使用2% DSS对大鼠进行造模，分别给予含12.75%果糖饲料或蔗糖饲料（按照等效剂量换算约为60kg成年人每天果糖摄入量50g）饲喂8周，评价添加糖对大鼠炎症因子（IL-6和IL-8）、内毒素LPS、结肠菌群及菌群代谢物等的影响，通过多组学手段挖掘果糖造成肠道微环境改变的机制。

【结果】（1）不同剂量果糖对正常大鼠结肠微环境的影响评价：与Con组比较，Fru-H组尿酸水平升高36.5%（P < 0.05）。果糖处理后血清促炎细胞因子IL-6、TNF-α和MIP-2显著升高（P < 0.05），抗炎细胞因子IL-10显著降低（P < 0.05）。高果糖（Fru-H组）摄入导致肝脏脂质堆积，胰腺和结肠炎症细胞浸润，结肠内容物中Lachnospira、Parasutterella、Marvinbryantia和Blantia的丰度增加。果糖摄入增加了结肠中脂质堆积蛋白Perilipin-1、ADRP和Tip-47的表达。此外，高果糖（Fru-H组）摄入会降低紧密连接蛋白（ZO-1和Occludin）的表达，从而损害肠道屏障功能。

（2）果糖、葡萄糖和蔗糖对健康结肠微环境的差异化影响：Fru组大鼠的体重、总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白（HDL-C）、低密度脂蛋白（LDL-C）、游离脂肪酸（FFA）等血液参数方面，与Glu、Sac、Con组均无显著性差异。与葡萄糖组（Glu）相比，果糖能显著降低空腹血糖（P< 0.05）和餐后血糖升高量。肠道微生物多样性没有显著差异。在科水平上，Glu组大鼠具有较高的Peptostreptococcaceae丰度，Fru组大鼠具有较高的Bacteroidaceae丰度。此外，消化性链球菌、Romboutsia和葡萄球菌的比例。Glu组Lentus显著高于Fru组，而Lachnospira、Lachnospiraceas Blautia、Bacteroides和Cellulosilyticus的比例在Fru组显著高于Glu组。各糖处理组异丁酸浓度均较Con组低，且Fru组与Con组相比显著降低（P< 0.05）。

（3）高果糖饮食对结肠微环境的影响机制：膳食中添加35%果糖（按照等效剂量换算约为60kg成年人每天果糖摄入量120g），可诱导大鼠结肠功能障碍，加重DSS诱导大鼠结肠损伤。随着结肠长度缩短（P< 0.05），杯状细胞数减少（P< 0.05），炎症浸润（P< 0.05）和炎症因子（P< 0.05）在结肠和血清中增加，结肠组织中紧密连接蛋白表达下降（P< 0.05），细胞凋亡信号变强（P< 0.05）。此外，果糖还引起了微生物群及其代谢产物的失调。筛选出Adlercreutzia，Turicibacter，Erysipelotrichaceae_f_Clostridium，Clostridium_f_Lachnospiracea和Holdemania作为潜在的标志菌群；色氨酸代谢中产物IAA和I3A（AhR的天然潜在受体）作为果糖抑制的代谢物生物标志物。数据显示高果糖饮食可抑制AhR的表达和活化。体外实验中，高果糖培养基中添加IAA和I3A可提高HT-29细胞跨膜电阻值，上调紧密连接蛋白Occludin表达并激活AhR以缓解果糖对HT-29细胞的损伤。

（4）果糖对结肠炎大鼠结肠微环境的影响：在结肠炎模型下，膳食中添加12.75%蔗糖和果糖（按照等效剂量换算约为60kg成年人每天果糖摄入量50g/day，世界卫生组织公布的添加糖限量为50g/day）均可显著降低大鼠体重，缩短结肠长度，增加结肠炎症浸润。蔗糖和果糖均通过抑制紧密连接蛋白ZO-1的表达，提高血浆中脂多糖（LPS）水平而使结肠功能恶化，果糖表现更为显著。此外，蔗糖和果糖显著改变了肠道菌群的组成，属水平下，降低具有益生作用的Adlercreutzia、Leuconostoc、Lactococcus和Oscillospira菌种相对丰度；代谢组学结果表明，果糖可减少结肠内多种氨基酸或功能性物质如瓜氨酸、天冬氨酸、精氨酸、脯氨酸、4-羟脯氨酸、GABA的含量。上述结果表明，与蔗糖相比，果糖可能通过诱导结肠精氨酸和脯氨酸代谢失调加重结肠炎症状。

【结论】（1）2.6 g/kg/day或5.3g/kg/day的果糖对大鼠体重、空腹血糖、肠道微生物群和结肠内容物中的SCFAs均未观察到显著影响。大量摄入果糖可增加尿酸、促炎细胞因子、肠通透性、肝脏脂质堆积，诱发胰腺和结肠炎症反应。

（2）果糖、葡萄糖和蔗糖剂量5.3g/kg/day条件下，不同种类的游离糖均对大鼠结肠肠道菌群有一定影响，其中果糖可导致大鼠结肠内异丁酸含量下降，血液指标方面各种糖之间并无显著差异。但在结肠炎模型下，膳食中12.5%果糖可导致结肠微环境失调，根据多组学结果，果糖可能通过影响精氨酸和脯氨酸代谢，加重大鼠结肠炎症状。

（3）膳食中35%果糖诱导了全身性的免疫应答，导致严重的结肠炎症浸润，结肠上皮细胞凋亡，通过多组学分析和细胞实验验证，果糖通过抑制结肠中吲哚丙烯酸和吲哚-3-甲醛的产生，从而抑制AhR的激活，最终导致结肠微环境恶化。同时，高剂量的果糖也导致了肠道菌群结构和数量的大幅改变，这些改变可能与吲哚丙烯酸和吲哚-3-甲醛高度相关。

（4）膳食中12.75%的蔗糖和果糖都能加重结肠炎大鼠的结肠微环境损伤，果糖更甚；果糖通过诱导内毒素和增加血清中的MDA，减少ZO-1的表达，改变结肠菌群的组成和结构，减少从Adlercreutzia，Lactobacillus，Roseburia，Leuconostoc，Lactococcus到Oscillospira的益生菌，增加条件致病菌相对丰度，如Allobaculum，Coprobacillus，Holdemania等，从整体上改变了结肠炎大鼠的结肠微环境。此外，通过降低精氨酸和脯氨酸代谢通路中的瓜氨酸、天冬氨酸、精氨酸、脯氨酸、4-羟基脯氨酸、GABA水平，改变了结肠内容物代谢情况，并最终诱发氨基酸代谢紊乱。我们的研究结果表明，IBD患者摄入果糖需要谨慎。

Objective: Excessive fructose intake increases the risk of metabolic diseases. The relationship between fructose and metabolic diseases has become a global public health concern. Studies have shown that fructose can alter the colonic microenvironment, increase endotoxins and inflammatory cytokines in the circulatory system, and change the structure and metabolites of the colonic microbiota, leading to non-alcoholic fatty liver disease. However, the mechanisms by which fructose alters the colonic microenvironment and affects colonic function are not yet clear.

The colonic microenvironment refers to all factors that maintain colonic health and stability, including biological barriers, chemical and physical barriers, and immune barriers. Aryl hydrocarbon receptor (AhR) is an important nuclear receptor protein that regulates biological processes highly related to tissue homeostasis. Studies have shown that moderate activation of AhR can protect the intestinal barrier, but the relationship between fructose and AhR has not been reported. Therefore, this study used in vivo and in vitro models, combined with microbiome and metabolome approaches, and applied molecular biology techniques to investigate the mechanisms by which fructose affects the colonic microenvironment.

Methods: (1) Evaluation of the effects of different doses of fructose on the colonic microenvironment of healthy rats: During a 20-week experimental period, healthy SD rats were randomly divided into four groups (n=10) and orally administered different doses of fructose 0 (Con), 2.6 (Fru-L), 5.3 (Fru-M), and 10.5 (Fru-H) g/kg/day. After 20 weeks, their body weight, fasting blood glucose, pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), anti-inflammatory cytokine interleukin-10 (IL-10), macrophage inflammatory protein-2 (MIP-2), colonic tight junction proteins zona occludens-1 (ZO-1) and occludin expression, and colonic microbiota were analyzed.

(2) Differential effects of fructose, glucose, and sucrose on the colonic microenvironment of healthy rats: During a 20-week experimental period, healthy SD rats were randomly divided into four groups (n=10) and orally administered the same dose (5.3 g/kg/day) of fructose (Fru), glucose (Glu), or sucrose (Sac). After 20 weeks, their body weight, fasting blood glucose, glucose tolerance, pro-inflammatory cytokines IL-6 and IL-8, colonic tight junction proteins ZO-1 and occludin, lipid droplet-associated proteins perilipin-1, adipose differentiation-related protein, and tail-interacting protein of 47 kDa expression, and colonic microbiota were analyzed.

(3) Mechanisms by which a high-fructose diet affects the colonic microenvironment of rats: SD rats were randomly divided into four groups (n=12), two of which were treated with 2% dextran sodium sulfate (DSS) to induce colitis and fed a diet containing 35% fructose for 8 weeks. Inflammatory cytokines interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNF-α), lipopolysaccharide (LPS), diamine oxidase (DAO), secretory immunoglobulin A (sIgA), immunoglobulin A (IgA), and immunoglobulin G (IgG) in tissue slices, serum, and colonic mucosa were analyzed. Tight junction proteins (ZO-1, occludin, claudin-1, and claudin-4), mucin proteins (Muc2, trefoil factor 3, and resistin-like molecule beta), and anti-apoptotic protein Bcl-2 and pro-apoptotic protein Bax were also analyzed. Metabolomic analysis was used to screen for biomarkers that cause colonic microenvironment imbalance, including indoleacrylic acid (IAA) and indole-3-carboxaldehyde (I3A) in tryptophan metabolism. The effects of these biomarkers on barrier function were investigated in HT-29 human colon cancer cells as a colonic epithelial cell model using 10 mM fructose, 10 ng/mL LPS, 0.1 mM IAA, and I3A for 48 h. Changes in the expression of tight junction proteins ZO-1, occludin, and claudin-4 were assessed, and nuclear-cytoplasmic separation was used to detect AhR nuclear translocation.

(4) Effects of fructose on the colonic microenvironment of rats with colitis: SD rats were randomly divided into four groups (n=12), two of which were treated with 2% DSS to induce colitis and fed a diet containing 12.75% fructose or sucrose for 8 weeks. The effects of added sugars on inflammatory cytokines (IL-6 and IL-8), endotoxin LPS, colonic microbiota, and microbial metabolites were evaluated using multi-omics approaches to explore the mechanisms by which fructose alters the gut microbiota and causes colonic microenvironmental changes.

Results: (1) Evaluation of the effects of different doses of fructose on the colonic microenvironment of healthy rats: compared with the Con group, the uric acid level was increased by 36.5% in the Fru-H group (P < 0.05). Serum pro-inflammatory cytokines IL-6, TNF-α and MIP-2 were significantly increased (P < 0.05) and anti-inflammatory cytokine IL-10 was significantly decreased (P < 0.05) after fructose treatment. High fructose (Fru-H group) intake resulted in hepatic lipid accumulation, pancreatic and colonic inflammatory cell infiltration, and increased abundance of Lachnospira, Parasutterella, Marvinbryantia, and Blantia in the colonic contents. Fructose intake increased the expression of lipid accumulation proteins Perilipin-1, ADRP and Tip-47 in the colon. In addition, high fructose (Fru-H group) intake decreased the expression of tight junction proteins (ZO-1 and Occludin), thereby impairing intestinal barrier function.

(2) Differential effects of fructose, glucose and sucrose on healthy colonic microenvironment: There were no significant differences from the Glu, Sac and Con groups in terms of blood parameters such as body weight, total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C) and free fatty acids (FFA) in the Fru group rats. Fructose significantly reduced fasting blood glucose (P< 0.05) and postprandial blood glucose elevation compared to the glucose group (Glu). There was no significant difference in gut microbial diversity. At the family level, rats in the Glu group had a higher abundance of Peptostreptococcaceae and rats in the Fru group had a higher abundance of Bacteroidaceae. In addition, the proportions of Streptococcus pepticus, Romboutsia and Staphylococcus. lentus were significantly higher in the Glu group than in the Fru group, while the proportions of Lachnospira, Lachnospiraceas Blautia, Bacteroides and Cellulosilyticus were significantly higher in the Fru group than in the Glu group. Isobutyric acid concentrations were lower in all sugar-treated groups compared to the Con group, and were significantly lower in the Fru group compared to the Con group (P< 0.05).

(3) Mechanism of the effect of high fructose diet on the colonic microenvironment: The addition of 35% fructose to the diet (converted to approximately 120 g of fructose intake per day for a 60 kg adult according to the equivalent dose) induced colonic dysfunction and aggravated DSS-induced colonic injury in rats. With shortened colon length (P< 0.05), the number of cupped cells decreased (P< 0.05), inflammatory infiltration (P< 0.05) and inflammatory factors (P< 0.05) increased in the colon and serum, tight junction protein expression decreased (P< 0.05) and apoptotic signals became stronger (P< 0.05) in colon tissue. In addition, fructose caused dysregulation of the microbiota and its metabolites. Adlercreutzia, Turicibacter, Erysipelotrichaceae_f_Clostridium, Clostridium_f_Lachnospiracea and Holdemania were screened as potential marker groups; the tryptophan metabolism intermediate products IAA and I3A ( natural potential receptors of AhR) as metabolite biomarkers of fructose inhibition. The data show that a high fructose diet inhibits AhR expression and activation. In in vitro experiments, the addition of IAA and I3A to high fructose medium increased the transmembrane electrical resistance of HT-29 cells, upregulated the expression of the tight junction protein Occludin and activated AhR to mitigate fructose damage to HT-29 cells.

(4) Effects of fructose on the colonic microenvironment of rats with colitis: In the colitis model, dietary addition of 12.75% sucrose and fructose (equivalent dose converted to approximately 50g/day of fructose intake for a 60kg adult, and the WHO published limit of 50g/day of added sugar) both significantly reduced body weight, shortened colonic length and increased colonic inflammatory infiltration in rats. Both sucrose and fructose worsened colonic function by inhibiting the expression of the tight junction protein ZO-1 and increasing plasma levels of lipopolysaccharide (LPS), with fructose showing more significant effects. In addition, sucrose and fructose significantly altered the composition of the intestinal flora, reducing the relative abundance of the probiotic Adlercreutzia, Leuconostoc, Lactococcus and Oscillospira species at the genus level; metabolomic results showed that fructose reduced the colonic composition of several amino acids or functional substances such as citrulline, aspartic acid, Arginine, proline, 4-hydroxyproline, and GABA in the colon. These results suggest that fructose may aggravate colitis symptoms by inducing dysregulation of colonic arginine and proline metabolism compared with sucrose.

Conclusions: (1) Intake of 2.6 g/kg/dayor 5.3 g/kg/dayof fructose had no negative effects were observed on body weight, fasting blood glucose, intestinal microbiota and SCFAs in colonic contents of rats. High fructose intake increased uric acid, pro-inflammatory cytokines, intestinal permeability, hepatic lipid accumulation, and induced inflammatory responses in the pancreas and colon.

(2) Under the conditions of fructose, glucose and sucrose dose of 5.3g/kg/day, different types of free sugars had some effects on the colon intestinal flora of rats, among which fructose could lead to the decrease of isobutyric acid content in the colon of rats, and there was no significant difference between various sugars in terms of blood index. However, in the colitis model, 12.5% fructose in the diet could lead to dysregulation of the colonic microenvironment. According to the multi-omics results, fructose may aggravate the symptoms of colitis in rats by affecting the metabolism of arginine and proline.

(3) Dietary 35% fructose induced a systemic immune response, leading to severe colonic inflammatory infiltration and apoptosis of colonic epithelial cells. It was verified by multi-omics analysis and cellular experiments that fructose inhibited the activation of AhR by suppressing the production of indole acrylic acid and indole-3-carboxaldehyde in the colon, which ultimately led to the deterioration of the colonic microenvironment. Also, high doses of fructose led to substantial changes in the structure and number of intestinal flora, and these changes may be highly correlated with indoleacrylic acid and indole-3-carboxaldehyde.

(4) Both 12.75% sucrose and fructose in the diet aggravated the damage of colonic microenvironment in rats with colitis, more so with fructose; fructose reduced the expression of ZO-1 by inducing endotoxin and increasing serum MDA, altered the composition and structure of the colonic flora, and reduced the number of bacteria from Adlercreutzia, Lactobacillus, Roseburia Leuconostoc, Lactococcus to Oscillospira and increasing the relative abundance of conditionally pathogenic bacteria, such as Allobaculum, Coprobacillus, Holdemania, etc., altering the colonic microenvironment of rats with colitis as a whole. In addition, by decreasing the levels of citrulline, aspartate, arginine, proline, 4-hydroxyproline, and GABA in the arginine and proline metabolic pathways, the metabolic profile of colonic contents was altered and amino acid metabolic disorders were ultimately induced. Our findings suggest that fructose intake in IBD patients requires caution.

目录
第一章　引言 1
1.1　果糖在机体内的吸收与代谢 1
1.2　果糖与营养代谢性疾病的关系 2
1.2.1　果糖与肥胖 2
1.2.2　果糖与血脂、血糖异常 3
1.2.3　果糖与非酒精性脂肪肝 4
1.2.4　果糖与肠道健康 4
1.3　结肠微环境 5
1.4　AhR活化对结肠微环境的保护作用 6
1.5　研究目的及意义 7
1.6　研究目标及内容 8
1.7　技术路线图 8
第二章　不同剂量果糖对正常大鼠结肠微环境的影响评价 9
2.1　材料和方法 9
2.1.1　主要试剂 9
2.1.2　实验动物 9
2.1.3　实验设计 10
2.1.4　血液指标检测 10
2.1.5　组织病理学分析 10
2.1.6　蛋白质表达分析 11
2.1.7　短链脂肪酸分析 11
2.1.8　ELISA 11
2.1.9　肠道微生物群分析 11
2.1.10　统计学分析 11
2.2　结果 12
2.2.1　不同剂量果糖对体重、采食量和空腹血糖的影响 12
2.2.2　不同剂量果糖对血清生化指标的影响 12
2.2.3　不同剂量果糖对大鼠血清中炎症因子的影响 13
2.2.4　不同剂量果糖对大鼠肝脏和胰腺病理学结构变化的影响 14
2.2.5　不同剂量果糖对结肠微环境的影响 15
2.3　讨论 18
2.4　小结 19
第三章　果糖、葡萄糖和蔗糖对正常大鼠结肠微环境的差异化影响 20
3.1　材料和方法 20
3.1.1　主要试剂 20
3.1.2　实验动物 20
3.1.3　实验设计 20
3.1.4　血液指标检测 21
3.1.5　组织病理学分析 21
3.1.6　蛋白质表达分析 21
3.1.7　短链脂肪酸分析 21
3.1.8　ELISA分析 21
3.1.9　肠道微生物分析 21
3.1.10　统计分析 21
3.2　结果 21
3.2.1　果糖、葡萄糖和蔗糖对体重、饲料摄入量、器官和血液参数的影响 21
3.2.2　果糖、葡萄糖和蔗糖对血糖和胰岛素水平的影响 22
3.2.3　果糖、葡萄糖和蔗糖对大鼠胰腺的影响 24
3.2.4　果糖、葡萄糖和蔗糖对大鼠肝脏的影响 25
3.2.5　果糖、葡萄糖和蔗糖对大鼠结肠微环境的影响 27
3.3　讨论 30
3.4　小结 31
第四章　高果糖饮食对结肠微环境的影响机制 32
4.1　材料和方法 33
4.1.1　实验材料 33
4.1.2　动物模型 34
4.1.3　ELISA检测 34
4.1.4　组织学分析 34
4.1.5　RNA分离提取和定量实时PCR（qRT-PCR） 35
4.1.6　免疫荧光分析 35
4.1.7　大鼠结肠微生物组分析 36
4.1.8　大鼠结肠内容物靶向代谢组学分析 36
4.1.9　蛋白质表达分析 37
4.1.10　细胞培养和处理 37
4.1.11　跨膜电阻测量 38
4.1.12　统计分析 38
4.2　结果 38
4.2.1　果糖诱导结肠生理形态改变 38
4.2.2　果糖诱导结肠上皮屏障功能受损 40
4.2.3　果糖诱发大鼠全身性炎症反应 42
4.2.4　果糖诱导大鼠结肠菌群失调 45
4.2.5　果糖诱导大鼠结肠菌群代谢物失衡 51
4.2.6　果糖抑制AhR在大鼠结肠和HT-29　细胞中的表达和激活 58
4.3　讨论 61
4.4　小结 64
第五章　果糖对结肠炎大鼠结肠微环境的影响 66
5.1　材料和方法 66
5.1.1　饲料配方和动物实验设计 66
5.1.2　组织学分析 68
5.1.3　血清中的氧化应激和内毒素测定 68
5.1.4　紧密连接蛋白的表达测定 68
5.1.5　肠道微生物组分析 69
5.1.6　代谢组分析 69
5.2　结果 70
5.2.1　果糖和蔗糖导致DSS大鼠结肠功能恶化 70
5.2.2　果糖诱发血清中的氧化应激和炎症 72
5.2.3　蔗糖和果糖改变了结肠炎大鼠的结肠菌群结构和组成 73
5.2.4　蔗糖和果糖改变了大鼠结肠菌群代谢物的组成 80
5.3　讨论 87
5.4　小结 90
第六章　结论及展望 91
6.1　主要结论 91
6.2　创新性 91
6.3　不足之处 92
6.4　展望 92
参考文献 93
文献综述：果糖与疾病关系研究进展 104
致谢 113
北京大学学位论文原创性声明和使用授权说明 115
个人在校期间发表学术论文和成果 113
论文答辩委员会成员 116

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