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研究生:董德璿
研究生(外文):TUNG, TE-HSUAN
論文名稱:n-3 多元不飽和脂肪酸對慢性非預期壓力模式誘發之類憂鬱症老化大鼠其腸腦膠細胞軸之影響
論文名稱(外文):Effects of n-3 Polyunsaturated Fatty Acids on the Gut-brain-glia Axis in Depressive-like Aging Rats under Chronic Unpredictable Mild Stress Model
指導教授:黃士懿黃士懿引用關係
指導教授(外文):HUANG, SHIH-YI
口試委員:蔡英傑黃啟彰黃惠宇張榮素黃士懿
口試委員(外文):TSAI, YING-CHIEHHUANG, CHI-CHANGHUANG, HUI-YUCHANG, JUNG-SUHUANG, SHIH-YI
口試日期:2022-07-08
學位類別:博士
校院名稱:臺北醫學大學
系所名稱:保健營養學系博士班
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
論文出版年:2022
畢業學年度:110
語文別:英文
論文頁數:174
中文關鍵詞:老年憂鬱症n-3不飽和脂肪酸慢性非預期壓力模式膽酸腸道菌
外文關鍵詞:Geriatric depressionn-3 polyunsaturated fatty acidChronic unpredictable mild stress modelBile acidGut microbiota
ORCID或ResearchGate:orcid.org/ 0000-0002-0712-4861
www.researchgate.net/profile/Te-Hsuan-Tung
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隨著科技以及文明的進步,緊湊的生活節奏逐漸使得人類在精神層面承受越來越大的壓力導致罹患精神疾病的人群逐漸增加。精神疾病在全世界都逐漸造成明顯的影響,其中,憂鬱症佔了極大的比例;根據 2019 年全球疾病負擔(Global Burden of Disease, GBD)報告,全世界憂鬱症患者約有二億七千九百萬,盛行率約 3.44%,且罹患憂鬱症的患者數量有逐年上升的趨勢,其中尤以老年憂鬱症(geriatric depression)較難以發現以及治療。老年憂鬱症患者常伴隨著腦部神經發炎(neuroinflammation)和腸道菌相異常(dysbiosis),且近來研究顯示,腸道菌會透過數條生理路徑影響大腦的生理以及免疫功能,本次實驗目的希望藉由新的動物老年憂鬱症模式—由半乳糖(D-galactose, D-gal)誘導的老化模式結合慢性非預期性壓力模式(chronic unpredictable mild stress, CUMS),觀察腸道菌相與大腦間的連結,並聚焦於探討腸腦膠細胞軸(gut-brain-glia axis)在老年憂鬱症當中所扮演的角色。同時也給予老鼠富含 n-3 多元不飽和脂肪酸(n-3 polyunsaturated fatty acid, n-3 PUFA)的魚油,以觀察n-3 PUFA對此軸線的影響。研究的第一階段使用一般成年大鼠,以 CUMS 憂鬱症模式,實驗成功誘發大鼠產生“失樂”症狀,並也觀察到腸道菌相會受到慢性壓力以及魚油介入改變。第二階段則結合利用 D-gal 誘導生物老 化結合前述 CUMS 模式,模擬人類老年憂鬱症。結果發現慢性壓力以及魚油介入造成腸道菌相組成顯著改變,相關之代謝物膽酸組成以及遠端海馬迴中的色胺酸代謝路徑也有顯著的改變。此外,老年憂鬱症模式老鼠亦證實血液中的 DNA 損害指標 8-hydroxyguanosine(8-OHdG)及脂多醣(lipopolysaccharide, LPS)含量上升,前額皮質中的緊密連接(tight junction)相關蛋白表現量顯著降低,腦中發炎性細胞激素含量較高,海馬迴及前額皮質中的神經膠細胞活化型態微膠細胞(microglia)及星狀細胞(astrocyte)相關的指標亦顯著增加,造成老鼠出現記憶受損以及類憂鬱症狀,上述發炎以及類憂鬱行為持續攝入魚油 12 週有顯著改善。結合兩階段實驗,得知 n-3 PUFA 能藉由改變腸道菌相及其相關代謝物,影響腦中免疫相關之神經膠細胞型態,進而降低腦中神經發炎(neuroinflammation)狀況,改善老鼠的憂鬱症狀。
With the advanced science and technology and civilization, the gradually intensive pace of life made human beings feel more and more stressed. Mental disorders have gradually caused a significant impact worldwide. Specifically, depression accounts for a large proportion of psychiatric disorders. According to the 2019 Global Burden of Disease (GBD) reports, there are 279 million depression patients worldwide, and the prevalence of depression is about 3.44%. The number of depression patients has been increasing over the years, and geriatric depression is more complicated to recognize and more difficult to treat than other psychiatric disorders. Elderly patients with depression are often accompanied by neuroinflammation in the brain and dysbiosis of gut microbiota. Recent studies have shown that gut microbiota affects the physiological and immune functions of the brain via several physical pathways. Therefore, this study aims to use a newly established aging depression animal model — aging pattern induced by D-galactose (D-gal) and depression pattern caused by chronic unpredictable mild stress (CUMS), which to explore the role of the gut-brain-glia axis in rats with geriatric depression. Rats were also given an n-3 PUFA- riched fish oil diet to observe the effects of n-3 PUFA on the gut-brain-glia axis. The first part of this study is to develop a CUMS depression model with normal adult SD rats in the college animal center. This experiment successfully induced the rats to perform "anhedonia" symptoms and showed that the gut microbiota was affected by CUMS and fish oil intervention. The second part of the study combines the D-gal-induced aging and the CUMS model to simulate geriatric depression in humans. Results showed that CUMS and fish oil intervention significantly changed the gut microbiota composition, and the related metabolites, such as bile acid profile and tryptophan metabolism in the hippocampus, were altered considerably. In addition, aged depression rats showed that DNA damage indicators and lipopolysaccharide (LPS) levels in the plasma were increased, the expression of tight junction-related proteins in the prefrontal cortex was reduced, and pro-inflammatory cytokines were significantly higher in the brain. The glia cell–activated microglia and astrocytes were substantially increased in the hippocampus and prefrontal cortex, resulting in memory impairment and depressive-like symptoms in rats. In short, depressed behaviors were significantly improved with consecutive fish oil diet intervention for a 12-week duration. Results demonstrated that n-3 PUFA could modulate the type of microglia and astrocytes in the brain by affecting the gut microbiota and related metabolites, thereby ameliorating the neuroinflammation in the brain and improving the cognitive functions and depressive-like symptoms in rats.
Content
中文摘要 ............................................................................................................................................................. I
ABSTRACT ..................................................................................................................................................... II
ACKNOWLEDGMENT ................................................................................................................................ IV
LIST OF TABLES .......................................................................................................................................... IX
LIST OF FIGURES..........................................................................................................................................X
LIST OF ABBREVIATIONS .......................................................................................................................XII
CHAPTER 1 INTRODUCTION .....................................................................................................................1
CHAPTER 2 LITERATURE REVIEW..........................................................................................................4
1. DEPRESSION COMPREHENSIVE NARRATIVES ................................................................................................4
2. AGING COMPREHENSIVE NARRATIVES .........................................................................................................8
3. AGING AND DEPRESSION............................................................................................................................12
4. AGING AND DEMENTIA ..............................................................................................................................16
4.1. Mild cognitive impairment (MCI).....................................................................................................16
4.2. Dementia...........................................................................................................................................17
4.3. Alzheimer’s disease ...........................................................................................................................19
5. GUT-BRAIN-MICROBIOTA AXIS...................................................................................................................20
6. CHRONIC CNS NEUROINFLAMMATION ......................................................................................................28
7. GUT-BRAIN-GLIA AXIS ...............................................................................................................................32
7.1. The gut microbiota and the integrity of the gut and BBB tight junction...........................................32
7.2. Regulation of the gut-brain-glia axis on glial cell maturation and function....................................33
7.3. Gut-brain-glia axis signaling pathway—The aryl hydrocarbon receptor (AHR).............................33
7.4. Gut-brain-glia axis signaling pathway—serotonin and kynurenine-related substances pathway ...34
8. THE ASSOCIATION BETWEEN NUTRITION AND GERIATRIC DEPRESSION.......................................................36
9. N-3 POLYUNSATURATED FATTY ACID..........................................................................................................38
9.1. n-3 PUFA and inflammation .............................................................................................................40
9.2. n-3 PUFA and cognitive impairment ................................................................................................40
9.3. n-3 PUFA and depression .................................................................................................................41
9.4. n-3 PUFA and neuroprotective effects ..............................................................................................43
10. ANIMAL EXPERIMENT MODEL ..................................................................................................................46
10.1. Chronic unpredictable mild stress model (CUMS) .........................................................................46
10.2. Aging animal model ........................................................................................................................47
10.3. Animal behavior experiment ...........................................................................................................48
CHAPTER 3 RESEARCH OBJECTIVES AND HYPOTHESES .............................................................55
CHAPTER 4 THE EFFECTS OF N-3 PUFA ON GUT MICROBIOTA COMPOSITION IN CUMS DEPRESSION ANIMAL MODEL ................................................................................................................56
1. OBJECTIVE.................................................................................................................................................56
2. MATERIALS AND METHODS ........................................................................................................................56
2.1. Animals and groups ..........................................................................................................................56
2.2. Experimental protocol ......................................................................................................................57
2.3. Experiment model and animal behavioral test .................................................................................59
2.4. Collection of organs and tissues .......................................................................................................62
2.5. Analyzed methods .............................................................................................................................63
3. RESULTS ....................................................................................................................................................69
3.1. Biochemical parameter analysis of rats ...........................................................................................69
3.2. Alteration of body weight and dietary intake....................................................................................69
3.3. Behavior tests....................................................................................................................................69
3.4. Plasma analysis ................................................................................................................................70
3.5. Neurotransmitters in the brain..........................................................................................................71
3.6. Fatty acid profiles .............................................................................................................................71
3.7. Colitis analysis of colon....................................................................................................................71
3.8. Short-chain fatty acid analysis .........................................................................................................72
3.9. Gut microbiota ..................................................................................................................................72
4. DISCUSSION ...............................................................................................................................................73
5. CONCLUSION .............................................................................................................................................79
6. TABLES AND FIGURES ................................................................................................................................80
CHAPTER 5 EFFECTS OF N-3 POLYUNSATURATED FATTY ACIDS ON THE GUT-BRAIN-GLIA AXIS OF DEPRESSIVE-LIKE AGING RATS IN CUMS MODEL .........................................................93
1. OBJECTIVE.................................................................................................................................................93
2. MATERIALS AND METHODS ........................................................................................................................93
2.1. Animals and groups ..........................................................................................................................93
2.2. Experiment protocol..........................................................................................................................96
2.3. Experiment model and animal behavior test ....................................................................................98
2.4. Collection of organs and tissues .....................................................................................................102
2.5. Analyzed methods ...........................................................................................................................103
3. RESULTS ..................................................................................................................................................113
3.1. Biochemical parameter analysis of rats ......................................................................................... 113
3.2. Alteration of body weight and food consumption ........................................................................... 113
3.3. Behavioral test results.....................................................................................................................114
3.4. Comparison of plasma biochemical parameter value .................................................................... 115
3.5. Colon H&E section analysis...........................................................................................................116
3.6. Gut microbiota composition diversity and statistical analysis.......................................................117
3.7. Quantitation of bile acid levels in the feces....................................................................................119
3.8. Neurotransmitter and pro-inflammatory cytokines in the brain.....................................................120
3.9. Immunohistochemistry of neuroinflammation in the hippocampus ................................................121
3.10. Neuroinflammation-related protein expression in prefrontal cortex ............................................122
4. DISCUSSION .............................................................................................................................................124
5. CONCLUSION ...........................................................................................................................................135
6. TABLES AND FIGURES ..............................................................................................................................136
REFERENCES ..............................................................................................................................................155
List of Tables
Table 1. Comparison between the clinical characteristics, etiology and prognosis of early-onset and late-onset geriatric depression.............................................................................................................................14
Table 2. The component of different diets.........................................................................................................58
Table 3. Biochemical variables of all rats .........................................................................................................80
Table 4. Fatty acid profiles of prefrontal cortex and hippocampus...................................................................87
Table 5. Fatty acid profiles of erythrocytes.......................................................................................................88
Table 6. Short chain fatty acids levels in feces..................................................................................................90
Table 7. The component of different diets in D-gal experiment .......................................................................95
Table 8. Biochemical variables of all D-gal experiment rats ..........................................................................137
Table 9. Biochemical parameter analysis in plasma of aging rats...................................................................142
Table 10. TRYCAT and inflammatory factors analysis in hippocampus and prefrontal cortex......................151
List of Figures
Figure 1. Statistics on the number of medical treatments for depression in 2016-2018 .....................................7
Figure 2. The 2018 edition of the estimated proportion of the aging population in the major countries worldwide ...........................................................................................................................................10
Figure 3. The 2018 edition of the estimated proportion of the aged population in Taiwan ..............................10
Figure 4. The proportion of various types dementia .........................................................................................18
Figure 5. The diseases closely related to gut microbiota ..................................................................................21
Figure 6. Schematic diagram of the gut-brain microbial axis ...........................................................................24
Figure 7. Signal transmission pathway of gut-brain-microbiome axis .............................................................24
Figure 8. The two-sided activation pathways of microglia and astrocyte.........................................................31
Figure 9. Metabolic pathway of n-6 and n-3 PUFA ..........................................................................................39
Figure 10. The roadmap of depression induced by a higher n-6/n-3 ratio ........................................................42
Figure 11. Schematic of M1 and M2 types of microglia...................................................................................45
Figure 12. Indicators of depressive-like symptoms in animal depression model .............................................50
Figure 13. Microglial morphology and MWM test results in the hippocampus of young and aged rats..........53
Figure 14. The experimental process of NORT ................................................................................................53
Figure 15. Flow diagram of the experimental protocol.....................................................................................57
Figure 16. Body weight and dietary intake in the period of experiment...........................................................81
Figure 17. Forced swimming test results ..........................................................................................................82
Figure 18. Open field test results ......................................................................................................................83
Figure 19. Sucrose preference test results.........................................................................................................84
Figure 20. Plasma corticosterone levels............................................................................................................84
Figure 21. Oxidative stress-related markers in plasma .....................................................................................85
Figure 22. Neurotransmitters analysis in prefrontal cortex...............................................................................86
Figure 23. Colitis analysis of colon H&E staining sections..............................................................................89
Figure 24. LEfSe analysis of the composition of microbiota............................................................................91
Figure 25. Correlation network of microbiota taxa...........................................................................................92
Figure 26. Flow diagram of the D-gal experimental protocol...........................................................................97
Figure 27. Plasma blood glucose and TBARS results at the 16th week ...........................................................97
Figure 28. The body weight and food consumption of aging rats...................................................................136
Figure 29. Sucrose preference test results of aging rats..................................................................................138
Figure 30. Forced swimming test results of aging rats ...................................................................................139
Figure 31. Open field test results of aging rats................................................................................................140
Figure 32. Cognitive function behavioral test results of aging rats.................................................................141
Figure 33. Colitis analysis of colon H&E staining sections............................................................................143
Figure 34. Diversity analysis of microbiota compositions..............................................................................144
Figure 35. Linear discriminant analysis effect size (LEfSe) analysis of microbiota compositions and network analysis of taxa .................................................................................................................................145
Figure 36. Heatmap of gut microbiota of family cluster in each group ..........................................................146
Figure 37. Spearman correlation analysis of microbiota taxa.........................................................................147
Figure 38. Bile acid profile analysis of rat fecal samples ...............................................................................148
Figure 39. Levels of taurine-conjugated bile acid and heatmap of bile acid profiles .....................................149
Figure 40. Heatmap of correlation analysis of bile acids, microbiota, and neurobehavioral outcomes..........150
Figure 41. Immunohistochemistry of M1 microglia markers in brain hippocampus......................................152
Figure 42. Tight junction and neuroinflammation-associated protein expression in the prefrontal cortex.....153
Figure 43. BDNF, IDO1, oxidative stress and RAGE protein expression in the prefrontal cortex ................154
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