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研究生：	林彥呈 Lin, Yen-Cheng
論文名稱：	研究胰高血糖素樣肽-1緩解由困難梭狀芽孢桿菌感染引起之發炎反應的機制 To study the mechanisms behind glucagon-like peptide-1 alleviating inflammation caused by Clostridioides difficile infection
指導教授：	洪元斌 Hung, Yuan-Pin
學位類別：	碩士 Master
系所名稱：	醫學院 - 微生物及免疫學研究所 Department of Microbiology & Immunology
論文出版年：	2024
畢業學年度：	112
語文別：	英文
論文頁數：	103
中文關鍵詞：	困難梭狀芽孢桿菌感染、胰高血糖素樣肽-1 、胰高血糖素樣肽-1 受體激動劑、抗發炎、屏障完整性
外文關鍵詞：	Clostridioides difficile infection, GLP-1, GLP-1RA, anti-inflammation, barrier integrity
相關次數：	點閱：42 下載：0
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近年來，困難梭狀芽孢桿菌(艱難梭菌)的盛行率，因抗生素廣泛使用而日漸上升，雖然目前有抗生素作為治療手段，但有其侷限性，例如抗藥性問題；其次，甲硝唑治療效果較差，萬古黴素治療效果雖佳，但會破壞腸道菌相，有較高的復發率，鼎腹欣治療效果優良且對菌相的干擾低，但價格高昂。因此開發新的治療藥物刻不容緩。困難梭狀芽孢桿菌感染會造成腸道嚴重發炎，組織損傷，破壞腸道上皮完整性，這為其創造了一個絕佳的生長環境，減緩組織發炎或可避免此現象，因此我們以抗發炎作為對抗困難梭狀芽孢桿菌感染的新策略。
臨床統計發現，肥胖 (BMI較高) 與第二型糖尿病患者，分別有著較高的困難梭狀芽孢桿菌感染率和復發率。胰高血糖素樣肽-1是一種由腸道內分泌L細胞所生產的賀爾蒙，參與食慾和血糖的調控，可用於治療肥胖症和第二型糖尿病。因為胰高血糖素樣肽-1較不穩定、半衰期短，因此臨床上主要使用胰高血糖素樣肽-1受體激動劑，作為治療選擇。胰高血糖素樣肽-1也具有抗發炎的作用，因此進入我們的視野中。
在小鼠模型中，皮下注射利拉魯肽 (一種長效型的胰高血糖素樣肽-1受體激動劑) 能有效減輕感染困難梭狀芽孢桿菌的症狀，顯示消除其適宜生長位的策略具可行性。對小鼠結腸組織進行RNA定序，發現多種發炎相關基因的RNA表現量降低，顯示利拉魯肽的抗發炎和維持上皮屏障的能力。組織切片和RNA反轉錄-即時定量聚合酶連鎖反應也發現上皮細胞較為完好，緊密、間隙連接基因的RNA表達量較高。此外，利拉魯肽對菌相的干擾程度較低，同時促進多種有益的共生菌生長如艾克曼嗜黏蛋白菌等。顯示利拉魯肽透過消除適合困難梭狀芽孢桿菌生長的環境以對抗感染，闡明其成為新興治療手段的潛力，並對未來藥物的開發提供一個全新的視野。

In recent years, the prevalence of Clostridioides difficile (C. difficile) has been rising due to the widespread use of antibiotics. While antibiotics remain the primary treatment option, they have limitations such as antibiotic resistance, high cost, and a high recurrence rate. Thus, the development of new therapeutic strategies is urgently needed. C. difficile infection (CDI) leads to severe intestinal inflammation, tissue damage, and disruption of epithelial integrity, creating a favorable environment for its growth. Mitigating inflammation may prevent this phenomenon, making anti-inflammatory approaches a potential new strategy to combat CDI.
Glucagon-like peptide-1 (GLP-1) is a hormone produced by enteroendocrine L-cells in the gut. It is known for regulating appetite and blood glucose levels. Additionally, GLP-1 has anti-inflammatory properties, which might help eliminate the growth niche of C. difficile.
In a mouse model, subcutaneous administration of Liraglutide, a long-acting GLP-1 receptor agonist, effectively alleviated the symptoms of CDI, demonstrating the feasibility of targeting the pathogen's growth niche as a therapeutic strategy. RNA sequencing of colon tissues revealed a decrease in the expression of various inflammation-related genes, indicating Liraglutide’s anti-inflammatory effects and ability to maintain epithelial barrier integrity. Histological analysis further showed that epithelial cells were more intact. Moreover, Liraglutide had minimal impact on the gut microbiota while promoting the growth of beneficial commensal bacteria such as Akkermansia muciniphila. These findings suggest that Liraglutide combats CDI by eliminating the pathogen's favorable growth environment, highlighting its potential as a novel therapeutic approach and providing a new perspective for future drug development.

摘要	I
ABSTRACT	II
致謝	III
TABLE OF CONTENTS	IV
LIST OF TABLES	VIII
LIST OF FIGURES	IX
ABBREVIATIONS	X
INTRODUCTION	1
1.1	Clostridioides difficile Infection and Epidemiology	1
1.2	The interplay between the immune system and metabolism	4
1.3	Glucagon-like peptide-1 (GLP-1)	6
1.4	GLP-1 Ameliorates Inflammation-related Damage	7
1.5	GLP-1 Orchestrate Microbiota, Epithelial Integrity, and Immune System	9
1.6	Rationale	11
MATERIALS AND METHODS	12
2.1	Materials	12
2.1.1	Bacterial strain	12
2.1.2	Animal	12
2.1.3	Cell line	12
2.1.4	GLP-1 receptor agonist (GLP-1RA, Liraglutide)	12
2.2	Methods	13
2.2.1	Bacterial culture	13
2.2.2	Determination of Liraglutide (GLP-1RA) MIC/MBC by broth microdilution 13
2.2.3	Cell culture	14
2.2.4	Infection of HT-29 cell with C. difficile	15
2.2.5	Total RNA extraction of HT-29 cells	15
2.2.6	RNA-sequencing of HT-29 cells	16
2.2.7	Preparation and purification of C. difficile spore	18
2.2.8	Quantification of C. difficile spores	18
2.2.9	C. difficile Infection (CDI) in mice	19
2.2.10	Sacrifice of mice	19
2.2.11	Biochemical analysis of mice serum	20
2.2.12	Serum amyloid A (SAA) analysis in mice	20
2.2.13	Serum GLP-1 analysis in mice	20
2.2.14	Mice fecal Microbiota DNA extraction	20
2.2.15	Quantification of C. difficile load in mice stool using real-time PCR targeting the TcdB gene	21
2.2.16	Microbiome analysis of mice stool DNA using 16S rRNA gene sequencing	21
2.2.17	RNA extraction of mice colon	23
2.2.18	Real-time PCR of mice colon RNA	23
2.2.19	RNA sequencing of mice colon	24
2.2.20	Mice colon section and histopathological scoring	24
2.2.21	Fluorescein isothiocyanate (FITC)-dextran translocation assay	24
2.2.22	Chromogenic endotoxin kinetic test	25
2.2.23	Statistical analysis	25
RESULTS	26
3.1	Liraglutide suppressed genes and pathways related to acute inflammatory response, chemotaxis, and apoptosis while regulating adherents and anchoring junctions	26
3.2	C. difficile infection resulted in the decrease of serum GLP-1 levels and blood sugar levels, while the use of Liraglutide could elevate serum GLP-1 levels and alleviate the drop in blood sugar levels in vivo	28
3.3	Liraglutide alleviated the severity of CDI	29
3.4	RNA-sequencing of mice colon revealed that multiple inflammatory pathways were downregulated	29
3.5	Liraglutide exhibited less interference with the microbiota and promoted the dominance of certain beneficial bacteria	32
3.6	Colon sections demonstrated that Liraglutide significantly reduced tissue inflammation and immune cell infiltration, maintaining the integrity and function of the epithelial barrier	33
3.7	Liraglutide maintained the integrity of the intestinal epithelium and reduced the fecal C. difficile load	35
3.8	Liraglutide maintained epithelial integrity and reduced stool C. difficile load even under conditions of C. difficile infection with additional dextran sulfate sodium (DSS)-induced epithelial disruption	36
DISCUSSION	38
TABLES	41
Table 1. Gene set enrichment analysis (GSEA) of M2 (curated gene sets)	41
Table 2. GSEA of M5 (ontology gene sets)	43
Table 3. GSEA of M8 (cell type signature gene sets)	45
Table 4. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of Liraglutide and vancomycin against C. difficile RT027.	46
FIGURES	47
Figure 1. Liraglutide suppressed genes and pathways related to acute inflammatory response, chemotaxis, and apoptosis while regulating adherents and anchoring junctions	49
Figure 2. C. difficile infection resulted in the decrease of serum GLP-1 levels and blood sugar levels, while the use of Liraglutide could elevate serum GLP-1 levels and alleviate the drop in blood sugar levels in vivo	52
Figure 3. Liraglutide alleviated the severity of CDI	54
Figure 4. RNA-sequencing of mice colon revealed that multiple inflammatory pathways were downregulated	60
Figure 5. Liraglutide exhibited less interference with the microbiota and promoted the dominance of certain beneficial bacteria	65
Figure 6. Colon sections demonstrated that Liraglutide significantly reduced tissue inflammation and immune cell infiltration, maintaining the integrity and function of the epithelial barrier	67
Figure 7. Liraglutide maintained the integrity of the intestinal epithelium and reduced the fecal C. difficile load	70
Figure 8. Liraglutide maintained epithelial integrity and reduced stool C. difficile load even under conditions of C. difficile infection with additional dextran sulfate sodium (DSS)-induced epithelial disruption	72
Figure 9. Proposed mechanism of GLP-1RA (Liraglutide) in inhibiting C. difficile growth	73
APPENDICES	74
Appendix 1. Real-time PCR (qPCR) primers	74
Appendix 2. Reagents and Chemicals	75
Appendix 3. Bacterial culture medium	77
Appendix 4. Mice experiment drinking water formula	78
Appendix 5. Kits	79
REFERENCES	80
                                    

1. George, R.H., et al., Identification of Clostridium difficile as a cause of pseudomembranous colitis. Br Med J, 1978. 1(6114): p. 695.
2. Smits, W.K., et al., Clostridium difficile infection. Nat Rev Dis Primers, 2016. 2: p. 16020.
3. Lawley, T.D., et al., Use of purified Clostridium difficile spores to facilitate evaluation of health care disinfection regimens. Appl Environ Microbiol, 2010. 76(20): p. 6895-900.
4. Dawson, L.F., et al., Hypervirulent Clostridium difficile PCR-ribotypes exhibit resistance to widely used disinfectants. PLoS One, 2011. 6(10): p. e25754.
5. Rodriguez-Palacios, A. and J.T. Lejeune, Moist-heat resistance, spore aging, and superdormancy in Clostridium difficile. Appl Environ Microbiol, 2011. 77(9): p. 3085-91.
6. Dubberke, E.R., et al., Prevalence of Clostridium difficile environmental contamination and strain variability in multiple health care facilities. Am J Infect Control, 2007. 35(5): p. 315-8.
7. Johnson, S., et al., Nosocomial Clostridium difficile colonisation and disease. Lancet, 1990. 336(8707): p. 97-100.
8. Burke, K.E. and J.T. Lamont, Clostridium difficile infection: a worldwide disease. Gut Liver, 2014. 8(1): p. 1-6.
9. Pepin, J., et al., Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis, 2005. 41(9): p. 1254-60.
10. Johnson, S., Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Infect, 2009. 58(6): p. 403-10.
11. Sonnenburg, J.L., et al., Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science, 2005. 307(5717): p. 1955-9.
12. Wong, J.M., et al., Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol, 2006. 40(3): p. 235-43.
13. Ng, K.M., et al., Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature, 2013. 502(7469): p. 96-9.
14. Ferreyra, J.A., et al., Gut microbiota-produced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance. Cell Host Microbe, 2014. 16(6): p. 770-7.
15. Rea, M.C., et al., Effect of broad- and narrow-spectrum antimicrobials on Clostridium difficile and microbial diversity in a model of the distal colon. Proc Natl Acad Sci U S A, 2011. 108 Suppl 1(Suppl 1): p. 4639-44.
16. Buffie, C.G., et al., Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature, 2015. 517(7533): p. 205-8.
17. Ridlon, J.M. and P.B. Hylemon, Identification and characterization of two bile acid coenzyme A transferases from Clostridium scindens, a bile acid 7alpha-dehydroxylating intestinal bacterium. J Lipid Res, 2012. 53(1): p. 66-76.
18. Shen, A., Clostridioides difficile Spore Formation and Germination: New Insights and Opportunities for Intervention. Annu Rev Microbiol, 2020. 74: p. 545-566.
19. Abt, M.C., P.T. McKenney, and E.G. Pamer, Clostridium difficile colitis: pathogenesis and host defence. Nat Rev Microbiol, 2016. 14(10): p. 609-20.
20. Aktories, K., C. Schwan, and T. Jank, Clostridium difficile Toxin Biology. Annu Rev Microbiol, 2017. 71: p. 281-307.
21. Kuehne, S.A., et al., The role of toxin A and toxin B in Clostridium difficile infection. Nature, 2010. 467(7316): p. 711-3.
22. Kordus, S.L., A.K. Thomas, and D.B. Lacy, Clostridioides difficile toxins: mechanisms of action and antitoxin therapeutics. Nat Rev Microbiol, 2022. 20(5): p. 285-298.
23. Gerding, D.N., et al., Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance. Gut Microbes, 2014. 5(1): p. 15-27.
24. Lee, J.Y., et al., Effects of transcription factor activator protein-1 on interleukin-8 expression and enteritis in response to Clostridium difficile toxin A. J Mol Med (Berl), 2007. 85(12): p. 1393-404.
25. Jefferson, K.K., M.F. Smith, Jr., and D.A. Bobak, Roles of intracellular calcium and NF-kappa B in the Clostridium difficile toxin A-induced up-regulation and secretion of IL-8 from human monocytes. J Immunol, 1999. 163(10): p. 5183-91.
26. Warny, M., et al., p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J Clin Invest, 2000. 105(8): p. 1147-56.
27. Kim, J.M., et al., NF-kappa B activation pathway is essential for the chemokine expression in intestinal epithelial cells stimulated with Clostridium difficile toxin A. Scand J Immunol, 2006. 63(6): p. 453-60.
28. Xu, H., et al., Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature, 2014. 513(7517): p. 237-41.
29. Ryan, A., et al., A role for TLR4 in Clostridium difficile infection and the recognition of surface layer proteins. PLoS Pathog, 2011. 7(6): p. e1002076.
30. Hasegawa, M., et al., Nucleotide-binding oligomerization domain 1 mediates recognition of Clostridium difficile and induces neutrophil recruitment and protection against the pathogen. J Immunol, 2011. 186(8): p. 4872-80.
31. Jarchum, I., et al., Critical role for MyD88-mediated neutrophil recruitment during Clostridium difficile colitis. Infect Immun, 2012. 80(9): p. 2989-96.
32. Hasegawa, M., et al., Protective role of commensals against Clostridium difficile infection via an IL-1beta-mediated positive-feedback loop. J Immunol, 2012. 189(6): p. 3085-91.
33. Cowardin, C.A., et al., Inflammasome activation contributes to interleukin-23 production in response to Clostridium difficile. mBio, 2015. 6(1).
34. Sadighi Akha, A.A., et al., Acute infection of mice with Clostridium difficile leads to eIF2alpha phosphorylation and pro-survival signalling as part of the mucosal inflammatory response. Immunology, 2013. 140(1): p. 111-22.
35. Sonnenberg, G.F. and D. Artis, Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat Med, 2015. 21(7): p. 698-708.
36. Fradrich, C., L.A. Beer, and R. Gerhard, Reactive Oxygen Species as Additional Determinants for Cytotoxicity of Clostridium difficile Toxins A and B. Toxins (Basel), 2016. 8(1).
37. El Feghaly, R.E., et al., Markers of intestinal inflammation, not bacterial burden, correlate with clinical outcomes in Clostridium difficile infection. Clin Infect Dis, 2013. 56(12): p. 1713-21.
38. Castagliuolo, I., et al., Clostridium difficile toxin A stimulates macrophage-inflammatory protein-2 production in rat intestinal epithelial cells. J Immunol, 1998. 160(12): p. 6039-45.
39. Kelly, C.P., et al., Neutrophil recruitment in Clostridium difficile toxin A enteritis in the rabbit. J Clin Invest, 1994. 93(3): p. 1257-65.
40. Buonomo, E.L., et al., Role of interleukin 23 signaling in Clostridium difficile colitis. J Infect Dis, 2013. 208(6): p. 917-20.
41. MacCannell, D.R., et al., Molecular analysis of Clostridium difficile PCR ribotype 027 isolates from Eastern and Western Canada. J Clin Microbiol, 2006. 44(6): p. 2147-52.
42. McDonald, L.C., et al., An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med, 2005. 353(23): p. 2433-41.
43. Warny, M., et al., Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet, 2005. 366(9491): p. 1079-84.
44. de Heredia, F.P., S. Gomez-Martinez, and A. Marcos, Obesity, inflammation and the immune system. Proc Nutr Soc, 2012. 71(2): p. 332-8.
45. Andersen, C.J., K.E. Murphy, and M.L. Fernandez, Impact of Obesity and Metabolic Syndrome on Immunity. Adv Nutr, 2016. 7(1): p. 66-75.
46. Sheridan, P.A., et al., Obesity is associated with impaired immune response to influenza vaccination in humans. Int J Obes (Lond), 2012. 36(8): p. 1072-7.
47. Huttunen, R. and J. Syrjanen, Obesity and the outcome of infection. Lancet Infect Dis, 2010. 10(7): p. 442-3.
48. Heymsfield, S.B. and T.A. Wadden, Mechanisms, Pathophysiology, and Management of Obesity. N Engl J Med, 2017. 376(3): p. 254-266.
49. Berbudi, A., et al., Type 2 Diabetes and its Impact on the Immune System. Curr Diabetes Rev, 2020. 16(5): p. 442-449.
50. Schleh, M.W., et al., Metaflammation in obesity and its therapeutic targeting. Sci Transl Med, 2023. 15(723): p. eadf9382.
51. Lumeng, C.N. and A.R. Saltiel, Inflammatory links between obesity and metabolic disease. J Clin Invest, 2011. 121(6): p. 2111-7.
52. Jais, A. and J.C. Bruning, Hypothalamic inflammation in obesity and metabolic disease. J Clin Invest, 2017. 127(1): p. 24-32.
53. Guilherme, A., et al., Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol, 2008. 9(5): p. 367-77.
54. Deng, J., et al., Lipolysis response to endoplasmic reticulum stress in adipose cells. J Biol Chem, 2012. 287(9): p. 6240-9.
55. Sartipy, P. and D.J. Loskutoff, Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci U S A, 2003. 100(12): p. 7265-70.
56. Lagathu, C., et al., Long-term treatment with interleukin-1beta induces insulin resistance in murine and human adipocytes. Diabetologia, 2006. 49(9): p. 2162-73.
57. Gu, X., et al., Adipose tissue adipokines and lipokines: Functions and regulatory mechanism in skeletal muscle development and homeostasis. Metabolism, 2023. 139: p. 155379.
58. Sahu, B. and N.C. Bal, Adipokines from white adipose tissue in regulation of whole body energy homeostasis. Biochimie, 2023. 204: p. 92-107.
59. Barrios-Correa, A.A., J.A. Estrada, and I. Contreras, Leptin Signaling in the Control of Metabolism and Appetite: Lessons from Animal Models. J Mol Neurosci, 2018. 66(3): p. 390-402.
60. Marti, A., A. Marcos, and J.A. Martinez, Obesity and immune function relationships. Obes Rev, 2001. 2(2): p. 131-40.
61. Tilg, H. and A.R. Moschen, Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol, 2006. 6(10): p. 772-83.
62. Caldefie-Chezet, F., A. Poulin, and M.P. Vasson, Leptin regulates functional capacities of polymorphonuclear neutrophils. Free Radic Res, 2003. 37(8): p. 809-14.
63. Gruen, M.L., et al., Leptin requires canonical migratory signaling pathways for induction of monocyte and macrophage chemotaxis. Am J Physiol Cell Physiol, 2007. 293(5): p. C1481-8.
64. Chandra, R.K., Cell-mediated immunity in genetically obese C57BL/6J ob/ob) mice. Am J Clin Nutr, 1980. 33(1): p. 13-6.
65. Farooqi, I.S., et al., Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest, 2002. 110(8): p. 1093-103.
66. Saeed, S., et al., High morbidity and mortality in children with untreated congenital deficiency of leptin or its receptor. Cell Rep Med, 2023. 4(9): p. 101187.
67. Ozata, M., I.C. Ozdemir, and J. Licinio, Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab, 1999. 84(10): p. 3686-95.
68. Mancuso, P., et al., Leptin-deficient mice exhibit impaired host defense in Gram-negative pneumonia. J Immunol, 2002. 168(8): p. 4018-24.
69. Ikejima, S., et al., Impairment of host resistance to Listeria monocytogenes infection in liver of db/db and ob/ob mice. Diabetes, 2005. 54(1): p. 182-9.
70. Guo, X., et al., Leptin signaling in intestinal epithelium mediates resistance to enteric infection by Entamoeba histolytica. Mucosal Immunol, 2011. 4(3): p. 294-303.
71. Considine, R.V., et al., Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med, 1996. 334(5): p. 292-5.
72. Myers, M.G., Jr., et al., Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab, 2010. 21(11): p. 643-51.
73. Park, H.S., J.Y. Park, and R. Yu, Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6. Diabetes Res Clin Pract, 2005. 69(1): p. 29-35.
74. Monteiro, R. and I. Azevedo, Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm, 2010. 2010.
75. Weisberg, S.P., et al., Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest, 2003. 112(12): p. 1796-808.
76. Nguyen, M.T., et al., A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem, 2007. 282(48): p. 35279-92.
77. Stienstra, R., et al., Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U S A, 2011. 108(37): p. 15324-9.
78. Vandanmagsar, B., et al., The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med, 2011. 17(2): p. 179-88.
79. Wen, H., et al., Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol, 2011. 12(5): p. 408-15.
80. Stienstra, R., et al., The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab, 2010. 12(6): p. 593-605.
81. Herder, C., et al., The IL-1 Pathway in Type 2 Diabetes and Cardiovascular Complications. Trends Endocrinol Metab, 2015. 26(10): p. 551-563.
82. Bishara, J., et al., Obesity as a risk factor for Clostridium difficile infection. Clin Infect Dis, 2013. 57(4): p. 489-93.
83. Qu, H.Q. and Z.D. Jiang, Clostridium difficile infection in diabetes. Diabetes Res Clin Pract, 2014. 105(3): p. 285-94.
84. Dial, S., et al., Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ, 2004. 171(1): p. 33-8.
85. Shakov, R., et al., Diabetes mellitus as a risk factor for recurrence of Clostridium difficile infection in the acute care hospital setting. Am J Infect Control, 2011. 39(3): p. 194-8.
86. Drucker, D.J., Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab, 2018. 27(4): p. 740-756.
87. Bell, G.I., et al., Exon duplication and divergence in the human preproglucagon gene. Nature, 1983. 304(5924): p. 368-71.
88. Meier, J.J., GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol, 2012. 8(12): p. 728-42.
89. Drucker, D.J., J.F. Habener, and J.J. Holst, Discovery, characterization, and clinical development of the glucagon-like peptides. J Clin Invest, 2017. 127(12): p. 4217-4227.
90. Drucker, D.J., GLP-1 physiology informs the pharmacotherapy of obesity. Mol Metab, 2022. 57: p. 101351.
91. Mayo, K.E., et al., International Union of Pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev, 2003. 55(1): p. 167-94.
92. Drucker, D.J., The Cardiovascular Biology of Glucagon-like Peptide-1. Cell Metab, 2016. 24(1): p. 15-30.
93. Ellingsgaard, H., et al., Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med, 2011. 17(11): p. 1481-9.
94. Breton, J., et al., Gut Commensal E. coli Proteins Activate Host Satiety Pathways following Nutrient-Induced Bacterial Growth. Cell Metab, 2016. 23(2): p. 324-34.
95. Chimerel, C., et al., Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep, 2014. 9(4): p. 1202-8.
96. Lebrun, L.J., et al., Enteroendocrine L Cells Sense LPS after Gut Barrier Injury to Enhance GLP-1 Secretion. Cell Rep, 2017. 21(5): p. 1160-1168.
97. Yusta, B., et al., GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R. Diabetes, 2015. 64(7): p. 2537-49.
98. Hunt, J.E., et al., GLP-1 and Intestinal Diseases. Biomedicines, 2021. 9(4).
99. Mehdi, S.F., et al., Glucagon-like peptide-1: a multi-faceted anti-inflammatory agent. Front Immunol, 2023. 14: p. 1148209.
100. Helmstadter, J., et al., GLP-1 Analog Liraglutide Improves Vascular Function in Polymicrobial Sepsis by Reduction of Oxidative Stress and Inflammation. Antioxidants (Basel), 2021. 10(8).
101. Tate, M., et al., Exendin-4 attenuates adverse cardiac remodelling in streptozocin-induced diabetes via specific actions on infiltrating macrophages. Basic Res Cardiol, 2016. 111(1): p. 1.
102. Steven, S., et al., Gliptin and GLP-1 analog treatment improves survival and vascular inflammation/dysfunction in animals with lipopolysaccharide-induced endotoxemia. Basic Res Cardiol, 2015. 110(2): p. 6.
103. Rakipovski, G., et al., The GLP-1 Analogs Liraglutide and Semaglutide Reduce Atherosclerosis in ApoE(-/-) and LDLr(-/-) Mice by a Mechanism That Includes Inflammatory Pathways. JACC Basic Transl Sci, 2018. 3(6): p. 844-857.
104. Bruen, R., et al., Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis. Cardiovasc Diabetol, 2017. 16(1): p. 143.
105. Gupta, N.A., et al., The glucagon-like peptide-1 receptor agonist Exendin 4 has a protective role in ischemic injury of lean and steatotic liver by inhibiting cell death and stimulating lipolysis. Am J Pathol, 2012. 181(5): p. 1693-701.
106. Harkavyi, A. and P.S. Whitton, Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection. Br J Pharmacol, 2010. 159(3): p. 495-501.
107. Yang, X., et al., Mesenchymal stem cells combined with liraglutide relieve acute lung injury through apoptotic signaling restrained by PKA/beta-catenin. Stem Cell Res Ther, 2020. 11(1): p. 182.
108. Yang, F., et al., Glucagon-like Peptide 1 Receptor Activation Inhibits Microglial Pyroptosis via Promoting Mitophagy to Alleviate Depression-like Behaviors in Diabetic Mice. Nutrients, 2022. 15(1).
109. Zhou, G., et al., Liraglutide Attenuates Myocardial Ischemia/Reperfusion Injury Through the Inhibition of Necroptosis by Activating GLP-1R/PI3K/Akt Pathway. Cardiovasc Toxicol, 2023. 23(3-4): p. 161-175.
110. Sazgarnejad, S., N. Yazdanpanah, and N. Rezaei, Anti-inflammatory effects of GLP-1 in patients with COVID-19. Expert Rev Anti Infect Ther, 2022. 20(3): p. 373-381.
111. Sternkopf, M., et al., Native, Intact Glucagon-Like Peptide 1 Is a Natural Suppressor of Thrombus Growth Under Physiological Flow Conditions. Arterioscler Thromb Vasc Biol, 2020. 40(3): p. e65-e77.
112. Grasset, E., et al., A Specific Gut Microbiota Dysbiosis of Type 2 Diabetic Mice Induces GLP-1 Resistance through an Enteric NO-Dependent and Gut-Brain Axis Mechanism. Cell Metab, 2017. 25(5): p. 1075-1090 e5.
113. Manion, J., et al., C. difficile intoxicates neurons and pericytes to drive neurogenic inflammation. Nature, 2023. 622(7983): p. 611-618.
114. Wong, C.K., et al., Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation. Cell Metab, 2024. 36(1): p. 130-143 e5.
115. Yang, G., et al., Role of the gut microbiota in type 2 diabetes and related diseases. Metabolism, 2021. 117: p. 154712.
116. Nicholson, J.K., et al., Host-gut microbiota metabolic interactions. Science, 2012. 336(6086): p. 1262-7.
117. Kamada, N., et al., Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol, 2013. 13(5): p. 321-35.
118. Zhang, Q., et al., Intestinal lysozyme liberates Nod1 ligands from microbes to direct insulin trafficking in pancreatic beta cells. Cell Res, 2019. 29(7): p. 516-532.
119. Gomes, A.C., C. Hoffmann, and J.F. Mota, The human gut microbiota: Metabolism and perspective in obesity. Gut Microbes, 2018. 9(4): p. 308-325.
120. Vreugdenhil, A.C., et al., Lipopolysaccharide (LPS)-binding protein mediates LPS detoxification by chylomicrons. J Immunol, 2003. 170(3): p. 1399-405.
121. Bervoets, L., et al., Differences in gut microbiota composition between obese and lean children: a cross-sectional study. Gut Pathog, 2013. 5(1): p. 10.
122. Simon, M.C., et al., Intake of Lactobacillus reuteri improves incretin and insulin secretion in glucose-tolerant humans: a proof of concept. Diabetes Care, 2015. 38(10): p. 1827-34.
123. Yoon, H.S., et al., Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice. Nat Microbiol, 2021. 6(5): p. 563-573.
124. Drucker, D.J. and B. Yusta, Physiology and pharmacology of the enteroendocrine hormone glucagon-like peptide-2. Annu Rev Physiol, 2014. 76: p. 561-83.
125. Koehler, J.A., et al., GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7. Cell Metab, 2015. 21(3): p. 379-91.
126. Liu, Q., et al., Liraglutide modulates gut microbiome and attenuates nonalcoholic fatty liver in db/db mice. Life Sci, 2020. 261: p. 118457.
127. Turner, J.R., Intestinal mucosal barrier function in health and disease. Nat Rev Immunol, 2009. 9(11): p. 799-809.
128. Nozu, T., et al., Glucagon-like peptide-1 analog, liraglutide, improves visceral sensation and gut permeability in rats. J Gastroenterol Hepatol, 2018. 33(1): p. 232-239.
129. Kedees, M.H., et al., Functional activity of murine intestinal mucosal cells is regulated by the glucagon-like peptide-1 receptor. Peptides, 2013. 48: p. 36-44.
130. Osinski, C., et al., Type 2 diabetes is associated with impaired jejunal enteroendocrine GLP-1 cell lineage in human obesity. Int J Obes (Lond), 2021. 45(1): p. 170-183.
131. Saklayen, M.G., The Global Epidemic of the Metabolic Syndrome. Curr Hypertens Rep, 2018. 20(2): p. 12.
132. Czepiel, J., et al., Clostridium difficile infection: review. Eur J Clin Microbiol Infect Dis, 2019. 38(7): p. 1211-1221.
133. Oksi, J., V.J. Anttila, and E. Mattila, Treatment of Clostridioides (Clostridium) difficile infection. Ann Med, 2020. 52(1-2): p. 12-20.
134. Shan, J., et al., Bacteriophages are more virulent to bacteria with human cells than they are in bacterial culture; insights from HT-29 cells. Sci Rep, 2018. 8(1): p. 5091.
135. Hansen, A., et al., The P2Y6 receptor mediates Clostridium difficile toxin-induced CXCL8/IL-8 production and intestinal epithelial barrier dysfunction. PLoS One, 2013. 8(11): p. e81491.
136. Anonye, B.O., et al., Probing Clostridium difficile Infection in Complex Human Gut Cellular Models. Front Microbiol, 2019. 10: p. 879.
137. Ewels, P., et al., MultiQC: summarize analysis results for multiple tools and samples in a single report. Bioinformatics, 2016. 32(19): p. 3047-8.
138. Bolger, A.M., M. Lohse, and B. Usadel, Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics, 2014. 30(15): p. 2114-20.
139. Liao, Y., G.K. Smyth, and W. Shi, featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics, 2014. 30(7): p. 923-30.
140. Dillies, M.A., et al., A comprehensive evaluation of normalization methods for Illumina high-throughput RNA sequencing data analysis. Brief Bioinform, 2013. 14(6): p. 671-83.
141. Love, M.I., W. Huber, and S. Anders, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol, 2014. 15(12): p. 550.
142. Sahraeian, S.M.E., et al., Gaining comprehensive biological insight into the transcriptome by performing a broad-spectrum RNA-seq analysis. Nat Commun, 2017. 8(1): p. 59.
143. Okonechnikov, K., A. Conesa, and F. Garcia-Alcalde, Qualimap 2: advanced multi-sample quality control for high-throughput sequencing data. Bioinformatics, 2016. 32(2): p. 292-4.
144. Hung, Y.P., et al., The first case of severe Clostridium difficile ribotype 027 infection in Taiwan. J Infect, 2015. 70(1): p. 98-101.
145. Livak, K.J. and T.D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 2001. 25(4): p. 402-8.
146. Caporaso, J.G., et al., Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample. Proc Natl Acad Sci U S A, 2011. 108 Suppl 1(Suppl 1): p. 4516-22.
147. Segata, N., et al., Metagenomic biomarker discovery and explanation. Genome Biol, 2011. 12(6): p. R60.
148. Youssef, N., et al., Comparison of species richness estimates obtained using nearly complete fragments and simulated pyrosequencing-generated fragments in 16S rRNA gene-based environmental surveys. Appl Environ Microbiol, 2009. 75(16): p. 5227-36.
149. Callahan, B.J., et al., DADA2: High-resolution sample inference from Illumina amplicon data. Nat Methods, 2016. 13(7): p. 581-3.
150. Shelby, R.D., et al., Development of a Standardized Scoring System to Assess a Murine Model of Clostridium difficile Colitis. J Invest Surg, 2020. 33(10): p. 887-895.
151. Yu, G., et al., clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS, 2012. 16(5): p. 284-7.
152. Gene Ontology, C., The Gene Ontology project in 2008. Nucleic Acids Res, 2008. 36(Database issue): p. D440-4.
153. Subramanian, A., et al., Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A, 2005. 102(43): p. 15545-50.
154. Liberzon, A., et al., Molecular signatures database (MSigDB) 3.0. Bioinformatics, 2011. 27(12): p. 1739-40.
155. Lai, Y.H., et al., Peroxisome proliferator-activated receptor-gamma as the gatekeeper of tight junction in Clostridioides difficile infection. Front Microbiol, 2022. 13: p. 986457.
156. Hung, Y.P., et al., Proton-Pump Inhibitor Exposure Aggravates Clostridium difficile-Associated Colitis: Evidence From a Mouse Model. J Infect Dis, 2015. 212(4): p. 654-63.
157. Faith, D.P. and A.M. Baker, Phylogenetic diversity (PD) and biodiversity conservation: some bioinformatics challenges. Evol Bioinform Online, 2007. 2: p. 121-8.
158. Chuandong, Z., et al., Distribution and roles of Ligilactobacillus murinus in hosts. Microbiol Res, 2024. 282: p. 127648.
159. Li, H., et al., Bacteroides thetaiotaomicron ameliorates mouse hepatic steatosis through regulating gut microbial composition, gut-liver folate and unsaturated fatty acids metabolism. Gut Microbes, 2024. 16(1): p. 2304159.
160. Hol, J., L. Wilhelmsen, and G. Haraldsen, The murine IL-8 homologues KC, MIP-2, and LIX are found in endothelial cytoplasmic granules but not in Weibel-Palade bodies. J Leukoc Biol, 2010. 87(3): p. 501-8.
161. Sack, G.H., Jr., Serum Amyloid A (SAA) Proteins. Subcell Biochem, 2020. 94: p. 421-436.
162. Chassaing, B., et al., Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol, 2014. 104: p. 15 25 1-15 25 14.
163. Gerkins, C., et al., Assessment of Gut Barrier Integrity in Mice Using Fluorescein-Isothiocyanate-Labeled Dextran. J Vis Exp, 2022(189).

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