Bidirectional Interactions Between the Gut Microbiota and Incretin-Based Therapies
Abstract
:1. Introduction
2. Incretins and Incretin-Based Therapies
3. Gut Microbiota
4. Incretin-Based Drugs and Gut Microbiota
4.1. Preclinical Studies
4.2. Clinical Studies
5. Gut Metabolites and Incretins
5.1. Preclinical Studies
5.2. Clinical Studies
6. The Relationship Between the Gut Microbiota and Incretin-Based Therapies: A Complex Bidirectional Interaction
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
BAs | Bile acids |
DPP-4 | Dipeptidyl peptidase IV |
EECs | Colonic enteroendocrine cells |
FFAR | Free fatty acid receptor |
FOS | Fructooligosaccharides |
FXR | Farnesoid X receptor |
GIP | Gastric inhibitory polypeptide |
GIPR | GIP receptor |
GLP-1 | Glucagon-like peptide-1 |
GLP-1R | GLP-1 receptors |
GPR | G-protein-coupled receptor |
LPS | Lipopolysaccharide |
NAFLD | Non-alcoholic fatty liver disease |
PCOS | Polycystic ovary syndrome |
PYY | Peptide YY |
SCFAs | Short-chain fatty acids |
T2DM | Type 2 diabetes mellitus |
TMAO | Trimethylamine N-oxide |
Treg | Regulatory T cell |
NAS | Non-caloric artificial sweetener |
References
- Caballero, B. Humans against Obesity: Who Will Win? Adv. Nutr. 2019, 10 (Suppl. S1), S4–S9. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Williams, E.P.; Mesidor, M.; Winters, K.; Dubbert, P.M.; Wyatt, S.B. Overweight and Obesity: Prevalence, Consequences, and Causes of a Growing Public Health Problem. Curr. Obes. Rep. 2015, 4, 363–370. [Google Scholar] [CrossRef] [PubMed]
- Safaei, M.; Sundararajan, E.A.; Driss, M.; Boulila, W.; Shapi’I, A. A systematic literature review on obesity: Understanding the causes & consequences of obesity and reviewing various machine learning approaches used to predict obesity. Comput. Biol. Med. 2021, 136, 104754. [Google Scholar] [CrossRef] [PubMed]
- Foretz, M.; Guigas, B.; Bertrand, L.; Pollak, M.; Viollet, B. Metformin: From mechanisms of action to therapies. Cell Metab. 2014, 20, 953–966. [Google Scholar] [CrossRef]
- Andujar-Plata, P.; Pi-Sunyer, X.; Laferrere, B. Metformin effects revisited. Diabetes Res. Clin. Pract. 2012, 95, 1–9. [Google Scholar] [CrossRef]
- Rena, G.; Pearson, E.R.; Sakamoto, K. Molecular mechanism of action of metformin: Old or new insights? Diabetologia 2013, 56, 1898–1906. [Google Scholar] [CrossRef]
- Rojas, L.B.A.; Gomes, M.B. Metformin: An old but still the best treatment for type 2 diabetes. Diabetol. Metab. Syndr. 2013, 5, 6. [Google Scholar] [CrossRef]
- ElSayed, N.A.; Aleppo, G.; Aroda, V.R.; Bannuru, R.R.; Brown, F.M.; Bruemmer, D.; Collins, B.S.; Hilliard, M.E.; Isaacs, D.; Johnson, E.L.; et al. 2. Classification and Diagnosis of Diabetes: Standards of Care in Diabetes-2023. Diabetes Care 2023, 46 (Suppl. S1), S19–S40, Erratum in Diabetes Care 2023, 46, 1106. https://doi.org/10.2337/dc23-er05. Erratum in Diabetes Care 2023, 46, 1715. https://doi.org/10.2337/dc23-ad08. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- ElSayed, N.A.; Aleppo, G.; Aroda, V.R.; Bannuru, R.R.; Brown, F.M.; Bruemmer, D.; Collins, B.S.; Hilliard, M.E.; Isaacs, D.; Johnson, E.L.; et al. 8. Obesity and Weight Management for the Prevention and Treatment of Type 2 Diabetes: Standards of Care in Diabetes—2023. Diabetes Care 2023, 46 (Suppl. S1), S128–S139. [Google Scholar] [CrossRef]
- ElSayed, N.A.; Aleppo, G.; Aroda, V.R.; Bannuru, R.R.; Brown, F.M.; Bruemmer, D.; Collins, B.S.; Hilliard, M.E.; Isaacs, D.; Johnson, E.L.; et al. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2023. Diabetes Care 2023, 46 (Suppl. S1), S140–S157. [Google Scholar] [CrossRef]
- Seino, Y.; Yabe, D. Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1: Incretin actions beyond the pancreas. J. Diabetes Investig. 2013, 4, 108–130. [Google Scholar] [CrossRef] [PubMed]
- Schirra, J.; Katschinski, M.; Weidmann, C.; Schäfer, T.; Wank, U.; Arnold, R.; Göke, B. Gastric emptying and release of incretin hormones after glucose ingestion in humans. J. Clin. Investig. 1996, 97, 92–103. [Google Scholar] [CrossRef] [PubMed]
- Tan, Q.; Akindehin, S.E.; Orsso, C.E.; Waldner, R.C.; DiMarchi, R.D.; Müller, T.D.; Haqq, A.M. Recent Advances in Incretin-Based Pharmacotherapies for the Treatment of Obesity and Diabetes. Front. Endocrinol. 2022, 13, 838410. [Google Scholar] [CrossRef] [PubMed]
- Brubaker, P.L.; Drucker, D.J. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology 2004, 145, 2653–2659. [Google Scholar] [CrossRef] [PubMed]
- Rudovich, N.N.; Rochlitz, H.J.; Pfeiffer, A.F. Reduced hepatic insulin extraction in response to gastric inhibitory polypeptide compensates for reduced insulin secretion in normal-weight and normal glucose tolerant first-degree relatives of type 2 dia-betic patients. Diabetes 2004, 53, 2359–2365. [Google Scholar] [CrossRef] [PubMed]
- Mentlein, R.; Gallwitz, B.; Schmidt, W.E. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur. J. Biochem. 1993, 214, 829–835. [Google Scholar] [CrossRef]
- Brubaker, P.L.; Crivici, A.; Izzo, A.; Ehrlich, P.; Tsai, C.H.; Drucker, D.J. Circulating and tissue forms of the intestinal growth factor, glucagon-like peptide-2. Endocrinology 1997, 138, 4837–4843. [Google Scholar] [CrossRef]
- Hartmann, B.; Harr, M.B.; Jeppesen, P.B.; Wojdemann, M.; Deacon, C.F.; Mortensen, P.B.; Holst, J.J. In vivo and in vitro degradation of glucagon-like peptide-2 in humans. J. Clin. Endocrinol. Metab. 2000, 85, 2884–2888. [Google Scholar] [CrossRef]
- Zhong, J.; Maiseyeu, A.; Davis, S.N.; Rajagopalan, S. DPP4 in cardiometabolic disease: Recent insights from the laboratory and clinical trials of DPP4 inhibition. Circ. Res. 2015, 116, 1491–1504. [Google Scholar] [CrossRef]
- Zhong, J.; Rao, X.; Deiuliis, J.; Braunstein, Z.; Narula, V.; Hazey, J.; Mikami, D.; Needleman, B.; Satoskar, A.R.; Rajagopalan, S. A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation. Diabetes 2013, 62, 149–157. [Google Scholar] [CrossRef]
- Drucker, D.J. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 2002, 122, 531–544. [Google Scholar] [CrossRef]
- Gupta, A.; Jelinek, H.F.; Al-Aubaidy, H. Glucagon like peptide-1 and its receptor agonists: Their roles in management of Type 2 diabetes mellitus. Diabetes Metab. Syndr. 2017, 11, 225–230. [Google Scholar] [CrossRef] [PubMed]
- Zhong, J.; Rao, X.; Rajagopalan, S. An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: Potential implica-tions in cardiovascular disease. Atherosclerosis 2013, 226, 305–314. [Google Scholar] [CrossRef] [PubMed]
- Gallwitz, B. GLP-1 agonists and dipeptidyl-peptidase IV inhibitors. Handb. Exp. Pharmacol. 2011, 53–74. [Google Scholar] [CrossRef] [PubMed]
- Stevens, J.E.; Buttfield, M.; Wu, T.; Hatzinikolas, S.; Pham, H.; Lange, K.; Rayner, C.K.; Horowitz, M.; Jones, K.L. Effects of sitagliptin on gastric emptying of, and the glycaemic and blood pressure responses to, a carbohydrate meal in type 2 diabetes. Diabetes Obes. Metab. 2020, 22, 51–58. [Google Scholar] [CrossRef] [PubMed]
- Wu, T.; Zhang, X.; Trahair, L.G.; Bound, M.J.; Little, T.J.; Deacon, C.F.; Horowitz, M.; Jones, K.L.; Rayner, C.K. Small Intestinal Glucose Delivery Affects the Lowering of Blood Glucose by Acute Vildagliptin in Type 2 Diabetes. J. Clin. Endocrinol. Metab. 2016, 101, 4769–4778. [Google Scholar] [CrossRef] [PubMed]
- Wu, T.; Bound, M.J.; Zhao, B.R.; Standfield, S.D.; Bellon, M.; Jones, K.L.; Horowitz, M.; Rayner, C.K. Effects of a D-xylose preload with or without sitagliptin on gastric emptying, glucagon-like peptide-1, and postprandial glycemia in type 2 diabetes. Diabetes Care 2013, 36, 1913–1918. [Google Scholar] [CrossRef] [PubMed]
- Wu, T.; Little, T.J.; Bound, M.J.; Borg, M.; Zhang, X.; Deacon, C.F.; Horowitz, M.; Jones, K.L.; Rayner, C.K. A Protein Preload Enhances the Glucose-Lowering Efficacy of Vildagliptin in Type 2 Diabetes. Diabetes Care 2016, 39, 511–517. [Google Scholar] [CrossRef] [PubMed]
- Marguet, D.; Baggio, L.; Kobayashi, T.; Bernard, A.M.; Pierres, M.; Nielsen, P.F.; Ribel, U.; Watanabe, T.; Drucker, D.J.; Wagtmann, N. Enhanced insulin secretion and improved glu-cose tolerance in mice lacking CD26. Proc. Natl. Acad. Sci. USA 2000, 97, 6874–6879. [Google Scholar] [CrossRef]
- Broxmeyer, H.E.; Hoggatt, J.; O’Leary, H.A.; Mantel, C.; Chitteti, B.R.; Cooper, S.; Messina-Graham, S.; Hangoc, G.; Farag, S.; Rohrabaugh, S.L.; et al. Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat. Med. 2012, 18, 1786–1796. [Google Scholar] [CrossRef]
- Shah, Z.; Kampfrath, T.; Deiuliis, J.A.; Zhong, J.; Pineda, C.; Ying, Z.; Xu, X.; Lu, B.; Moffatt-Bruce, S.; Durairaj, R.; et al. Long-term dipeptidyl-peptidase 4 inhibition reduces ath-erosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation 2011, 124, 2338–2349. [Google Scholar] [CrossRef] [PubMed]
- Zhong, J.; Rajagopalan, S. Dipeptidyl peptidase-4 regulation of SDF-1/CXCR4 axis: Implications for cardiovascular disease. Front. Immunol. 2015, 6, 477. [Google Scholar] [CrossRef] [PubMed]
- Kameoka, J.; Tanaka, T.; Nojima, Y.; Schlossman, S.F.; Morimoto, C. Direct association of adenosine deaminase with a T cell acti-vation antigen, CD26. Science 1993, 261, 466–469. [Google Scholar] [CrossRef] [PubMed]
- Wagner, L.; Klemann, C.; Stephan, M.; von Hörsten, S. Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins. Clin. Exp. Immunol. 2016, 184, 265–283. [Google Scholar] [CrossRef]
- Zheng, Z.; Zong, Y.; Ma, Y.; Tian, Y.; Pang, Y.; Zhang, C.; Gao, J. Glucagon-like peptide-1 receptor: Mechanisms and advances in therapy. Signal Transduct. Target. Ther. 2024, 9, 234. [Google Scholar] [CrossRef] [PubMed]
- Burcelin, R.; Gourdy, P. Harnessing glucagon-like peptide-1 receptor agonists for the pharmacological treatment of overweight and obesity. Obes. Rev. 2017, 18, 86–98. [Google Scholar] [CrossRef]
- Muscogiuri, G.; DeFronzo, R.A.; Gastaldelli, A.; Holst, J.J. Glucagon-like peptide-1 and the central/peripheral nervous system: Crosstalk in diabetes. Trends Endocrinol. Metab. 2017, 28, 88–103. [Google Scholar] [CrossRef]
- Baggio, L.L.; Ussher, J.R.; McLean, B.A.; Cao, X.; Kabir, M.G.; Mulvihill, E.E.; Mighiu, A.S.; Zhang, H.; Ludwig, A.; Seeley, R.J.; et al. The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice. Mol. Metab. 2017, 6, 1339–1349. [Google Scholar] [CrossRef] [PubMed]
- Baggio, L.L.; Yusta, B.; Mulvihill, E.E.; Cao, X.; Streutker, C.J.; Butany, J.; Cappola, T.P.; Margulies, K.B.; Drucker, D.J. GLP-1 Receptor Expression Within the Human Heart. Endocrinology 2018, 159, 1570–1584. [Google Scholar] [CrossRef] [PubMed]
- Amato, A.; Cinci, L.; Rotondo, A.; Serio, R.; Faussone-Pellegrini, M.S.; Vannucchi, M.G.; Mulè, F. Peripheral motor action of glucagon-like peptide-1 through enteric neuronal receptors. Neurogastroenterol. Motil. 2010, 22, 664-e203. [Google Scholar] [CrossRef] [PubMed]
- Gorgojo-Martínez, J.J.; Mezquita-Raya, P.; Carretero-Gómez, J.; Castro, A.; Cebrián-Cuenca, A.; de Torres-Sánchez, A.; García-de-Lucas, M.D.; Núñez, J.; Obaya, J.C.; Soler, M.J.; et al. Clinical Recommendations to Manage Gastrointestinal Adverse Events in Patients Treated with Glp-1 Receptor Agonists: A Multidisciplinary Expert Consensus. J. Clin. Med. 2022, 12, 145. [Google Scholar] [CrossRef] [PubMed]
- Claustre, J.; Brechet, S.; Plaisancie, P.; Chayvialle, J.A.; Cuber, J.C. Stimulatory effect of beta-adrenergic agonists on ileal L cell secretion and modulation by alpha-adrenergic activation. J. Endocrinol. 1999, 162, 271–278. [Google Scholar] [CrossRef] [PubMed]
- Chen, N.; Chen, Y.; Lai, F.; Chen, L.; Zeng, R.; Pei, L.; Wu, L.; Wang, C.; Li, Y.; Xiao, H.; et al. Circulating GLP-1 Levels in Patients with Pheochromocytoma/Paraganglioma. Int. J. Endocrinol. 2022, 2022, 4203018. [Google Scholar] [CrossRef] [PubMed]
- Jastreboff, A.M.; Aronne, L.J.; Ahmad, N.N.; Wharton, S.; Connery, L.; Alves, B.; Kiyosue, A.; Zhang, S.; Liu, B.; Bunck, M.C.; et al. Tirzepatide Once Weekly for the Treatment of Obesity. New Engl. J. Med. 2022, 387, 205–216. [Google Scholar] [CrossRef] [PubMed]
- Garvey, W.T.; Frias, J.P.; Jastreboff, A.M.; le Roux, C.W.; Sattar, N.; Aizenberg, D.; Mao, H.; Zhang, S.; Ahmad, N.N.; Bunck, M.C.; et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): A double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2023, 402, 613–626. [Google Scholar] [CrossRef] [PubMed]
- Wadden, T.A.; Chao, A.M.; Machineni, S.; Kushner, R.; Ard, J.; Srivastava, G.; Halpern, B.; Zhang, S.; Chen, J.; Bunck, M.C.; et al. Author Correction: Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: The SURMOUNT-3 phase 3 trial. Nat. Med. 2024, 30, 1784, Erratum in Nat. Med. 2023, 29, 2909–2918. https://doi.org/10.1038/s41591-023-02597-w. [Google Scholar] [CrossRef] [PubMed]
- Thursby, E.; Juge, N. Introduction to the human gut microbiota. Biochem. J. 2017, 474, 1823–1836. [Google Scholar] [CrossRef]
- Poretsky, R.; Rodriguez-R, L.M.; Luo, C.; Tsementzi, D.; Konstantinidis, K.T.; Rodriguez-Valera, F. Strengths and limitations of 16S rRNA gene amplicon sequencing in revealing temporal microbial community dynamics. PLoS ONE 2014, 9, e93827. [Google Scholar] [CrossRef]
- Hugon, P.; Dufour, J.C.; Colson, P.; Fournier, P.E.; Sallah, K.; Raoult, D. A comprehensive repertoire of prokaryotic species identified in human beings. Lancet Infect. Dis. 2015, 15, 1211–1219. [Google Scholar] [CrossRef]
- Li, J.; Jia, H.; Cai, X.; Zhong, H.; Feng, Q.; Sunagawa, S.; Arumugam, M.; Kultima, J.R.; Prifti, E.; Nielsen, T.; et al. An integrated catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 2014, 32, 834–841. [Google Scholar] [CrossRef]
- Donaldson, G.P.; Lee, S.M.; Mazmanian, S.K. Gut biogeography of the bacterial microbiota. Nat. Rev. Microbiol. 2016, 14, 20–32. [Google Scholar] [CrossRef] [PubMed]
- Ferranti, E.P.; Dunbar, S.B.; Dunlop, A.L.; Corwin, E.J. 20 things you didn’t know about the human gut microbiome. J. Cardiovasc. Nurs. 2014, 29, 479–481. [Google Scholar] [CrossRef] [PubMed]
- Arumugam, M.; Raes, J.; Pelletier, E.; Le Paslier, D.; Yamada, T.; Mende, D.R.; Fernandes, G.D.R.; Tap, J.; Bruls, T.; Batto, J.M.; et al. Entero-types of the human gut microbiome. Nature 2011, 473, 174–180. [Google Scholar] [CrossRef] [PubMed]
- Turpin, W.; Espin-Garcia, O.; Xu, W.; Silverberg, M.S.; Kevans, D.; Smith, M.I.; Guttman, D.S.; Griffiths, A.; Panaccione, R.; Otley, A.; et al. Association of host genome with intestinal microbial composition in a large healthy cohort. Nat. Genet 2016, 48, 1413–1417. [Google Scholar] [CrossRef]
- Burton, C.L.; Chhabra, S.R.; Swift, S.; Baldwin, T.J.; Withers, H.; Hill, S.J.; Williams, P. The growth response of Escherichia coli to neu-rotransmitters and related catecholamine drugs requires a functional enterobactin biosynthesis and uptake system. Infect. Immun. 2002, 70, 5913–5923. [Google Scholar] [CrossRef] [PubMed]
- Santiago-Rodriguez, T.M.; Hollister, E.B. Human virome and disease: High-throughput sequencing for virus discovery, identifcation of phage-bacteria dysbiosis and development of therapeutic approaches with emphasis on the human gut. Viruses 2019, 11, 656. [Google Scholar] [CrossRef]
- Tetz, G.; Tetz, V. Bacteriophages as New Human Viral Pathogens. Microorganisms 2018, 6, 54. [Google Scholar] [CrossRef] [PubMed]
- De Paepe, M.; Leclerc, M.; Tinsley, C.R.; Petit, M.A. Bacteriophages: An underestimated role in human and animal health? Front. Cell. Infect. Microbiol. 2014, 4, 39. [Google Scholar] [CrossRef]
- Kho, Z.Y.; Lal, S.K. The human gut microbiome—A potential controller of wellness and disease. Front. Microbiol. 2018, 9, 1835. [Google Scholar] [CrossRef]
- Hooper, L.V.; Gordon, J.I. Commensal host-bacterial relationships in the gut. Science 2001, 292, 1115–1118. [Google Scholar] [CrossRef]
- Afzaal, M.; Saeed, F.; Shah, Y.A.; Hussain, M.; Rabail, R.; Socol, C.T.; Hassoun, A.; Pateiro, M.; Lorenzo, J.M.; Rusu, A.V.; et al. Human gut microbiota in health and disease: Unveiling the relationship. Front. Microbiol. 2022, 13, 999001. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Yan, X.; Feng, B.; Li, P.; Tang, Z.; Wang, L. Microflora disturbance during progression of glucose intolerance and effect of sitagliptin: An animal study. J. Diabetes Res. 2016, 2016, 2093171. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Q.; Xiao, X.; Li, M.; Yu, M.; Ping, F.; Zheng, J.; Wang, T.; Wang, X. Vildagliptin Increases Butyrate-Producing Bacteria in the Gut of Diabetic Rats. PLoS ONE 2017, 12, e0184735. [Google Scholar] [CrossRef] [PubMed]
- Ryan, P.M.; Patterson, E.; Carafa, I.; Mandal, R.; Wishart, D.S.; Dinan, T.G.; Cryan, J.F.; Tuohy, K.M.; Stanton, C.; Ross, R.P. Metformin and Dipeptidyl Peptidase-4 Inhibitor Differentially Modulate the Intestinal Microbiota and Plasma Metabolome of Metabolically Dysfunctional Mice. Can. J. Diabetes 2020, 44, 146–155.e2. [Google Scholar] [CrossRef] [PubMed]
- Olivares, M.; Neyrinck, A.M.; Pötgens, S.A.; Beaumont, M.; Salazar, N.; Cani, P.D.; Bindels, L.B.; Delzenne, N.M. The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice. Diabetologia 2018, 61, 1838–1848. [Google Scholar] [CrossRef]
- Liao, X.; Song, L.; Zeng, B.; Liu, B.; Qiu, Y.; Qu, H.; Zheng, Y.; Long, M.; Zhou, H.; Wang, Y.; et al. Alteration of gut microbiota induced by DPP-4i treatment improves glucose homeostasis. EBioMedicine 2019, 44, 665–674. [Google Scholar] [CrossRef] [PubMed]
- Silva-Veiga, F.M.; Miranda, C.S.; Vasques-Monteiro, I.M.L.; Souza-Tavares, H.; Martins, F.F.; Daleprane, J.B.; Souza-Mello, V. Peroxisome proliferator-activated receptor-alpha activation and dipeptidyl peptidase-4 inhibition target dysbiosis to treat fatty liver in obese mice. World J. Gastroenterol. 2022, 28, 1814–1829. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.; Li, P.; Tang, Z.; Yan, X.; Feng, B. Structural modulation of the gut microbiota and the relationship with body weight: Compared evaluation of liraglutide and saxagliptin treatment. Sci. Rep. 2016, 6, 33251. [Google Scholar] [CrossRef]
- Kato, S.; Sato, T.; Fujita, H.; Kawatani, M.; Yamada, Y. Effects of GLP-1 receptor agonist on changes in the gut bacterium and the underlying mechanisms. Sci. Rep. 2021, 11, 9167. [Google Scholar] [CrossRef] [PubMed]
- Duan, X.; Zhang, L.; Liao, Y.; Lin, Z.; Guo, C.; Luo, S.; Wang, F.; Zou, Z.; Zeng, Z.; Chen, C.; et al. Semaglutide alleviates gut microbiota dysbiosis induced by a high-fat diet. Eur. J. Pharmacol. 2024, 969, 176440. [Google Scholar] [CrossRef] [PubMed]
- Feng, J.; Teng, Z.; Yang, Y.; Liu, J.; Chen, S. Effects of semaglutide on gut microbiota, cognitive function and inflammation in obese mice. PeerJ 2024, 12, e17891. [Google Scholar] [CrossRef] [PubMed]
- Mao, T.; Zhang, C.; Yang, S.; Bi, Y.; Li, M.; Yu, J. Semaglutide alters gut microbiota and improves NAFLD in db/db mice. Biochem. Biophys. Res. Commun. 2024, 710, 149882. [Google Scholar] [CrossRef] [PubMed]
- De Paiva, I.H.R.; da Silva, R.S.; Mendonça, I.P.; de Souza, J.R.B.; Peixoto, C.A. Semaglutide Attenuates Anxious and Depressive-Like Behaviors and Reverses the Cognitive Impairment in a Type 2 Diabetes Mellitus Mouse Model Via the Microbiota-Gut-Brain Axis. J. Neuroimmune Pharmacol. 2024, 19, 36. [Google Scholar] [CrossRef] [PubMed]
- Luo, Y.; Li, J.E.; Zeng, H.; Zhang, Y.; Yang, S.; Liu, J. Semaglutide alleviates the pancreatic β cell function via the METTL14 signaling and modulating gut microbiota in type 2 diabetes mellitus mice. Life Sci. 2025, 361, 123328. [Google Scholar] [CrossRef] [PubMed]
- Xiong, C.; Wu, J.; Ma, Y.; Li, N.; Wang, X.; Li, Y.; Ding, X. Effects of Glucagon-Like Peptide-1 Receptor Agonists on Gut Microbiota in Dehydroepiandrosterone-Induced Polycystic Ovary Syndrome Mice: Compared Evaluation of Liraglutide and Semaglutide Intervention. Diabetes Metab. Syndr. Obes. 2024, 17, 865–880. [Google Scholar] [CrossRef] [PubMed]
- Madsen, M.S.A.; Holm, J.B.; Pallejà, A.; Wismann, P.; Fabricius, K.; Rigbolt, K.; Mikkelsen, M.; Sommer, M.; Jelsing, J.; Nielsen, H.B.; et al. Metabolic and gut microbiome changes following GLP-1 or dual GLP-1/GLP-2 receptor agonist treatment in diet-induced obese mice. Sci. Rep. 2019, 9, 15582. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Q.; Xiao, X.; Zheng, J.; Li, M.; Yu, M.; Ping, F.; Wang, T.; Wang, X. Featured article: Structure moderation of gut microbiota in liraglutide-treated diabetic male rats. Exp. Biol. Med. 2018, 243, 34–44. [Google Scholar] [CrossRef] [PubMed]
- Charpentier, J.; Briand, F.; Lelouvier, B.; Servant, F.; Azalbert, V.; Puel, A.; Christensen, J.E.; Waget, A.; Branchereau, M.; Garret, C.; et al. Liraglutide Targets the Gut Microbiota and the In-testinal Immune System to Regulate Insulin Secretion. Acta Diabetol. 2021, 58, 881–897. [Google Scholar] [CrossRef]
- Moreira, G.; Azevedo, F.; Ribeiro, L.; Santos, A.; Guadagnini, D.; Gama, P.; Liberti, E.; Saad, M.; Carvalho, C. Liraglutide modulates gut microbiota and reduces NAFLD in obese mice. J. Nutr. Biochem. 2018, 62, 143–154. [Google Scholar] [CrossRef]
- Yuan, X.; Ni, H.; Chen, X.; Feng, X.; Wu, Q.; Chen, J. Identification of therapeutic effect of glucagon-like peptide 1 in the treatment of STZ-induced diabetes mellitus in rats by restoring the balance of intestinal flora. J. Cell. Biochem. 2018, 119, 10067–10074. [Google Scholar] [CrossRef] [PubMed]
- Zhao, L.; Chen, Y.; Xia, F.; Abudukerimu, B.; Zhang, W.; Guo, Y.; Wang, N.; Lu, Y. A glucagon-like peptide-1 receptor agonist lowers weight by modulating the structure of gut microbiota. Front. Endocrinol. 2018, 9, 233. [Google Scholar] [CrossRef] [PubMed]
- Liu, Q.; Cai, B.Y.; Zhu, L.X.; Xin, X.; Wang, X.; An, Z.M.; Li, S.; Hu, Y.Y.; Feng, Q. Liraglutide modulates gut microbiome and attenuates nonalcoholic fatty liver in db/db mice. Life Sci. 2020, 261, 118457. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.; Wang, L.; Li, Y.; Luo, S.; Ye, J.; Lu, Z.; Li, X.; Lu, H. The HIF-2α/PPARα pathway is essential for liraglutide-alleviated, lipid-induced hepatic steatosis. Biomed. Pharmacother. 2021, 140, 111778. [Google Scholar] [CrossRef]
- Chavda, V.P.; Ajabiya, J.; Teli, D.; Bojarska, J.; Apostolopoulos, V. Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review. Molecules 2022, 27, 4315, Erratum in Molecules 2025, 30, 1190. https://doi.org/10.3390/molecules30061190. [Google Scholar] [CrossRef] [PubMed]
- Hu, W.; Gong, W.; Yang, F.; Cheng, R.; Zhang, G.; Gan, L.; Zhu, Y.; Qin, W.; Gao, Y.; Li, X.; et al. Dual GIP and GLP-1 receptor agonist tirzepatide alleviates hepatic steatosis and modulates gut microbiota and bile acid metabolism in diabetic mice. Int. Immunopharmacol. 2025, 147, 113937. [Google Scholar] [CrossRef]
- Silva-Veiga, F.M.; Marinho, T.S.; de Souza-Mello, V.; Aguila, M.B.; Mandarim-De-Lacerda, C.A. Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), positively impacts the altered microbiota of obese, diabetic, ovariectomized mice. Life Sci. 2024, 361, 123310. [Google Scholar] [CrossRef]
- Bendotti, G.; Montefusco, L.; Lunati, M.E.; Usuelli, V.; Pastore, I.; Lazzaroni, E.; Assi, E.; Seelam, A.J.; El Essawy, B.; Jang, J.; et al. The anti-inflammatory and immunological properties of GLP-1 Receptor Agonists. Pharmacol. Res. 2022, 182, 106320. [Google Scholar] [CrossRef] [PubMed]
- Yusta, B.; Baggio, L.L.; Koehler, J.; Holland, D.; Cao, X.; Pinnell, L.J.; Johnson-Henry, K.C.; Yeung, W.; Surette, M.G.; Bang, K.A.; et al. GLP-1R agonists modulate enteric immune responses through the intestinal intraepithelial lymphocyte GLP-1R. Diabetes 2015, 64, 2537–2549. [Google Scholar] [CrossRef] [PubMed]
- Wong, C.K.; Yusta, B.; Koehler, J.A.; Baggio, L.L.; McLean, B.A.; Matthews, D.; Seeley, R.J.; Drucker, D.J. Divergent roles for the gut intraepithelial lymphocyte GLP-1R in control of metabolism, microbiota, and T cell-induced inflammation. Cell Metab. 2022, 34, 1514–1531.e7. [Google Scholar] [CrossRef] [PubMed]
- Hammoud, R.; Kaur, K.D.; Koehler, J.A.; Baggio, L.L.; Wong, C.K.; Advani, K.E.; Yusta, B.; Efimova, I.; Gribble, F.M.; Reimann, F.; et al. Glucose-dependent insulinotropic polypeptide receptor signaling alleviates gut inflammation in mice. J. Clin. Investig. 2024, 10, e174825. [Google Scholar] [CrossRef]
- Ying, X.; Rongjiong, Z.; Kahaer, M.; Chunhui, J.; Wulasihan, M. Therapeutic efficacy of liraglutide versus metformin in modulating the gut microbiota for treating type 2 diabetes mellitus complicated with nonalcoholic fatty liver disease. Front. Microbiol. 2023, 14, 1088187. [Google Scholar] [CrossRef] [PubMed]
- Wu, H.; Esteve, E.; Tremaroli, V.; Khan, M.T.; Caesar, R.; Mannerås-Holm, L.; Ståhlman, M.; Olsson, L.M.; Serino, M.; Planas-Fèlix, M.; et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 2017, 23, 850–858. [Google Scholar] [CrossRef] [PubMed]
- Wang, Z.; Saha, S.; Van Horn, S.; Thomas, E.; Traini, C.; Sathe, G.; Rajpal, D.K.; Brown, J.R. Gut microbiome differences between metformin- and liraglutide-treated T2DM subjects. Endocrinol. Diabetes Metab. Case Rep. 2018, 1, e00009. [Google Scholar] [CrossRef]
- Smits, M.M.; Fluitman, K.S.; Herrema, H.; Davids, M.; Kramer, M.H.; Groen, A.K.; Belzer, C.; de Vos, W.M.; Cahen, D.L.; Nieuwdorp, M.; et al. Liraglutide and sitagliptin have no effect on intestinal microbiota composition: A 12-week randomized placebo-controlled trial in adults with type 2 diabetes. Diabetes Metab. 2021, 47, 101223. [Google Scholar] [CrossRef] [PubMed]
- Rizza, S.; Pietrucci, D.; Longo, S.; Menghini, R.; Teofani, A.; Piciucchi, G.; Montagna, M.; Federici, M. Impact of insulin De-gludec/Liraglutide fixedcombination on the gut microbiomes of elderly patients with type 2 diabetes: Results from A Suba-nalysis of A small non-randomised single arm study. Aging Dis. 2023, 14, 319–324. [Google Scholar] [CrossRef]
- Tsai, C.Y.; Lu, H.C.; Chou, Y.H.; Liu, P.Y.; Chen, H.Y.; Huang, M.C.; Lin, C.H.; Tsai, C.N. Gut Microbial Signatures for Glycemic Responses of GLP-1 Receptor Agonists in Type 2 Diabetic Patients: A Pilot Study. Front. Endocrinol. 2021, 12, 814770. [Google Scholar] [CrossRef]
- Liang, L.; Su, X.; Guan, Y.; Wu, B.; Zhang, X.; Nian, X. Correlation between intestinal flora and GLP-1 receptor agonist dulaglutide in type 2 diabetes mellitus treatment—A preliminary longitudinal study. iScience 2024, 27, 109784. [Google Scholar] [CrossRef] [PubMed]
- Kimura, I.; Ozawa, K.; Inoue, D.; Imamura, T.; Kimura, K.; Maeda, T.; Terasawa, K.; Kashihara, D.; Hirano, K.; Tani, T.; et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun. 2013, 4, 1829. [Google Scholar] [CrossRef]
- Freeland, K.R.; Wolever, T.M.S. Acute effects of intravenous and rectal acetate on glucagon-like peptide-1, peptide YY, ghrelin, adiponectin and tumour necrosis factor-α. Br. J. Nutr. 2010, 103, 460–466. [Google Scholar] [CrossRef]
- Tolhurst, G.; Heffron, H.; Lam, Y.S.; Parker, H.E.; Habib, A.M.; Diakogiannaki, E.; Cameron, J.; Grosse, J.; Reimann, F.; Gribble, F.M. Short-chain fatty acids stimulate gluca-gon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 2012, 61, 364–371. [Google Scholar] [CrossRef]
- Cani, P.D.; Hoste, S.; Guiot, Y.; Delzenne, N.M. Dietary non-digestible carbohydrates promote L-cell differentiation in the proximal colon of rats. Br. J. Nutr. 2007, 98, 32–37. [Google Scholar] [CrossRef] [PubMed]
- Psichas, A.; Sleeth, M.L.; Murphy, K.G.; Brooks, L.; Bewick, G.A.; Hanyaloglu, A.C.; Ghatei, M.A.; Bloom, S.R.; Frost, G. The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int. J. Obes. 2015, 39, 424–429. [Google Scholar] [CrossRef] [PubMed]
- Cani, P.D.; Dewever, C.; Delzenne, N.M. Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagon-like peptide-1 and ghrelin) in rats. Br. J. Nutr. 2004, 92, 521–526. [Google Scholar] [CrossRef] [PubMed]
- Piche, T.; des Varannes, S.B.; Sacher-Huvelin, S.; Holst, J.J.; Cuber, J.C.; Galmiche, J.P. Colonic fermentation influences lower esopha-geal sphincter function in reflux disease. Gastroenterology 2003, 124, 894–902. [Google Scholar] [CrossRef]
- Ropert, A.; Cherbut, C.; Roze, C.; Le Quellec, A.; Holst, J.; Fu-Cheng, X.; Bruley des Varannes, S.; Galmiche, J.P. Colonic fermentation and proximal gastric tone in humans. Gastroenterology 1996, 111, 289–296. [Google Scholar] [CrossRef]
- Cani, P.D.; Lecourt, E.; Dewulf, E.M.; Sohet, F.M.; Pachikian, B.D.; Naslain, D.; De Backer, F.; Neyrinck, A.M.; Delzenne, N.M. Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. Am. J. Clin. Nutr. 2009, 90, 1236–1243. [Google Scholar] [CrossRef] [PubMed]
- Harach, T.; Pols, T.W.H.; Nomura, M.; Maida, A.; Watanabe, M.; Auwerx, J.; Schoonjans, K. TGR5 potentiates GLP-1 secretion in response to anionic exchange resins. Sci. Rep. 2012, 2, 430. [Google Scholar] [CrossRef]
- Thomas, C.; Gioiello, A.; Noriega, L.; Strehle, A.; Oury, J.; Rizzo, G.; Macchiarulo, A.; Yamamoto, H.; Mataki, C.; Pruzanski, M.; et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009, 10, 167–177. [Google Scholar] [CrossRef]
- Trabelsi, M.-S.; Daoudi, M.; Prawitt, J.; Ducastel, S.; Touche, V.; Sayin, S.I.; Perino, A.; Brighton, C.A.; Sebti, Y.; Kluza, J.; et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat. Commun. 2015, 6, 7629. [Google Scholar] [CrossRef]
- Ducastel, S.; Touche, V.; Trabelsi, M.-S.; Boulinguiez, A.; Butruille, L.; Nawrot, M.; Peschard, S.; Chávez-Talavera, O.; Dorchies, E.; Vallez, E.; et al. The nuclear receptor FXR inhibits glucagon-like peptide-1 secretion in response to microbiota-derived short-chain fatty acids. Sci. Rep. 2020, 10, 174. [Google Scholar] [CrossRef]
- Kuhre, R.E.; Albrechtsen, N.J.W.; Larsen, O.; Jepsen, S.L.; Balk-Møller, E.; Andersen, D.B.; Deacon, C.F.; Schoonjans, K.; Reimann, F.; Gribble, F.M.; et al. Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Mol. Metab. 2018, 11, 84–95. [Google Scholar] [CrossRef] [PubMed]
- Adrian, T.E.; Gariballa, S.; Parekh, K.A.; Thomas, S.A.; Saadi, H.; Al Kaabi, J.; Nagelkerke, N.; Gedulin, B.; Young, A.A. Rectal taurocholate increases L cell and insulin secretion, and decreases blood glucose and food intake in obese type 2 diabetic volunteers. Diabetologia 2012, 55, 2343–2347. [Google Scholar] [CrossRef] [PubMed]
- Wu, T.; Bound, M.J.; Standfield, S.D.; Gedulin, B.; Jones, K.L.; Horowitz, M.; Rayner, C.K. Effects of rectal administration of taurocholic acid on glucagon-like peptide-1 and peptide YY secretion in healthy humans. Diabetes Obes. Metab. 2013, 15, 474–477. [Google Scholar] [CrossRef] [PubMed]
- Wu, T.; Bound, M.J.; Standfield, S.D.; Jones, K.L.; Horowitz, M.; Rayner, C.K. Effects of taurocholic acid on glycemic, glucagon-like peptide-1, and insulin responses to small intestinal glucose infusion in healthy humans. J. Clin. Endocrinol. Metab. 2013, 98, E718–E722. [Google Scholar] [CrossRef] [PubMed]
- Chimerel, C.; Emery, E.; Summers, D.K.; Keyser, U.; Gribble, F.M.; Reimann, F. Bacterial metabolite indole modulates incretin secre-tion from intestinal enteroendocrine L cells. Cell Rep. 2014, 9, 1202–1208. [Google Scholar] [CrossRef] [PubMed]
- Hartstra, A.V.; Bouter, K.E.C.; Bäckhed, F.; Nieuwdorp, M. Insights into the role of the microbiome in obesity and type 2 diabetes. Diabetes Care 2015, 38, 159–165. [Google Scholar] [CrossRef] [PubMed]
- Tremaroli, V.; Bäckhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 2012, 489, 242–249. [Google Scholar] [CrossRef]
- Le Chatelier, E.; Nielsen, T.; Qin, J.; Prifti, E.; Hildebrand, F.; Falony, G.; Almeida, M.; Arumugam, M.; Batto, J.M.; Kennedy, S.; et al. Richness of human gut microbiome correlates with metabolic markers. Nature 2013, 500, 541–546. [Google Scholar] [CrossRef]
- Bellono, N.W.; Bayrer, J.R.; Leitch, D.B.; Castro, J.; Zhang, C.; O’Donnell, T.A.; Brierley, S.M.; Ingraham, H.A.; Julius, D. Enterochromaffin cells are gut Chemosensors that couple to sensory neural pathways. Cell 2017, 170, 185–198. [Google Scholar] [CrossRef]
- Lebrun, L.J.; Lenaerts, K.; Kiers, D.; Pais de Barros, J.-P.; Le Guern, N.; Plesnik, J.; Thomas, C.; Bourgeois, T.; Dejong, C.H.C.; Kox, M.; et al. Enteroendocrine L cells sense LPS after gut barrier injury to enhance GLP-1 secretion. Cell Rep. 2017, 21, 1160–1168. [Google Scholar] [CrossRef]
- Chaudhari, S.N.; Luo, J.N.; Harris, D.A.; Aliakbarian, H.; Yao, L.; Paik, D.; Subramaniam, R.; Adhikari, A.A.; Vernon, A.H.; Kiliç, A.; et al. A microbial metabolite Remodels the gut-liver axis following Bariatric surgery. Cell Host Microbe 2021, 29, 408–424. [Google Scholar] [CrossRef] [PubMed]
- Nilsson, A.C.; Johansson-Boll, E.V.; Björck, I.M.E. Increased gut hormones and insulin sensitivity index following a 3-d interven-tion with a barley kernel-based product: A randomised cross-over study in healthy middle-aged subjects. Br. J. Nutr. 2015, 114, 899–907. [Google Scholar] [CrossRef]
- Koopen, A.; Witjes, J.; Wortelboer, K.; Majait, S.; Prodan, A.; Levin, E.; Herrema, H.; Winkelmeijer, M.; Aalvink, S.; Bergman, J.; et al. Duodenal Anaerobutyricum soehngenii infusion stimulates GLP-1 production, ameliorates glycaemic control and beneficially shapes the duodenal transcriptome in metabolic syndrome subjects: A randomised double-blind placebo-controlled cross-over study. Gut 2022, 71, 1577–1587. [Google Scholar] [CrossRef] [PubMed]
- Hansen, K.B.; Rosenkilde, M.M.; Knop, F.K.; Wellner, N.; Diep, T.A.; Rehfeld, J.F.; Andersen, U.B.; Holst, J.J.; Hansen, H.S. 2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans. J. Clin. Endocrinol. Metab. 2011, 96, E1409–E1417. [Google Scholar] [CrossRef]
- Qin, J.; Li, R.; Raes, J.; Arumugam, M.; Burgdorf, K.S.; Manichanh, C.; Nielsen, T.; Pons, N.; Levenez, F.; Yamada, T.; et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010, 464, 59–65. [Google Scholar] [CrossRef] [PubMed]
- Zeng, Y.; Wu, Y.; Zhang, Q.; Xiao, X. Crosstalk between glucagon-like peptide 1 and gut microbiota in metabolic diseases. mBio 2024, 15, e0203223. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Gofron, K.K.; Wasilewski, A.; Małgorzewicz, S. Effects of GLP-1 Analogues and Agonists on the Gut Microbiota: A Systematic Review. Nutrients 2025, 17, 1303. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Vallianou, N.G.; Stratigou, T.; Tsagarakis, S. Metformin and gut microbiota: Their interactions and their impact on diabetes. Hormones 2019, 18, 141–144. [Google Scholar] [CrossRef] [PubMed]
- Perler, B.K.; Friedman, E.S.; Wu, G.D. The role of the gut microbiota in the Relationship between diet and human health. Annu. Rev. Physiol. 2023, 85, 449–468. [Google Scholar] [CrossRef] [PubMed]
- Center for Disease Control and Prevention. Type 2 Diabetes. 2019. Available online: https://www.cdc.gov/diabetes/about/about-type-2-diabetes.html?CDC_AAref_Val=https://www.cdc.gov/diabetes/basics/type2.html (accessed on 12 February 2021).
- Baothman, O.A.; Zamzami, M.A.; Taher, I.; Abubaker, J.; Abu-Farha, M. The role of Gut Microbiota in the development of obesity and Diabetes. Lipids Health Dis. 2016, 15, 108. [Google Scholar] [CrossRef]
- Suez, J.; Korem, T.; Zeevi, D.; Zilberman-Schapira, G.; Thaiss, C.A.; Maza, O.; Israeli, D.; Zmora, N.; Gilad, S.; Weinberger, A.; et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 2014, 514, 181–186. [Google Scholar] [CrossRef] [PubMed]
- Rayner, C.K.; Watson, L.E.; Phillips, L.K.; Lange, K.; Bound, M.J.; Grivell, J.; Wu, T.; Jones, K.L.; Horowitz, M.; Ferrannini, E.; et al. Effects of sustained treatment with lixisenatide on gastric emptying and postprandial glucose metabolism in type 2 diabetes: A randomized controlled trial. Diabetes Care 2020, 43, 1813–1821. [Google Scholar] [CrossRef] [PubMed]
- Jones, K.L.; Huynh, L.Q.; Hatzinikolas, S.; Rigda, R.S.; Phillips, L.K.; Pham, H.T.; Marathe, C.S.; Wu, T.; Malbert, C.H.; Stevens, J.E.; et al. Exenatide once weekly slows gastric emptying of solids and liquids in healthy, overweight people at steady-state concentrations. Diabetes Obes. Metab. 2020, 22, 788–797. [Google Scholar] [CrossRef] [PubMed]
- Thazhath, S.S.; Marathe, C.S.; Wu, T.; Chang, J.; Khoo, J.; Kuo, P.; Checklin, H.L.; Bound, M.J.; Rigda, R.S.; Crouch, B.; et al. The glucagon-like peptide 1 receptor agonist exenatide inhibits small intestinal motility, flow, transit, and absorption of glucose in healthy subjects and patients with type 2 diabetes: A randomized controlled trial. Diabetes 2016, 65, 269–275. [Google Scholar] [CrossRef] [PubMed]
- Shanahan, E.R.; Kang, S.; Staudacher, H.; Shah, A.; Do, A.; Burns, G.; Chachay, V.S.; A Koloski, N.; Keely, S.; Walker, M.M.; et al. Alterations to the duodenal microbiota are linked to gastric emptying and symptoms in functional dyspepsia. Gut 2023, 72, 929–938. [Google Scholar] [CrossRef] [PubMed]
- Santos-Marcos, J.A.; Mora-Ortiz, M.; Tena-Sempere, M.; Lopez-Miranda, J.; Camargo, A. Interaction between gut microbiota and sex hormones and their relation to sexual dimorphism in metabolic diseases. Biol. Sex Differ. 2023, 14, 4. [Google Scholar] [CrossRef] [PubMed]
- Xie, C.; Huang, W.; Sun, Y.; Xiang, C.; Trahair, L.; Jones, K.L.; Horowitz, M.; Rayner, C.K.; Wu, T. Disparities in the Glycemic and Incretin Responses to Intraduodenal Glucose Infusion Between Healthy Young Men and Women. J. Clin. Endocrinol. Metab. 2023, 108, e712–e719. [Google Scholar] [CrossRef] [PubMed]
- Tang, D.; Wang, C.; Liu, H.; Wu, J.; Tan, L.; Liu, S.; Lv, H.; Wang, C.; Wang, F.; Liu, J. Integrated Multi-Omics Analysis Reveals Mountain-Cultivated Ginseng Ameliorates Cold-Stimulated Steroid-Resistant Asthma by Regulating Interactions among Microbiota, Genes, and Metabolites. Int. J. Mol. Sci. 2024, 25, 9110, Erratum in Int. J. Mol. Sci. 2024, 25, 10021. https://doi.org/10.3390/ijms251810021. [Google Scholar] [CrossRef] [PubMed]
Incretinis Drugs | Subjects | Changes in Gut Microbiota | References |
---|---|---|---|
DPP4 inhibitors | mice | Increased abundance of phyla Firmicutes and Bacteroidetes | Liao X et al., 2019 [66] |
DPP4 inhibitors | diabetic rats | Increased Firmicutes and Tenericutes and as decreased Bacteroidetes | Zhang Q. et al., 2017 [63] |
DPP4 inhibitors | type 2 diabetic high-fat diet-fed rats | High-fat diet increased Firmicutes and Tenericutes and decreased Bacteroidetes, and sitagliptin induced a reversal of the gut microbiota changes and modified a set of bacteria producing SCFA | Yan X. et al., 2016 [62] |
DPP4 inhibitors | Western diet-fed mice | Increased Lactobacilli spp. and propionate production along with decreased Oscillibacter spp. | Olivares M et al., 2018 [65] |
DPP4 inhibitors | obese mice | Increased the abundance of Bacteroidetes and succinate | Silva-Veiga FM ET AL., 2022. [67] |
DPP4 inhibitors | metabolically dysfunctional mice | Decreased Firmicutes/Bacteroidete ratios and increased butyrate-producing bacteria | Ryan PM et al., 2020 [64] |
GLP-1 receptor agonists and DPP4 inhibitors | mice | Liraglutide, but not with saxagliptin, increased ratio of Firmicutes to Bacteroides | Wang L et al., 2016 [68] |
GLP-1 receptor agonists | simple obese and diabetic obese rats | Increased ratio of Firmicutes to Bacteroides | Zhao L et al., 2018 [81] |
GLP-1 receptor agonists | diabetic male rats | Elevated SCFA-producing bacteria (Bacteroides and Lachnospiraceae) and Bifidobacterium | Zhang Q et al., 2018 [77] |
GLP-1 receptor agonists | dysmetabolic mice | Increased frequency of Bacteroidetes to Firmicutes phyla Ratio | Charpentier J et al., 2021 [78] |
GLP-1 receptor agonists | db/db mice | Increased abundance of intestinal Akkermansia muciniphila | Liu Q et al., 2020 [82] |
GLP-1 receptor agonists | obese mice | Increased abundance of intestinal Akkermansia muciniphila | Moreira GV et al., 2018. [79] |
GLP-1 receptor agonists | wild type mice | Increased abundance of intestinal Akkermansia muciniphila | Wang H et al., 2021 [83] |
GLP-1 receptor agonists | diabetic rats | Increased Bacteroides–Firmicutes ratio | Yuan X et al., 2018 [80] |
GLP-1 receptor agonists | obese mice | Varied distribution of phelotypes of Proteobacteria and Verrucomicrobia without modifying proportion of Firmicutes | Madsen MSA et al., 2019 [76] |
GLP-1 receptor agonists | obese mice | Mitigated microbial dysbiosis induced by high-fat diet by impacting diversity of gut microbiota | Duan X et al., 2024 [70] |
GLP-1 receptor agonists | db/db mice | Altered gut microbiota, especially Alloprevotella, Alistpes, Ligilactobacillus and Lactobacillus | Mao T et al., 2024 [72] |
GLP-1 receptor agonists | obese mice | Abundance of gut microbiota changed, decreased Akkermansia, Muribaculaceae, Coriobacteriaceae, Clostridia and increased Romboutsia, Dubosiella, Enterorhabdus | Feng J et al., 2024 [71] |
GLP-1 receptor agonists | diabetic rats | Changed gut microbiota profile, increased Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides | De Paiva IHR et al., 2024 [73] |
GLP-1 receptor agonists | diabetic rats | Decreased abundance of Firmicutes, Actinobacteriota, and Lactobacillus and increased Bacteroides and norank_f_Muribaculaceae content. | Luo Y et al., 2024 [74] |
GLP-1 receptor Agonists | PCOS mice | Modulated alpha and beta diversity of the gut microbiota | Xiong C et al., 2024 [75] |
GLP-1 receptor agonists | humans | Increased genus Akkermansia bacteria | Wang, Z et al., 2018 [93] |
GLP-1 receptor agonists | humans | Increased diversity and richness of gut microbiota, especially Bacteroidetes, Proteobacteria, and Bacilli | Ying X et al., 2023 [91] |
GLP-1 receptor agonists and DPP4 inhibitors | humans | No change in alpha or beta diversity of gut microbiota when they were used as add-on therapies with metformin or sulfonylureas | Smits MM et al., 2021 [94] |
GLP-1 receptor agonists | humans | No change in microbiome biodiversity or community | Rizza S et al., 2023 [95] |
GLP-1 receptor agonists | humans | Change in microbiome composition, with significant reduction in abundance of intestinal flora | Liang L. et al., 2024 [97] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Trapanese, V.; Dagostino, A.; Natale, M.R.; Giofrè, F.; Vatalaro, C.; Melina, M.; Cosentino, F.; Sergi, S.; Imoletti, F.; Spagnuolo, R.; et al. Bidirectional Interactions Between the Gut Microbiota and Incretin-Based Therapies. Life 2025, 15, 843. https://doi.org/10.3390/life15060843
Trapanese V, Dagostino A, Natale MR, Giofrè F, Vatalaro C, Melina M, Cosentino F, Sergi S, Imoletti F, Spagnuolo R, et al. Bidirectional Interactions Between the Gut Microbiota and Incretin-Based Therapies. Life. 2025; 15(6):843. https://doi.org/10.3390/life15060843
Chicago/Turabian StyleTrapanese, Vincenzo, Annamaria Dagostino, Maria Resilde Natale, Federica Giofrè, Clara Vatalaro, Melania Melina, Francesca Cosentino, Silvia Sergi, Felice Imoletti, Rocco Spagnuolo, and et al. 2025. "Bidirectional Interactions Between the Gut Microbiota and Incretin-Based Therapies" Life 15, no. 6: 843. https://doi.org/10.3390/life15060843
APA StyleTrapanese, V., Dagostino, A., Natale, M. R., Giofrè, F., Vatalaro, C., Melina, M., Cosentino, F., Sergi, S., Imoletti, F., Spagnuolo, R., & Arturi, F. (2025). Bidirectional Interactions Between the Gut Microbiota and Incretin-Based Therapies. Life, 15(6), 843. https://doi.org/10.3390/life15060843