mvjrМедицинский вестник Юга РоссииMedical Herald of the South of Russia2219-80752618-7876The Rostov State Medical University10.21886/2219-8075-2022-13-1-24-42mvjr-1463Research ArticleЭНДОКРИНОЛОГИЯENDOCRYNOLOGYАбнормальная кишечная микробиота и нарушение инкретинового эффекта как причины развития сахарного диабета 2 типаAbnormal gut microbiota and impaired incretin effect as a cause of type 2 diabetes mellitushttps://orcid.org/0000-0001-6385-540XДемидоваТ. Ю.DemidovaT. Y.

Демидова Татьяна Юльевна - доктор медицинских наук, профессор, зав. кафедрой эндокринологии лечебного факультета.

Москва

Tatiana Y. Demidova - Dr. Sci. (Med.), Professor, head of department of endocrinology medical faculty.

Moscow Russia

t.y.demidova@gmail.comhttps://orcid.org/0000-0002-3656-0312ЛобановаК. Г.LobanovaK. G.

Лобанова Кристина Геннадьевна - ассистент кафедры эндокринологии лечебного факультета.

Москва

Kristina G. Lobanova - assistant of the department of endocrinology medical faculty.

Moscow

miss.sapog@mail.ruhttps://orcid.org/0000-0002-3684-9992КоротковаТ. Н.KorotkovaT. N.

Короткова Татьяна Николаевна - заведующий лабораторией клинической биохимии, иммунологии и аллергологии.

Москва

Tatiana N. Korotkova - head of the Laboratory of Clinical Biochemistry, Immunology and Allergology.

Moscow

tntisha@mail.ruhttps://orcid.org/0000-0003-2954-395XХарчилаваЛ. Д.KharchilavaL. D.

Харчилава Лия Джаникоевна - клинический ординатор кафедры эндокринологии лечебного факультета.

Москва

Liya D. Kharchilava - clinical resident of department of endocrinology medical faculty.

Moscow

harchilava.lia@yandex.ruРоссийский национальный исследовательский медицинский университет им. Н.И. ПироговаРоссияPirogov Russian National Research Medical UniversityRussian FederationФедеральный исследовательский центр питания и биотехнологииРоссияFederal Research Center of Nutrition and BiotechnologyRussian Federation2022300320221312442Copyright © Демидова Т.Ю., Лобанова К.Г., Короткова Т.Н., Харчилава Л.Д., 20222022Демидова Т.Ю., Лобанова К.Г., Короткова Т.Н., Харчилава Л.Д.Demidova T.Y., Lobanova K.G., Korotkova T.N., Kharchilava L.D.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medicalherald.ru/jour/article/view/1463

В настоящее время установлено, что кишечная микробиота является одним из 11 звеньев патогенеза сахарного диабета 2 типа. Дело в том, что при нарушении состава кишечной микробиоты и изменении концентрации её активных метаболитов нарушаются процессы синтеза и секреции инкретиновых гормонов, нарушается гомеостаз углеводов и жиров в организме, изменяются процессы центральной регуляции аппетита, развивается хроническое воспаление и инсулинорезистентность периферических тканей. В данном обзоре обсуждаются возможные пути нарушения синтеза инкретиновых гормонов и инкретинового эффекта у пациентов с сахарным диабетом 2 типа через призму кишечной микробиоты и её активных метаболитов и рассматриваются возможные пути коррекции измененного состава кишечной микробиоты препаратами инкретинового ряда. Поиск литературы проводился по базам данных Scopus, PubMed, Web of Science.

It has now been established that the intestinal microbiota (CM) is one of the 11 links in the pathogenesis of type 2 diabetes mellitus (DM2). Th e fact is that when the composition of BM is disrupted and the concentration of its active metabolites changes, the processes of synthesis and secretion of incretin hormones are disrupted, the homeostasis of carbohydrates and fats in the body is disrupted, the processes of central regulation of appetite change, chronic infl ammation and insulin resistance of peripheral tissues develop. Th is review discusses possible ways of impairing the synthesis of incretin hormones and the incretin eff ect in patients with T2DM through the prism of BM and its active metabolites, and discusses possible ways of correcting the altered composition of BM with incretin drugs.A systematic literature search was carried out using the Scopus, PubMed, Web of Science databases.

кишечная микробиотаинкретиновый эффектглюкагоноподобный пептид-1глюкозозависимый инсулинотропный пептидсахарный диабет 2 типаобзорgut microbiotaincretin eff ectglucagon-like peptide-1glucose-dependent insulinotropic peptidetype 2 diabetes mellitusreviewИсследование не имело спонсорской поддержкиReferences. Th ursby E, Juge N. Introduction to the human gut microbiota. Biochem J. 2017;474(11):1823-1836. DOI: 10.1042/BCJ20160510.Th ursby E, Juge N. Introduction to the human gut microbiota. Biochem J. 2017;474(11):1823-1836. DOI: 10.1042/BCJ20160510.Gurung M, Li Z, You H, Rodrigues R, Jump DB, et al. Role of gut microbiota in type 2 diabetes pathophysiology. EBioMedicine. 2020;51:102590. DOI: 10.1016/j.ebiom.2019.11.051.Gurung M, Li Z, You H, Rodrigues R, Jump DB, et al. Role of gut microbiota in type 2 diabetes pathophysiology. EBioMedicine. 2020;51:102590. DOI: 10.1016/j.ebiom.2019.11.051Lloyd-Price J, Abu-Ali G, Huttenhower C. Th e healthy human microbiome. Genome Med. 2016;8(1):51. DOI: 10.1186/s13073-016-0307-yLloyd-Price J, Abu-Ali G, Huttenhower C. Th e healthy human microbiome. Genome Med. 2016;8(1):51. DOI: 10.1186/s13073-016-0307-yКожевников А.А., Раскина К.В., Мартынова Е.Ю., Тяхт А.В., Перфильев А.В., и др. Кишечная микробиота: современные представления о видовом составе, функциях и методах исследования. РМЖ. 2017;25(17):1244-1247. eLIBRARY ID: 30397484Kozhevnikov A.A., Raskina K.V., Martynova E.Yu., Tyakht A.V., Perfi liev A.V., et al. Intestinal microbiota: modern concepts of the species composition, functions and diagnostic techniques. RMJ. 2017;25(17):1244-1247. (In Russ.) eLIBRARY ID: 30397484Schmidt TS, Matias Rodrigues JF, von Mering C. Ecological consistency of SSU rRNA-based operational taxonomic units at a global scale. PLoS Comput Biol. 2014;10(4):e1003594. DOI: 10.1371/journal.pcbi.1003594Schmidt TS, Matias Rodrigues JF, von Mering C. Ecological consistency of SSU rRNA-based operational taxonomic units at a global scale. PLoS Comput Biol. 2014;10(4):e1003594. DOI: 10.1371/journal.pcbi.1003594Sternini C, Anselmi L, Rozengurt E. Enteroendocrine cells: a site of ‘taste’ in gastrointestinal chemosensing. Curr Opin Endocrinol Diabetes Obes. 2008;15(1):73-8. DOI: 10.1097/MED.0b013e3282f43a73Sternini C, Anselmi L, Rozengurt E. Enteroendocrine cells: a site of ‘taste’ in gastrointestinal chemosensing. Curr Opin Endocrinol Diabetes Obes. 2008;15(1):73-8. DOI: 10.1097/MED.0b013e3282f43a73Müller TD, Finan B, Bloom SR, D’Alessio D, Drucker DJ, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130. DOI: 10.1016/j.molmet.2019.09.010Müller TD, Finan B, Bloom SR, D’Alessio D, Drucker DJ, et al. Glucagonlike peptide 1 (GLP-1). Mol Metab. 2019;30:72-130. DOI: 10.1016/j.molmet.2019.09.010D’Alessio D. Is GLP-1 a hormone: Whether and When? J Diabetes Investig. 2016;7 Suppl 1(Suppl 1):50-5. DOI: 10.1111/jdi.12466D’Alessio D. Is GLP-1 a hormone: Whether and When? J Diabetes Investig. 2016;7 Suppl 1(Suppl 1):50-5. DOI: 10.1111/jdi.12466Holst JJ. Th e incretin system in healthy humans: Th e role of GIP and GLP-1. Metabolism. 2019;96:46-55. DOI: 10.1016/j.metabol.2019.04.014.Holst JJ. Th e incretin system in healthy humans: Th e role of GIP and GLP-1. Metabolism. 2019;96:46-55. DOI: 10.1016/j.metabol.2019.04.014Howick K, Griffi n BT, Cryan JF, Schellekens H. From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation. Int J Mol Sci. 2017;18(2):273. DOI: 10.3390/ijms18020273Howick K, Griffi n BT, Cryan JF, Schellekens H. From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation. Int J Mol Sci. 2017;18(2):273. DOI: 10.3390/ijms18020273Тихоненко Е.В., Цой У.А., Васильева Е.Ю., Бабенко А.Ю. Характеристики пищевого поведения и уровень гормонов, регулирующих аппетит, у пациентов с сахарным диабетом 2 типа и индексом массы тела выше 35 кг/м2. Ожирение и метаболизм. 2018;15(1):30-38. DOI: 10.14341/omet2018130-38Тихоненко Е.В., Цой У.А., Васильева Е.Ю., Бабенко А.Ю. Характеристики пищевого поведения и уровень гормонов, регулирующих аппетит, у пациентов с сахарным диабетом 2 типа и индексом массы тела выше 35 кг/м2. Ожирение и метаболизм. 2018;15(1):30-38. DOI: 10.14341/omet2018130-38Цыганкова О.В., Веретюк В.В., Аметов А.С. Инкретины сегодня: множественные эффекты и терапевтический потенциал. Сахарный диабет. 2019;22(1):70-78. DOI: 10.14341/DM9841Tsygankova O.V., Veretyuk V.V., Ametov A.S. Incretins today: multiple eff ects and therapeutic potential. Diabetes mellitus. 2019;22(1):70-78. (In Russ.) DOI: 10.14341/DM9841Демидова Т.Ю., Лобанова К.Г., Ойноткинова О.Ш. Кишечная микробиота как эндокринный орган. Ожирение и метаболизм. 2020;17(3):299-306. DOI: 10.14341/omet12457Demidova T.Y., Lobanova K.G., Oynotkinova O.S. Gut microbiota is an endocrine organ. Obesity and metabolism. 2020;17(3):299306. (In Russ.) DOI: 10.14341/omet12457Rehfeld JF. Th e Origin and Understanding of the Incretin Concept. Front Endocrinol (Lausanne). 2018;9:387. DOI: 10.3389/fendo.2018.00387Rehfeld JF. Th e Origin and Understanding of the Incretin Concept. Front Endocrinol (Lausanne). 2018;9:387. DOI: 10.3389/fendo.2018.00387Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, et al. Incretin eff ects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63(2):492-8. DOI: 10.1210/jcem-63-2-492Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, et al. Incretin eff ects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63(2):492-8. DOI: 10.1210/jcem-63-2-492Nauck MA, Quast DR, Wefers J, Pfeiff er AFH. Th e evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes Obes Metab. 2021;23 Suppl 3:5-29. DOI: 10.1111/dom.14496Nauck MA, Quast DR, Wefers J, Pfeiff er AFH. Th e evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes Obes Metab. 2021;23 Suppl 3:5-29. DOI: 10.1111/dom.14496Smith NK, Hackett TA, Galli A, Flynn CR. GLP-1: Molecular mechanisms and outcomes of a complex signaling system. Neurochem Int. 2019;128:94-105. DOI: 10.1016/j.neuint.2019.04.010Smith NK, Hackett TA, Galli A, Flynn CR. GLP-1: Molecular mechanisms and outcomes of a complex signaling system. Neurochem Int. 2019;128:94-105. DOI: 10.1016/j.neuint.2019.04.010Pala L, Ciani S, Dicembrini I, Bardini G, Cresci B, et al. Relationship between GLP-1 levels and dipeptidyl peptidase-4 activity in diff erent glucose tolerance conditions. Diabet Med. 2010;27(6):691-5. DOI: 10.1111/j.1464-5491.2010.03010.xPala L, Ciani S, Dicembrini I, Bardini G, Cresci B, et al. Relationship between GLP-1 levels and dipeptidyl peptidase-4 activity in diff erent glucose tolerance conditions. Diabet Med. 2010;27(6):691-5. DOI: 10.1111/j.1464-5491.2010.03010.xRask E, Olsson T, Söderberg S, Holst Jj Jj, Tura A, et al. Insulin secretion and incretin hormones aft er oral glucose in nonobese subjects with impaired glucose tolerance. Metabolism. 2004;53(5):624-31. DOI: 10.1016/j.metabol.2003.11.011Rask E, Olsson T, Söderberg S, Holst Jj Jj, Tura A, et al. Insulin secretion and incretin hormones aft er oral glucose in nonobese subjects with impaired glucose tolerance. Metabolism. 2004;53(5):624-31. DOI: 10.1016/j.metabol.2003.11.011Kimura I, Ichimura A, Ohue-Kitano R, Igarashi M. Free Fatty Acid Receptors in Health and Disease. Physiol Rev. 2020;100(1):171-210. DOI: 10.1152/physrev.00041.2018Kimura I, Ichimura A, Ohue-Kitano R, Igarashi M. Free Fatty Acid Receptors in Health and Disease. Physiol Rev. 2020;100(1):171210. DOI: 10.1152/physrev.00041.2018Röder PV, Geillinger KE, Zietek TS, Th orens B, Koepsell H, Daniel H. Th e role of SGLT1 and GLUT2 in intestinal glucose transport and sensing. PLoS One. 2014;9(2):e89977. DOI: 10.1371/journal.pone.0089977Röder PV, Geillinger KE, Zietek TS, Th orens B, Koepsell H, Daniel H. Th e role of SGLT1 and GLUT2 in intestinal glucose transport and sensing. PLoS One. 2014;9(2):e89977. DOI: 10.1371/journal.pone.0089977Tazoe H, Otomo Y, Karaki S, Kato I, Fukami Y, et al. Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed Res. 2009;30(3):149-56. DOI: 10.2220biomedres.30.149Tazoe H, Otomo Y, Karaki S, Kato I, Fukami Y, et al. Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed Res. 2009;30(3):149-56. DOI: 10.2220biomedres.30.149Herrmann C, Göke R, Richter G, Fehmann HC, Arnold R, Göke B. Glucagon-like peptide-1 and glucose-dependent insulinreleasing polypeptide plasma levels in response to nutrients. Digestion. 1995;56(2):117-26. DOI: 10.1159/000201231Herrmann C, Göke R, Richter G, Fehmann HC, Arnold R, Göke B. Glucagonlike peptide-1 and glucose-dependent insulinreleasing polypeptide plasma levels in response to nutrients. Digestion. 1995;56(2):117-26. DOI: 10.1159/000201231Ramracheya R, Chapman C, Chibalina M, Dou H, Miranda C, et al. GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca2+ channels. Physiol Rep. 2018;6(17):e13852. DOI: 10.14814/phy2.13852Ramracheya R, Chapman C, Chibalina M, Dou H, Miranda C, et al. GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca2+ channels. Physiol Rep. 2018;6(17):e13852. DOI: 10.14814/phy2.13852El K, Gray SM, Capozzi ME, Knuth ER, Jin E, et al. GIP mediates the incretin eff ect and glucose tolerance by dual actions on α cells and β cells. Sci Adv. 2021;7(11):eabf1948. DOI: 10.1126/sciadv.abf1948El K, Gray SM, Capozzi ME, Knuth ER, Jin E, et al. GIP mediates the incretin eff ect and glucose tolerance by dual actions on α cells and β cells. Sci Adv. 2021;7(11):eabf1948. DOI: 10.1126/sciadv.abf1948Reed J, Bain S, Kanamarlapudi V. Recent advances in understanding the role of glucagon-like peptide 1. F1000Res. 2020;9:F1000 Faculty Rev-239. DOI: 10.12688/f1000research.20602.1Reed J, Bain S, Kanamarlapudi V. Recent advances in understanding the role of glucagon-like peptide 1. F1000Res. 2020;9:F1000 Faculty Rev-239. DOI: 10.12688/f1000research.20602.1de Heer J, Rasmussen C, Coy DH, Holst JJ. Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas. Diabetologia. 2008;51(12):2263-70. DOI: 10.1007/s00125-008-1149-yde Heer J, Rasmussen C, Coy DH, Holst JJ. Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas. Diabetologia. 2008;51(12):2263-70. DOI: 10.1007/s00125-008-1149-yAhrén B, Carr RD, Deacon CF. Incretin hormone secretion over the day. Vitam Horm. 2010;84:203-20. DOI: 10.1016/B978-0-12-381517-0.00007-2Ahrén B, Carr RD, Deacon CF. Incretin hormone secretion over the day. Vitam Horm. 2010;84:203-20. DOI: 10.1016/B978-0-12-381517-0.00007-2Tura A, Bagger JI, Ferrannini E, Holst JJ, Knop FK, et al. Impaired beta cell sensitivity to incretins in type 2 diabetes is insuffi ciently compensated by higher incretin response. Nutr Metab Cardiovasc Dis. 2017;27(12):1123-1129. DOI: 10.1016/j.numecd.2017.10.006Tura A, Bagger JI, Ferrannini E, Holst JJ, Knop FK, et al. Impaired beta cell sensitivity to incretins in type 2 diabetes is insuffi ciently compensated by higher incretin response. Nutr Metab Cardiovasc Dis. 2017;27(12):1123-1129. DOI: 10.1016/j.numecd.2017.10.006Tura A, Muscelli E, Gastaldelli A, Ferrannini E, Mari A. Altered pattern of the incretin eff ect as assessed by modelling in individuals with glucose tolerance ranging from normal to diabetic. Diabetologia. 2014;57(6):1199-203. DOI: 10.1007/s00125-014-3219-7Tura A, Muscelli E, Gastaldelli A, Ferrannini E, Mari A. Altered pattern of the incretin eff ect as assessed by modelling in individuals with glucose tolerance ranging from normal to diabetic. Diabetologia. 2014;57(6):1199-203. DOI: 10.1007/s00125-014-3219-7Knop FK, Vilsbøll T, Madsbad S, Holst JJ, Krarup T. Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin eff ect in type 2 diabetes mellitus. Diabetologia. 2007;50(4):797-805. doi: 10.1007/s00125-006-0566-zKnop FK, Vilsbøll T, Madsbad S, Holst JJ, Krarup T. Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin eff ect in type 2 diabetes mellitus. Diabetologia. 2007;50(4):797-805. doi: 10.1007/s00125-006-0566-zKozawa J, Okita K, Imagawa A, Iwahashi H, Holst JJ, et al. Similar incretin secretion in obese and non-obese Japanese subjects with type 2 diabetes. Biochem Biophys Res Commun. 2010;393(3):410-3. DOI: 10.1016/j.bbrc.2010.01.134Kozawa J, Okita K, Imagawa A, Iwahashi H, Holst JJ, et al. Similar incretin secretion in obese and non-obese Japanese subjects with type 2 diabetes. Biochem Biophys Res Commun. 2010;393(3):4103. DOI: 10.1016/j.bbrc.2010.01.134Laakso M, Zilinskaite J, Hansen T, Boesgaard TW, Vänttinen M, et al. Insulin sensitivity, insulin release and glucagonlike peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study. Diabetologia. 2008;51(3):502-11. DOI: 10.1007/s00125-007-0899-2Laakso M, Zilinskaite J, Hansen T, Boesgaard TW, Vänttinen M, et al. Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study. Diabetologia. 2008;51(3):502-11. DOI: 10.1007/s00125-007-0899-2Oh TJ, Kim MY, Shin JY, Lee JC, Kim S, et al. Th e incretin eff ect in Korean subjects with normal glucose tolerance or type 2 diabetes. Clin Endocrinol (Oxf). 2014;80(2):221-7. DOI: 10.1111/cen.12167Oh TJ, Kim MY, Shin JY, Lee JC, Kim S, et al. Th e incretin eff ect in Korean subjects with normal glucose tolerance or type 2 diabetes. Clin Endocrinol (Oxf). 2014;80(2):221-7. DOI: 10.1111/cen.12167Yabe D, Kuroe A, Watanabe K, Iwasaki M, Hamasaki A, et al. Early phase glucagon and insulin secretory abnormalities, but not incretin secretion, are similarly responsible for hyperglycemia aft er ingestion of nutrients. J Diabetes Complications. 2015;29(3):413-21. DOI: 10.1016/j.jdiacomp.2014.12.010Yabe D, Kuroe A, Watanabe K, Iwasaki M, Hamasaki A, et al. Early phase glucagon and insulin secretory abnormalities, but not incretin secretion, are similarly responsible for hyperglycemia aft er ingestion of nutrients. J Diabetes Complications. 2015;29(3):413-21. DOI: 10.1016/j.jdiacomp.2014.12.010Th eodorakis MJ, Carlson O, Muller DC, Egan JM. Elevated plasma glucose-dependent insulinotropic polypeptide associates with hyperinsulinemia in impaired glucose tolerance. Diabetes Care. 2004;27(7):1692-8. DOI: 10.2337/diacare.27.7.1692Th eodorakis MJ, Carlson O, Muller DC, Egan JM. Elevated plasma glucose-dependent insulinotropic polypeptide associates with hyperinsulinemia in impaired glucose tolerance. Diabetes Care. 2004;27(7):1692-8. DOI: 10.2337/diacare.27.7.1692Faerch K, Vaag A, Holst JJ, Glümer C, Pedersen O, BorchJohnsen K. Impaired fasting glycaemia vs impaired glucose tolerance: similar impairment of pancreatic alpha and beta cell function but diff erential roles of incretin hormones and insulin action. Diabetologia. 2008;51(5):853-61. DOI: 10.1007/s00125-008-0951-xFaerch K, Vaag A, Holst JJ, Glümer C, Pedersen O, BorchJohnsen K. Impaired fasting glycaemia vs impaired glucose tolerance: similar impairment of pancreatic alpha and beta cell function but diff erential roles of incretin hormones and insulin action. Diabetologia. 2008;51(5):853-61. DOI: 10.1007/s00125-008-0951-xLouis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol. 2017;19(1):2941. DOI: 10.1111/1462-2920.13589Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol. 2017;19(1):29-41. DOI: 10.1111/1462-2920.13589Parada Venegas D, De la Fuente MK, Landskron G, González MJ, Quera R, et al. Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Infl ammatory Bowel Diseases. Front Immunol. 2019;10:277. DOI: 10.3389/fimmu.2019.00277. Erratum in: Front Immunol. 2019;10:1486.Parada Venegas D, De la Fuente MK, Landskron G, González MJ, Quera R, et al. Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Infl ammatory Bowel Diseases. Front Immunol. 2019;10:277. DOI: 10.3389/fimmu.2019.00277. Erratum in: Front Immunol. 2019;10:1486Reichardt N, Duncan SH, Young P, Belenguer A, McWilliam Leitch C, et al. Phylogenetic distribution of three pathways for propionate production within the human gut microbiota. ISME J. 2014;8(6):1323-35. DOI: 10.1038/ismej.2014.14. Erratum in: ISME J. 2014;8(6):1352.Reichardt N, Duncan SH, Young P, Belenguer A, McWilliam Leitch C, et al. Phylogenetic distribution of three pathways for propionate production within the human gut microbiota. ISME J. 2014;8(6):1323-35. DOI: 10.1038/ismej.2014.14. Erratum in: ISME J. 2014;8(6):1352.Bilotta AJ, Cong Y. Gut microbiota metabolite regulation of host defenses at mucosal surfaces: implication in precision medicine. Precis Clin Med. 2019;2(2):110-119. DOI: 10.1093/pcmedi/pbz008Bilotta AJ, Cong Y. Gut microbiota metabolite regulation of host defenses at mucosal surfaces: implication in precision medicine. Precis Clin Med. 2019;2(2):110-119. DOI: 10.1093/pcmedi/pbz008Mishra SP, Karunakar P, Taraphder S, Yadav H. Free Fatty Acid Receptors 2 and 3 as Microbial Metabolite Sensors to Shape Host Health: Pharmacophysiological View. Biomedicines. 2020;8(6):154. DOI: 10.3390/biomedicines8060154Mishra SP, Karunakar P, Taraphder S, Yadav H. Free Fatty Acid Receptors 2 and 3 as Microbial Metabolite Sensors to Shape Host Health: Pharmacophysiological View. Biomedicines. 2020;8(6):154. DOI: 10.3390/biomedicines8060154Psichas A, Sleeth ML, Murphy KG, Brooks L, Bewick GA, et al. Th e short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int J Obes (Lond). 2015;39(3):424-9. DOI: 10.1038/ijo.2014.153Psichas A, Sleeth ML, Murphy KG, Brooks L, Bewick GA, et al. Th e short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int J Obes (Lond). 2015;39(3):424-9. DOI: 10.1038/ijo.2014.153Lee EY, Zhang X, Miyamoto J, Kimura I, Taknaka T, et al. Gut carbohydrate inhibits GIP secretion via a microbiota/SCFA/ FFAR3 pathway. J Endocrinol. 2018;239(3):267-276. DOI: 10.1530/JOE-18-0241Lee EY, Zhang X, Miyamoto J, Kimura I, Taknaka T, et al. Gut carbohydrate inhibits GIP secretion via a microbiota/SCFA/ FFAR3 pathway. J Endocrinol. 2018;239(3):267-276. DOI: 10.1530/JOE-18-0241Christiansen CB, Gabe MBN, Svendsen B, Dragsted LO, Rosenkilde MM, Holst JJ. Th e impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon. Am J Physiol Gastrointest Liver Physiol. 2018;315(1):G53-G65. DOI: 10.1152/ajpgi.00346.2017Christiansen CB, Gabe MBN, Svendsen B, Dragsted LO, Rosenkilde MM, Holst JJ. Th e impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon. Am J Physiol Gastrointest Liver Physiol. 2018;315(1):G53-G65. DOI: 10.1152/ajpgi.00346.2017Gérard C, Vidal H. Impact of Gut Microbiota on Host Glycemic Control. Front Endocrinol (Lausanne). 2019;10:29. DOI: 10.3389/fendo.2019.00029Gérard C, Vidal H. Impact of Gut Microbiota on Host Glycemic Control. Front Endocrinol (Lausanne). 2019;10:29. DOI: 10.3389/fendo.2019.00029Tolhurst G, Heff ron H, Lam YS, Parker HE, Habib AM, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes. 2012;61(2):364-71. DOI: 10.2337/db11-1019Tolhurst G, Heff ron H, Lam YS, Parker HE, Habib AM, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes. 2012;61(2):364-71. DOI: 10.2337/db11-1019Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes. 2009;58(7):1509-17. DOI: 10.2337/db08-1637Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes. 2009;58(7):1509-17. DOI: 10.2337/db08-1637Blachier F, Andriamihaja M, Larraufi e P, Ahn E, Lan A, Kim E. Production of hydrogen sulfi de by the intestinal microbiota and epithelial cells and consequences for the colonic and rectal mucosa. Am J Physiol Gastrointest Liver Physiol. 2021;320(2):G125-G135. DOI: 10.1152/ajpgi.00261.2020. Erratum in: Am J Physiol Gastrointest Liver Physiol. 2021;320(4):G484.Blachier F, Andriamihaja M, Larraufi e P, Ahn E, Lan A, Kim E. Production of hydrogen sulfi de by the intestinal microbiota and epithelial cells and consequences for the colonic and rectal mucosa. Am J Physiol Gastrointest Liver Physiol. 2021;320(2):G125-G135. DOI: 10.1152/ajpgi.00261.2020. Erratum in: Am J Physiol Gastrointest Liver Physiol. 2021;320(4):G484.Xiao A, Liu C, Li J. The Role of H2S in the Gastrointestinal Tract and Microbiota. Adv Exp Med Biol. 2021;1315:67-98.: 10.1007/978-981-16-0991-6_4Xiao A, Liu C, Li J. Th e Role of H2S in the Gastrointestinal Tract and Microbiota. Adv Exp Med Biol. 2021;1315:67-98. DOI: 10.1007/978-981-16-0991-6_4Verbeure W, van Goor H, Mori H, van Beek AP, Tack J, van Dijk PR. Th e Role of Gasotransmitters in Gut Peptide Actions. Front Pharmacol. 2021;12:720703. DOI: 10.3389/fphar.2021.720703Verbeure W, van Goor H, Mori H, van Beek AP, Tack J, van Dijk PR. The Role of Gasotransmitters in Gut Peptide Actions. Front Pharmacol. 2021;12:720703. DOI: 10.3389/fphar.2021.720703Pichette J, Fynn-Sackey N, Gagnon J. Hydrogen Sulfi de and Sulfate Prebiotic Stimulates the Secretion of GLP1 and Improves Glycemia in Male Mice. Endocrinology. 2017;158(10):3416-3425. DOI: 10.1210/en.2017-00391Pichette J, Fynn-Sackey N, Gagnon J. Hydrogen Sulfi de and Sulfate Prebiotic Stimulates the Secretion of GLP-1 and Improves Glycemia in Male Mice. Endocrinology. 2017;158(10):3416-3425. DOI: 10.1210/en.2017-00391Zhang LS, Davies SS. Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions. Genome Med. 2016;8(1):46. DOI: 10.1186/s13073-016-0296-xZhang LS, Davies SS. Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions. Genome Med. 2016;8(1):46. DOI: 10.1186/s13073-016-0296-xChimerel C, Emery E, Summers DK, Keyser U, Gribble FM, Reimann F. Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep. 2014;9(4):1202-8. DOI: 10.1016/j.celrep.2014.10.032Chimerel C, Emery E, Summers DK, Keyser U, Gribble FM, Reimann F. Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep. 2014;9(4):1202-8. DOI: 10.1016/j.celrep.2014.10.032Winston JA, Th eriot CM. Diversifi cation of host bile acids by members of the gut microbiota. Gut Microbes. 2020;11(2):158171. DOI: 10.1080/19490976.2019.1674124Winston JA, Th eriot CM. Diversifi cation of host bile acids by members of the gut microbiota. Gut Microbes. 2020;11(2):158171. DOI: 10.1080/19490976.2019.1674124Xie C, Huang W, Young RL, Jones KL, Horowitz M, et al. Role of Bile Acids in the Regulation of Food Intake, and Th eir Dysregulation in Metabolic Disease. Nutrients. 2021;13(4):1104. DOI: 10.3390/nu13041104Xie C, Huang W, Young RL, Jones KL, Horowitz M, et al. Role of Bile Acids in the Regulation of Food Intake, and Th eir Dysregulation in Metabolic Disease. Nutrients. 2021;13(4):1104. DOI: 10.3390/nu13041104Ma Q, Li Y, Li P, Wang M, Wang J, et al. Research progress in the relationship between type 2 diabetes mellitus and intestinal fl ora. Biomed Pharmacother. 2019;117:109138. DOI: 10.1016/j.biopha.2019.109138Ma Q, Li Y, Li P, Wang M, Wang J, et al. Research progress in the relationship between type 2 diabetes mellitus and intestinal fl ora. Biomed Pharmacother. 2019;117:109138. DOI: 10.1016/j.biopha.2019.109138Kaska L, Sledzinski T, Chomiczewska A, Dettlaff -Pokora A, Swierczynski J. Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome. World J Gastroenterol. 2016;22(39):8698-8719. DOI: 10.3748/wjg.v22.i39.8698Kaska L, Sledzinski T, Chomiczewska A, Dettlaff-Pokora A, Swierczynski J. Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome. World J Gastroenterol. 2016;22(39):8698-8719. DOI: 10.3748/wjg.v22.i39.8698Parker HE, Wallis K, le Roux CW, Wong KY, Reimann F, Gribble FM. Molecular mechanisms underlying bile acidstimulated glucagon-like peptide-1 secretion. Br J Pharmacol. 2012;165(2):414-23. DOI: 10.1111/j.1476-5381.2011.01561.xParker HE, Wallis K, le Roux CW, Wong KY, Reimann F, Gribble FM. Molecular mechanisms underlying bile acidstimulated glucagon-like peptide-1 secretion. Br J Pharmacol. 2012;165(2):414-23. DOI: 10.1111/j.1476-5381.2011.01561.xLi P, Zhu L, Yang X, Li W, Sun X, et al. Farnesoid X receptor interacts with cAMP response element binding protein to modulate glucagon-like peptide-1 (7-36) amide secretion by intestinal L cell. J Cell Physiol. 2019;234(8):12839-12846. DOI: 10.1002/jcp.27940Li P, Zhu L, Yang X, Li W, Sun X, et al. Farnesoid X receptor interacts with cAMP response element binding protein to modulate glucagon-like peptide-1 (7-36) amide secretion by intestinal L cell. J Cell Physiol. 2019;234(8):12839-12846. DOI: 10.1002/jcp.27940Trabelsi MS, Daoudi M, Prawitt J, Ducastel S, Touche V, et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat Commun. 2015;6:7629. DOI: 10.1038/ncomms8629Trabelsi MS, Daoudi M, Prawitt J, Ducastel S, Touche V, et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat Commun. 2015;6:7629. DOI: 10.1038/ncomms8629Cunningham AL, Stephens JW, Harris DA. Gut microbiota infl uence in type 2 diabetes mellitus (T2DM). Gut Pathog. 2021;13(1):50. DOI: 10.1186/s13099-021-00446-0Cunningham AL, Stephens JW, Harris DA. Gut microbiota infl uence in type 2 diabetes mellitus (T2DM). Gut Pathog. 2021;13(1):50. DOI: 10.1186/s13099-021-00446-0Sedighi M, Razavi S, Navab-Moghadam F, Khamseh ME, Alaei-Shahmiri F, et al. Comparison of gut microbiota in adult patients with type 2 diabetes and healthy individuals. Microb Pathog. 2017;111:362-369. DOI: 10.1016/j.micpath.2017.08.038Sedighi M, Razavi S, Navab-Moghadam F, Khamseh ME, AlaeiShahmiri F, et al. Comparison of gut microbiota in adult patients with type 2 diabetes and healthy individuals. Microb Pathog. 2017;111:362-369. DOI: 10.1016/j.micpath.2017.08.038Zhao L, Lou H, Peng Y, Chen S, Zhang Y, Li X. Comprehensive relationships between gut microbiome and faecal metabolome in individuals with type 2 diabetes and its complications. Endocrine. 2019;66(3):526-537. DOI: 10.1007/s12020-019-02103-8Zhao L, Lou H, Peng Y, Chen S, Zhang Y, Li X. Comprehensive relationships between gut microbiome and faecal metabolome in individuals with type 2 diabetes and its complications. Endocrine. 2019;66(3):526-537. DOI: 10.1007/s12020-019-02103-8Pascale A, Marchesi N, Govoni S, Coppola A, Gazzaruso C. Th e role of gut microbiota in obesity, diabetes mellitus, and eff ect of metformin: new insights into old diseases. Curr Opin Pharmacol. 2019;49:1-5. DOI: 10.1016/j.coph.2019.03.011Pascale A, Marchesi N, Govoni S, Coppola A, Gazzaruso C. Th e role of gut microbiota in obesity, diabetes mellitus, and eff ect of metformin: new insights into old diseases. Curr Opin Pharmacol. 2019;49:1-5. DOI: 10.1016/j.coph.2019.03.011Gu Y, Wang X, Li J, Zhang Y, Zhong H, et al. Analyses of gut microbiota and plasma bile acids enable stratifi cation of patients for antidiabetic treatment. Nat Commun. 2017;8(1):1785. DOI: 10.1038/s41467-017-01682-2Gu Y, Wang X, Li J, Zhang Y, Zhong H, et al. Analyses of gut microbiota and plasma bile acids enable stratifi cation of patients for antidiabetic treatment. Nat Commun. 2017;8(1):1785. DOI: 10.1038/s41467-017-01682-2Olivares M, Neyrinck AM, Pötgens SA, Beaumont M, Salazar N, et al. Th e DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice. Diabetologia. 2018;61(8):1838-1848. DOI: 10.1007/s00125-018-4647-6Olivares M, Neyrinck AM, Pötgens SA, Beaumont M, Salazar N, et al. Th e DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice. Diabetologia. 2018;61(8):1838-1848. DOI: 10.1007/s00125-018-4647-6Zhang M, Feng R, Yang M, Qian C, Wang Z, et al. Eff ects of metformin, acarbose, and sitagliptin monotherapy on gut microbiota in Zucker diabetic fatty rats. BMJ Open Diabetes Res Care. 2019;7(1):e000717. DOI: 10.1136/bmjdrc-2019-000717Zhang M, Feng R, Yang M, Qian C, Wang Z, et al. Eff ects of metformin, acarbose, and sitagliptin monotherapy on gut microbiota in Zucker diabetic fatty rats. BMJ Open Diabetes Res Care. 2019;7(1):e000717. DOI: 10.1136/bmjdrc-2019-000717Zhang Q, Xiao X, Li M, Yu M, Ping F, et al. Vildagliptin increases butyrate-producing bacteria in the gut of diabetic rats. PLoS One. 2017;12(10):e0184735. DOI: 10.1371/journal.pone.0184735Zhang Q, Xiao X, Li M, Yu M, Ping F, et al. Vildagliptin increases butyrate-producing bacteria in the gut of diabetic rats. PLoS One. 2017;12(10):e0184735. DOI: 10.1371/journal.pone.0184735Yan X, Feng B, Li P, Tang Z, Wang L. Microfl ora Disturbance during Progression of Glucose Intolerance and Eff ect of Sitagliptin: An Animal Study. J Diabetes Res. 2016;2016:2093171. DOI: 10.1155/2016/2093171Yan X, Feng B, Li P, Tang Z, Wang L. Microfl ora Disturbance during Progression of Glucose Intolerance and Eff ect of Sitagliptin: An Animal Study. J Diabetes Res. 2016;2016:2093171. DOI: 10.1155/2016/2093171Ryan PM, Patterson E, Carafa I, Mandal R, Wishart DS, et al. Metformin and Dipeptidyl Peptidase-4 Inhibitor Diff erentially Modulate the Intestinal Microbiota and Plasma Metabolome of Metabolically Dysfunctional Mice. Can J Diabetes. 2020;44(2):146-155.e2. DOI: 10.1016/j.jcjd.2019.05.008Ryan PM, Patterson E, Carafa I, Mandal R, Wishart DS, et al. Metformin and Dipeptidyl Peptidase-4 Inhibitor Diff erentially Modulate the Intestinal Microbiota and Plasma Metabolome of Metabolically Dysfunctional Mice. Can J Diabetes. 2020;44(2):146-155.e2. DOI: 10.1016/j.jcjd.2019.05.008Zhao L, Chen Y, Xia F, Abudukerimu B, Zhang W, et al. A Glucagon-Like Peptide-1 Receptor Agonist Lowers Weight by Modulating the Structure of Gut Microbiota. Front Endocrinol (Lausanne). 2018;9:233. DOI: 10.3389/fendo.2018.00233Zhao L, Chen Y, Xia F, Abudukerimu B, Zhang W, et al. A Glucagon-Like Peptide-1 Receptor Agonist Lowers Weight by Modulating the Structure of Gut Microbiota. Front Endocrinol (Lausanne). 2018;9:233. DOI: 10.3389/fendo.2018.00233Zhang Q, Xiao X, Zheng J, Li M, Yu M, et al. Featured article: Structure moderation of gut microbiota in liraglutide-treated diabetic male rats. Exp Biol Med (Maywood). 2018;243(1):3444. DOI: 10.1177/1535370217743765Zhang Q, Xiao X, Zheng J, Li M, Yu M, et al. Featured article: Structure moderation of gut microbiota in liraglutide-treated diabetic male rats. Exp Biol Med (Maywood). 2018;243(1):34-44. DOI: 10.1177/1535370217743765Liu Q, Cai BY, Zhu LX, Xin X, Wang X, et al. Liraglutide modulates gut microbiome and attenuates nonalcoholic fatty liver in db/db mice. Life Sci. 2020;261:118457. DOI: 10.1016/j.lfs.2020.118457Liu Q, Cai BY, Zhu LX, Xin X, Wang X, et al. Liraglutide modulates gut microbiome and attenuates nonalcoholic fatty liver in db/db mice. Life Sci. 2020;261:118457. DOI: 10.1016/j.lfs.2020.118457Moreira GV, Azevedo FF, Ribeiro LM, Santos A, Guadagnini D, et al. Liraglutide modulates gut microbiota and reduces NAFLD in obese mice. J Nutr Biochem. 2018;62:143-154. DOI: 10.1016/j.jnutbio.2018.07.009Moreira GV, Azevedo FF, Ribeiro LM, Santos A, Guadagnini D, et al. Liraglutide modulates gut microbiota and reduces NAFLD in obese mice. J Nutr Biochem. 2018;62:143-154. DOI: 10.1016/j.jnutbio.2018.07.009Wang 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. DOI: 10.1038/srep33251Wang 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. DOI: 10.1038/srep33251Mrozinska S., Gosiewski T., Sroka-Oleksiak A., Szopa M, Bulanda M., et al. Th e eff ect of linagliptin treatment on gut microbiota in patients with HNF1A-MODY or type 2 diabetes — a preliminary cohort study. Clinical Diabetology. 2019;8(6):263-270. DOI: 10.5603/DK.2019.0024Mrozinska S., Gosiewski T., Sroka-Oleksiak A., Szopa M, Bulanda M., et al. Th e eff ect of linagliptin treatment on gut microbiota in patients with HNF1A-MODY or type 2 diabetes — a preliminary cohort study. Clinical Diabetology. 2019;8(6):263-270. DOI: 10.5603/DK.2019.0024Wang Z, Saha S, Van Horn S, Th omas E, Traini C, Sathe G, et al. Gut microbiome diff erences between metformin- and liraglutide-treated T2DM subjects. Endocrinol Diabetes Metab. 2017;1(1):e00009. DOI: 10.1002/edm2.9Wang Z, Saha S, Van Horn S, Th omas E, Traini C, Sathe G, et al. Gut microbiome diff erences between metformin- and liraglutide-treated T2DM subjects. Endocrinol Diabetes Metab. 2017;1(1):e00009. DOI: 10.1002/edm2.9Shang J, Liu F, Zhang B, Dong K, Lu M, et al. Liraglutideinduced structural modulation of the gut microbiota in patients with type 2 diabetes mellitus. PeerJ. 2021;9:e11128. DOI: 10.7717/peerj.11128Shang J, Liu F, Zhang B, Dong K, Lu M, et al. Liraglutide-induced structural modulation of the gut microbiota in patients with type 2 diabetes mellitus. PeerJ. 2021;9:e11128. DOI: 10.7717/peerj.11128Smits MM, Fluitman KS, Herrema H, Davids M, Kramer MHH, et al. Liraglutide and sitagliptin have no eff ect on intestinal microbiota composition: A 12-week randomized placebocontrolled trial in adults with type 2 diabetes. Diabetes Metab. 2021;47(5):101223. DOI: 10.1016/j.diabet.2021.101223Smits MM, Fluitman KS, Herrema H, Davids M, Kramer MHH, et al. Liraglutide and sitagliptin have no eff ect on intestinal microbiota composition: A 12-week randomized placebocontrolled trial in adults with type 2 diabetes. Diabetes Metab. 2021;47(5):101223. DOI: 10.1016/j.diabet.2021.101223Allin KH, Nielsen T, Pedersen O. Mechanisms in endocrinology: Gut microbiota in patients with type 2 diabetes mellitus. Eur J Endocrinol. 2015;172(4):R167-77. DOI: 10.1530/EJE-14-0874Allin KH, Nielsen T, Pedersen O. Mechanisms in endocrinology: Gut microbiota in patients with type 2 diabetes mellitus. Eur J Endocrinol. 2015;172(4):R167-77. DOI: 10.1530/EJE-14-0874

The authors declare that there are no conflicts of interest present.