Diabetes Mellitus’ta Mikrobiyotanın Rolü ve Hedeflenmesi
Yıl 2021,
Cilt: 5 Sayı: 1, 51 - 58, 24.04.2021
Zinnet Şevval Aksoyalp
,
Cahit Nacitarhan
Öz
İnsanlarda çoğu kalın bağırsakta olmak üzere 100 trilyonun üzerinde mikrobiyal hücre bulunmaktadır ve bu organizmaların tamamı bağırsak mikrobiyotası olarak adlandırılmıştır. Bağırsak mikrobiyotası gastrointestinal mukoza geçirgenliğinde, bağırsak hormonlarının salımında ve polisakkaritlerin fermantasyonu ve emiliminde önemli rol oynamaktadır. Buna ek olarak bağırsak mikrobiyotası konak
bağışıklık sisteminde, inflamatuvar süreçlerin düzenlenmesinde ve besinlerden enerji üretilmesinde önemli bir role sahiptir. Sağlıklı bağırsak mikrobiyotasında simbiyotik ve patojen bakteriler denge hâlinde bulunmaktadır. Bu dengenin bozulması hem hayvanlarda hem de insanlarda immünolojik ve metabolik bozukluklar ile ilişkilendirilmiştir.
Diabetes mellitus hiperglisemi ile belirgin kronik bir hastalıktır. Son yirmi yılda diabetes mellitus insidansı tüm dünyada hızlı bir şekilde artmış ve önemli bir halk sağlığı sorunu hâline gelmiştir. Genetik ve çevresel faktörlerin yanında bağırsak mikrobiyotası da diabetes mellitus ile ilişkilendirilmiştir. Birçok çalışmada diyabetik hastaların bağırsak mikrobiyotasında orta derecede disbiyozis olduğu gösterilmiştir. Ancak insanlarda diyabet gelişimi ile bağırsak mikrobiyota bileşimi arasındaki ilişki hâlâ belirsizliğini korumaktadır. Bu derlemede bağırsak mikrobiyotası ve diabetes mellitus arasındaki ilişkiye odaklanılarak, diyabet tedavisinde terapötik olarak bağırsak mikrobiyotasının düzenlenmesinin sonuçları tartışılmıştır.
Kaynakça
- 1. Saeedi P, Petersohn I, Salpea P, Global and regional
diabetes prevalence estimates for 2019 and projections for
2030 and 2045: Results from the International Diabetes
Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin
Pract. 2019;157:107843.
- 2. Burcelin R, Serino M, Chabo C, Blasco-Baque V, Amar J. Gut
microbiota and diabetes: From pathogenesis to therapeutic
perspective. Acta Diabetol. 2011;48:257-273.
- 3. Thursby E, Juge N. Introduction to the human gut microbiota.
Biochem J. 2017;474:1823-1836.
- 4. Rodriguez JM, Murphy K, Stanton C, Ross R P, Kober OI, Juge
N, Avershina E, Rudi K, Narbad A, Jenmalm MC, Marchesi
JR, Collado M C. The composition of the gut microbiota
throughout life, with an emphasis on early life. Microb Ecol
Health Dis. 2015;26:26050.
- 5. Aagaard K, Ma J, Antony K M, Ganu R, Petrosino J, Versalovic
J. The placenta harbors a unique microbiome. Sci Transl Med.
2014;6:237ra65.
- 6. Clarke G, Stilling RM, Kennedy PJ, Stanton C, Cryan JF, Dinan
TG. Minireview: Gut microbiota: The neglected endocrine
organ. Mol Endocrinol. 2014;28:1221-1238.
- 7. Marchesi JR, Adams DH, Fava F, Hermes GD, Hirschfield G
M, Hold G, Quraishi MN, Kinross J, Smidt H, Tuohy KM,
Thomas LV, Zoetendal EG, Hart A. The gut microbiota and
host health: A new clinical frontier. Gut. 2016;65:330-339.
- 8. Gulden E, Wong F S, Wen L. The gut microbiota and Type 1
Diabetes. Clin Immunol. 2015;159:143-53.
- 9. Kachapati K, Adams D, Bednar K, Ridgway WM. The nonobese
diabetic (NOD) mouse as a model of human type 1
diabetes. Methods Mol Biol. 2012;933:3-16.
- 10. Pozzilli P, Signore A, Williams AJ, Beales PE. NOD mouse
colonies around the world--recent facts and figures. Immunol
Today. 1993;14:193-196.
- 11. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L,
Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA,
Gordon JI, Chervonsky AV. Innate immunity and intestinal
microbiota in the development of Type 1 diabetes. Nature.
2008;455:1109-1113.
- 12. Brugman S, Klatter FA, Visser JT, Wildeboer-Veloo AC,
Harmsen HJ, Rozing J, Bos NA. Antibiotic treatment partially
protects against type 1 diabetes in the Bio-Breeding diabetesprone
rat. Is the gut flora involved in the development of type
1 diabetes? Diabetologia. 2006;49:2105-2108.
- 13. Roesch LF, Lorca G L, Casella G, Giongo A, Naranjo A,
Pionzio AM, Li N, Mai V, Wasserfall CH, Schatz D, Atkinson
MA, Neu J, Triplett EW. Culture-independent identification
of gut bacteria correlated with the onset of diabetes in a rat
model. ISME J. 2009;3:536-548.
- 14. Li WZ, Stirling K, Yang JJ, Zhang L. Gut microbiota and
diabetes: From correlation to causality and mechanism. World
J Diabetes. 2020;11:293-308.
- 15. Cardwell CR, Stene LC, Joner G, Cinek O, Svensson J, Goldacre
MJ, Parslow RC, Pozzilli P, Brigis G, Stoyanov D, Urbonaite
B, Sipetic S, Schober E, Ionescu-Tirgoviste C, Devoti G, de
Beaufort CE, Buschard K, Patterson CC. Caesarean section
is associated with an increased risk of childhood-onset type
1 diabetes mellitus: A meta-analysis of observational studies.
Diabetologia. 2008;51:726-735.
- 16. Murri M, Leiva I, Gomez-Zumaquero JM, Tinahones FJ,
Cardona F, Soriguer F, Queipo-Ortuno MI. Gut microbiota
in children with type 1 diabetes differs from that in healthy
children: A case-control study. BMC Med. 2013;11:46.
- 17. Brown CT, Davis-Richardson AG, Giongo A, Gano KA,
Crabb DB, Mukherjee N, Casella G, Drew JC, Ilonen J, Knip
M, Hyoty H, Veijola R, Simell T, Simell O, Neu J, Wasserfall
CH, Schatz D, Atkinson MA, Triplett EW. Gut microbiome
metagenomics analysis suggests a functional model for the
development of autoimmunity for type 1 diabetes. PLoS One.
2011;6:e25792.
- 18. Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH. Shortchain
fatty acids activate GPR41 and GPR43 on intestinal
epithelial cells to promote inflammatory responses in mice.
Gastroenterology. 2013;145:396-406 e1-10.
- 19. Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda
T, Terasawa K, Kashihara D, Hirano K, Tani T, Takahashi T,
Miyauchi S, Shioi G, Inoue H, Tsujimoto G. The gut microbiota
suppresses insulin-mediated fat accumulation via the shortchain
fatty acid receptor GPR43. Nat Commun. 2013;4:1829.
- 20. Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura
I. Dietary gut microbial metabolites, short-chain fatty acids,
and host metabolic regulation. Nutrients. 2015;7:2839-2849.
- 21. Cani PD Delzenne NM. The role of the gut microbiota in
energy metabolism and metabolic disease. Curr Pharm Des.
2009;15:1546-1558.
- 22. Louis P, Flint HJ. Diversity, metabolism and microbial ecology
of butyrate-producing bacteria from the human large intestine.
FEMS Microbiol Lett. 2009;294:1-8.
- 23. Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL,
Casella G, Drew JC, Ilonen J, Knip M, Hyoty H, Veijola R,
Simell T, Simell O, Neu J, Wasserfall CH, Schatz D, Atkinson
M A, Triplett EW. Toward defining the autoimmune
microbiome for type 1 diabetes. ISME J. 2011;5:82-91.
- 24. Kostic AD, Gevers D, Siljander H, Vatanen T, Hyotylainen
T, Hamalainen AM, Peet A, Tillmann V, Poho P, Mattila I,
Lahdesmaki H, Franzosa EA, Vaarala O, de Goffau M, Harmsen
H, Ilonen J, Virtanen SM, Clish CB, Oresic M, Huttenhower
C, Knip M, Xavier RJ. The dynamics of the human infant gut
microbiome in development and in progression toward type 1
diabetes. Cell Host Microbe. 2015;17:260-273.
- 25. Lavasani S, Dzhambazov B, Nouri M, Fak F, Buske S, Molin
G, Thorlacius H, Alenfall J, Jeppsson B, Westrom B. A novel
probiotic mixture exerts a therapeutic effect on experimental
autoimmune encephalomyelitis mediated by IL-10 producing
regulatory T cells. PLoS One. 2010;5:e9009.
- 26. Valladares R, Sankar D, Li N, Williams E, Lai KK, Abdelgeliel
AS, Gonzalez CF, Wasserfall CH, Larkin J, Schatz D, Atkinson
MA, Triplett EW, Neu J, Lorca GL. Lactobacillus johnsonii
N6.2 mitigates the development of type 1 diabetes in BB-DP
rats. PLoS One. 2010;5:e10507.
- 27. Higuchi T, Hayashi H, Abe K. Exchange of glutamate and
gamma-aminobutyrate in a Lactobacillus strain. J Bacteriol.
1997;179:3362-3364.
- 28. Tian J, Dang H, Chen Z, Guan A, Jin Y, Atkinson MA,
Kaufman DL. Gamma-Aminobutyric acid regulates both
the survival and replication of human beta-cells. Diabetes.
2013;62:3760-3765.
- 29. Jin Z, Mendu SK, Birnir B. GABA is an effective
immunomodulatory molecule. Amino Acids. 2013;45:87-94.
- 30. Marques TM, Wall R, O’Sullivan O, Fitzgerald GF, Shanahan
F, Quigley EM, Cotter PD, Cryan JF, Dinan TG, Ross RP,
Stanton C. Dietary trans-10, cis-12-conjugated linoleic acid
alters fatty acid metabolism and microbiota composition in
mice. Br J Nutr. 2015;113:728-738.
- 31. Marques TM, Patterson E, Wall R, O’Sullivan O, Fitzgerald
GF, Cotter PD, Dinan TG, Cryan JF, Ross RP, Stanton C.
Influence of GABA and GABA-producing Lactobacillus brevis
DPC 6108 on the development of diabetes in a streptozotocin
rat model. Benef Microbes. 2016;7:409-420.
- 32. Duan F, Curtis KL, March JC. Secretion of insulinotropic
proteins by commensal bacteria: rewiring the gut to treat
diabetes. Appl Environ Microbiol. 2008;74:7437-7438.
- 33. Duan FF, Liu JH, March JC. Engineered commensal bacteria
reprogram intestinal cells into glucose-responsive insulinsecreting
cells for the treatment of diabetes. Diabetes.
2015;64:1794-1803.
- 34. Pussinen PJ, Havulinna AS, Lehto M, Sundvall J, Salomaa V.
Endotoxemia is associated with an increased risk of incident
diabetes. Diabetes Care. 2011;34:392-397.
- 35. Serino M, Luche E, Gres S, Baylac A, Berge M, Cenac C, Waget
A, Klopp P, Iacovoni J, Klopp C, Mariette J, Bouchez O, Lluch
J, Ouarne F, Monsan P, Valet P, Roques C, Amar J, Bouloumie
A, Theodorou V, Burcelin R. Metabolic adaptation to a highfat
diet is associated with a change in the gut microbiota. Gut.
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The Role and Targeting of Microbiota in Diabetes Mellitus
Yıl 2021,
Cilt: 5 Sayı: 1, 51 - 58, 24.04.2021
Zinnet Şevval Aksoyalp
,
Cahit Nacitarhan
Öz
There are over 100 trillion microbial cells in the human, mostly in the large intestine, and all of these organisms are gut microbiota. The gut microbiota plays an important role in gastrointestinal mucosal permeability, the secretion of intestinal hormone and fermentation and absorption of dietary polysaccharides. In addition, gut microbiota play an important role in the host’s immune system, regulation
of inflammatory processes and energy production from foods. Symbiotic bacteria and pathogenic bacteria are in equilibrium in the gut microbiota of healthy organisms. The imbalance of gut microbiota has been associated with increased immunological and metabolic
disorders in both animals and humans.
Diabetes mellitus is a chronic disease characterized by hyperglycemia. The incidence of diabetes mellitus has increased rapidly throughout the world in the last twenty-years and has become an important public health problem. Besides genetic and environmental factors, diabetes mellitus has also been associated with gut microbiota. Many studies have shown that diabetic patients have moderate dysbiosis in gut microbiota. However, the relationship between diabetes development and gut microbiota composition remains unclear in humans. In this review, we aimed to focus on the relationship between gut microbiota and diabetes mellitus, and to discuss the results of modulation gut microbiota therapeutically in the treatment of diabetes mellitus.
Kaynakça
- 1. Saeedi P, Petersohn I, Salpea P, Global and regional
diabetes prevalence estimates for 2019 and projections for
2030 and 2045: Results from the International Diabetes
Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin
Pract. 2019;157:107843.
- 2. Burcelin R, Serino M, Chabo C, Blasco-Baque V, Amar J. Gut
microbiota and diabetes: From pathogenesis to therapeutic
perspective. Acta Diabetol. 2011;48:257-273.
- 3. Thursby E, Juge N. Introduction to the human gut microbiota.
Biochem J. 2017;474:1823-1836.
- 4. Rodriguez JM, Murphy K, Stanton C, Ross R P, Kober OI, Juge
N, Avershina E, Rudi K, Narbad A, Jenmalm MC, Marchesi
JR, Collado M C. The composition of the gut microbiota
throughout life, with an emphasis on early life. Microb Ecol
Health Dis. 2015;26:26050.
- 5. Aagaard K, Ma J, Antony K M, Ganu R, Petrosino J, Versalovic
J. The placenta harbors a unique microbiome. Sci Transl Med.
2014;6:237ra65.
- 6. Clarke G, Stilling RM, Kennedy PJ, Stanton C, Cryan JF, Dinan
TG. Minireview: Gut microbiota: The neglected endocrine
organ. Mol Endocrinol. 2014;28:1221-1238.
- 7. Marchesi JR, Adams DH, Fava F, Hermes GD, Hirschfield G
M, Hold G, Quraishi MN, Kinross J, Smidt H, Tuohy KM,
Thomas LV, Zoetendal EG, Hart A. The gut microbiota and
host health: A new clinical frontier. Gut. 2016;65:330-339.
- 8. Gulden E, Wong F S, Wen L. The gut microbiota and Type 1
Diabetes. Clin Immunol. 2015;159:143-53.
- 9. Kachapati K, Adams D, Bednar K, Ridgway WM. The nonobese
diabetic (NOD) mouse as a model of human type 1
diabetes. Methods Mol Biol. 2012;933:3-16.
- 10. Pozzilli P, Signore A, Williams AJ, Beales PE. NOD mouse
colonies around the world--recent facts and figures. Immunol
Today. 1993;14:193-196.
- 11. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L,
Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA,
Gordon JI, Chervonsky AV. Innate immunity and intestinal
microbiota in the development of Type 1 diabetes. Nature.
2008;455:1109-1113.
- 12. Brugman S, Klatter FA, Visser JT, Wildeboer-Veloo AC,
Harmsen HJ, Rozing J, Bos NA. Antibiotic treatment partially
protects against type 1 diabetes in the Bio-Breeding diabetesprone
rat. Is the gut flora involved in the development of type
1 diabetes? Diabetologia. 2006;49:2105-2108.
- 13. Roesch LF, Lorca G L, Casella G, Giongo A, Naranjo A,
Pionzio AM, Li N, Mai V, Wasserfall CH, Schatz D, Atkinson
MA, Neu J, Triplett EW. Culture-independent identification
of gut bacteria correlated with the onset of diabetes in a rat
model. ISME J. 2009;3:536-548.
- 14. Li WZ, Stirling K, Yang JJ, Zhang L. Gut microbiota and
diabetes: From correlation to causality and mechanism. World
J Diabetes. 2020;11:293-308.
- 15. Cardwell CR, Stene LC, Joner G, Cinek O, Svensson J, Goldacre
MJ, Parslow RC, Pozzilli P, Brigis G, Stoyanov D, Urbonaite
B, Sipetic S, Schober E, Ionescu-Tirgoviste C, Devoti G, de
Beaufort CE, Buschard K, Patterson CC. Caesarean section
is associated with an increased risk of childhood-onset type
1 diabetes mellitus: A meta-analysis of observational studies.
Diabetologia. 2008;51:726-735.
- 16. Murri M, Leiva I, Gomez-Zumaquero JM, Tinahones FJ,
Cardona F, Soriguer F, Queipo-Ortuno MI. Gut microbiota
in children with type 1 diabetes differs from that in healthy
children: A case-control study. BMC Med. 2013;11:46.
- 17. Brown CT, Davis-Richardson AG, Giongo A, Gano KA,
Crabb DB, Mukherjee N, Casella G, Drew JC, Ilonen J, Knip
M, Hyoty H, Veijola R, Simell T, Simell O, Neu J, Wasserfall
CH, Schatz D, Atkinson MA, Triplett EW. Gut microbiome
metagenomics analysis suggests a functional model for the
development of autoimmunity for type 1 diabetes. PLoS One.
2011;6:e25792.
- 18. Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH. Shortchain
fatty acids activate GPR41 and GPR43 on intestinal
epithelial cells to promote inflammatory responses in mice.
Gastroenterology. 2013;145:396-406 e1-10.
- 19. Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda
T, Terasawa K, Kashihara D, Hirano K, Tani T, Takahashi T,
Miyauchi S, Shioi G, Inoue H, Tsujimoto G. The gut microbiota
suppresses insulin-mediated fat accumulation via the shortchain
fatty acid receptor GPR43. Nat Commun. 2013;4:1829.
- 20. Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura
I. Dietary gut microbial metabolites, short-chain fatty acids,
and host metabolic regulation. Nutrients. 2015;7:2839-2849.
- 21. Cani PD Delzenne NM. The role of the gut microbiota in
energy metabolism and metabolic disease. Curr Pharm Des.
2009;15:1546-1558.
- 22. Louis P, Flint HJ. Diversity, metabolism and microbial ecology
of butyrate-producing bacteria from the human large intestine.
FEMS Microbiol Lett. 2009;294:1-8.
- 23. Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL,
Casella G, Drew JC, Ilonen J, Knip M, Hyoty H, Veijola R,
Simell T, Simell O, Neu J, Wasserfall CH, Schatz D, Atkinson
M A, Triplett EW. Toward defining the autoimmune
microbiome for type 1 diabetes. ISME J. 2011;5:82-91.
- 24. Kostic AD, Gevers D, Siljander H, Vatanen T, Hyotylainen
T, Hamalainen AM, Peet A, Tillmann V, Poho P, Mattila I,
Lahdesmaki H, Franzosa EA, Vaarala O, de Goffau M, Harmsen
H, Ilonen J, Virtanen SM, Clish CB, Oresic M, Huttenhower
C, Knip M, Xavier RJ. The dynamics of the human infant gut
microbiome in development and in progression toward type 1
diabetes. Cell Host Microbe. 2015;17:260-273.
- 25. Lavasani S, Dzhambazov B, Nouri M, Fak F, Buske S, Molin
G, Thorlacius H, Alenfall J, Jeppsson B, Westrom B. A novel
probiotic mixture exerts a therapeutic effect on experimental
autoimmune encephalomyelitis mediated by IL-10 producing
regulatory T cells. PLoS One. 2010;5:e9009.
- 26. Valladares R, Sankar D, Li N, Williams E, Lai KK, Abdelgeliel
AS, Gonzalez CF, Wasserfall CH, Larkin J, Schatz D, Atkinson
MA, Triplett EW, Neu J, Lorca GL. Lactobacillus johnsonii
N6.2 mitigates the development of type 1 diabetes in BB-DP
rats. PLoS One. 2010;5:e10507.
- 27. Higuchi T, Hayashi H, Abe K. Exchange of glutamate and
gamma-aminobutyrate in a Lactobacillus strain. J Bacteriol.
1997;179:3362-3364.
- 28. Tian J, Dang H, Chen Z, Guan A, Jin Y, Atkinson MA,
Kaufman DL. Gamma-Aminobutyric acid regulates both
the survival and replication of human beta-cells. Diabetes.
2013;62:3760-3765.
- 29. Jin Z, Mendu SK, Birnir B. GABA is an effective
immunomodulatory molecule. Amino Acids. 2013;45:87-94.
- 30. Marques TM, Wall R, O’Sullivan O, Fitzgerald GF, Shanahan
F, Quigley EM, Cotter PD, Cryan JF, Dinan TG, Ross RP,
Stanton C. Dietary trans-10, cis-12-conjugated linoleic acid
alters fatty acid metabolism and microbiota composition in
mice. Br J Nutr. 2015;113:728-738.
- 31. Marques TM, Patterson E, Wall R, O’Sullivan O, Fitzgerald
GF, Cotter PD, Dinan TG, Cryan JF, Ross RP, Stanton C.
Influence of GABA and GABA-producing Lactobacillus brevis
DPC 6108 on the development of diabetes in a streptozotocin
rat model. Benef Microbes. 2016;7:409-420.
- 32. Duan F, Curtis KL, March JC. Secretion of insulinotropic
proteins by commensal bacteria: rewiring the gut to treat
diabetes. Appl Environ Microbiol. 2008;74:7437-7438.
- 33. Duan FF, Liu JH, March JC. Engineered commensal bacteria
reprogram intestinal cells into glucose-responsive insulinsecreting
cells for the treatment of diabetes. Diabetes.
2015;64:1794-1803.
- 34. Pussinen PJ, Havulinna AS, Lehto M, Sundvall J, Salomaa V.
Endotoxemia is associated with an increased risk of incident
diabetes. Diabetes Care. 2011;34:392-397.
- 35. Serino M, Luche E, Gres S, Baylac A, Berge M, Cenac C, Waget
A, Klopp P, Iacovoni J, Klopp C, Mariette J, Bouchez O, Lluch
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