Research of relationship between frailty and gut microbiota on middle-aged and the aged patients with diabetes_Journal of Biomedical Engineering

Authors：

PENG Xuchao , ZHAO Yanli , LIN Taiping , SHU Xiaoyu , HOU Lisha , GAO Langli , WANG Hui ,  GE Ning ,  YUE Jirong

Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, P.R.China;

Corresponding author：

GE Ning, Email: grace7733@163.com; YUE Jirong, Email: yuejirong11@hotmail.com

Keywords：

diabetes; frailty; gut microbiota; microbiota analysis; metagenomics sequencing

DOI：

10.7507/1001-5515.202101083

Video：

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Gut microbiota plays an important role in development of diabetes with frailty. Therefore, it is of great significance to study the structural and functional characteristics of gut microbiota in Chinese with frailty. Totally 30 middle-aged and the aged participants in communities with diabetes were enrolled in this study, and their feces were collected. At the same time, we developed a metagenome analysis to explore the different of the structural and functional characteristics between diabetes with frailty and diabetes without frailty. The results showed the alpha diversity of intestinal microbiota in diabetes with frailty was lower. Collinsella and Butyricimonas were more abundant in diabetes with frailty. The functional characteristics showed that histidine metabolism, Epstein-Barr virus infection, sulfur metabolism, and biosynthesis of type Ⅱ polyketide products were upregulated in diabetes with frailty. Otherwise, butanoate metabolism and phenylalanine metabolism were down-regulated in diabetes with frailty. This research provides theoretical basic for exploring the mechanism of the gut microbiota on the occurrence and development of diabetes with frailty, and provides a basic for prevention and intervention of it.

Citation： PENG Xuchao, ZHAO Yanli, LIN Taiping, SHU Xiaoyu, HOU Lisha, GAO Langli, WANG Hui, GE Ning, YUE Jirong. Research of relationship between frailty and gut microbiota on middle-aged and the aged patients with diabetes. Journal of Biomedical Engineering, 2021, 38(6): 1126-1133. doi: 10.7507/1001-5515.202101083 Copy

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7.	Chen L K, Chen Y M, lin M H, et al. Care of elderly patients with diabetes mellitus: a focus on frailty. Ageing Res Rev, 2010, 9 Suppl 1: S18-22.
8.	田鹏, 杨宁, 郝秋奎, 等. 中国老年衰弱患病率的系统评价. 中国循证医学杂志, 2019, 19(6): 656-664.
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10.	Jackson M A, Jeffery I B, Beaumont M, et al. Signatures of early frailty in the gut microbiota. Genome Med, 2016, 8(1): 8.
11.	van Tongeren S P, Slaets J P, Harmsen H J, et al. Fecal microbiota composition and frailty. Appl Environ Microbiol, 2005, 71(10): 6438-6442.
12.	Biagi E, Franceschi C, Rampelli S, et al. Gut microbiota and extreme longevity. Curr Biol, 2016, 26(11): 1480-1485.
13.	Ticinesi A, Nouvenne A, Cerundolo N, et al. Gut microbiota, muscle mass and function in aging: A focus on physical frailty and sarcopenia. Nutrients, 2019, 11(7): 1633.
14.	Casati M, Ferri E, Azzolino D, et al. Gut microbiota and physical frailty through the mediation of sarcopenia. Exp Gerontol, 2019, 124: 110639.
15.	Leduc-Gaudet J P, Picard M, Pelletier F S, et al. Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice. Oncotarget, 2015, 6(20): 17923-17937.
16.	Pols T W H, Noriega L G, Nomura M, et al. The bile acid membrane receptor TGR5: a valuable metabolic target. Digest Dis, 2011, 29(1): 37-44.
17.	Yatsunenko T, Rey F E, Manary M J, et al. Human gut microbiome viewed across age and geography. Nature, 2012, 486(7402): 222-227.
18.	Buigues C, Fernandez-Garrido J, Pruimboom L, et al. Effect of a prebiotic formulation on frailty syndrome: A randomized, double-blind clinical trial. Int J Mol Sci, 2016, 17(6): 932.
19.	Richard M L, Sokol H. The gut mycobiota: insights into analysis, environmental interactions and role in gastrointestinal diseases. Nat Rev Gastroenterol Hepatol, 2019, 16(6): 331-345.
20.	Kultima J R, Coelho L P, Forslund K, et al. MOCAT2: a metagenomic assembly, annotation and profiling framework. Bioinformatics, 2016, 32(16): 2520-2523.
21.	Zhu W, Lomsadze A, Borodovsky M. Ab initio gene identification in metagenomic sequences. Nucleic Acids Res, 2010, 38(12): e132.
22.	Fu Limin, Niu Beifang, Zhu Zhengwei, et al. CD-HIT: accelerated for clustering the next-generation sequencing data. Bioinformatics, 2012, 28(23): 3150-3152.
23.	Segata N, Waldron L, Ballarini A, et al. Metagenomic microbial community profiling using unique clade-specific marker genes. Nat Methods, 2012, 9(8): 811-814.
24.	Sunagawa S, Mende D R, Zeller G, et al. Metagenomic species profiling using universal phylogenetic marker genes. Nat Methods, 2013, 10(12): 1196-1199.
25.	Luo Weijun, Friedman M S, Shedden K, et al. GAGE: generally applicable gene set enrichment for pathway analysis. Bmc Bioinformatics, 2009, 10(1): 161.
26.	Ticinesi A, Nouvenne A, Tana C, et al. The impact of intestinal microbiota on bio-medical research: definitions, techniques and physiology of a "new frontier". Acta Biomed, 2018, 89(9-S): 52-59.
27.	Dejong E N, Surette M G, Bowdish D M E. The gut microbiota and unhealthy aging: Disentangling cause from consequence. Cell Host Microbe, 2020, 28(2): 180-189.
28.	Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol, 2018, 15(9): 505-522.
29.	Wu Hao, Tremaroli V, Schmidt C, et al. The gut microbiota in prediabetes and diabetes: A population-based cross-sectional study. Cell Metab, 2020, 32(3): 379-390.
30.	Chow J, Tang H, Mazmanian S K. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol, 2011, 23(4): 473-480.
31.	Gomez-Arango L F, Barrett H L, Wilkinson S A, et al. Low dietary fiber intake increases Collinsella abundance in the gut microbiota of overweight and obese pregnant women. Gut Microbes, 2018, 9(3): 189-201.
32.	Cani P D, Possemiers S, Wiele T V, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut, 2009, 58(8): 1091-1103.
33.	Ju Tingting, Kong J Y, Stothard P, et al. Defining the role of Parasutterella, a previously uncharacterized member of the core gut microbiota. ISME J, 2019, 13(6): 1520-1534.
34.	Wang Qi, Wang Yunzhang, Lehto K, et al. Genetically-predicted life-long lowering of low-density lipoprotein cholesterol is associated with decreased frailty: A Mendelian randomization study in UK biobank. EBioMedicine, 2019, 45: 487-494.
35.	Hemsworth G R, Thompson A J, Stepper J, et al. Structural dissection of a complex Bacteroides ovatus gene locus conferring xyloglucan metabolism in the human gut. Open Biol, 2016, 6(7): 160142.
36.	Yang Chao, Mogno I, Contijoch E J, et al. Fecal IgA levels are determined by strain-level differences in Bacteroides ovatus and are modifiable by gut microbiota manipulation. Cell Host Microbe, 2020, 27(3): 467-475 e6.
37.	Tokuhara D, Yuki Y, Nochi T, et al. Secretory IgA-mediated protection against V. cholerae and heat-labile enterotoxin-producing enterotoxigenic Escherichia coli by rice-based vaccine. Proc Natl Acad Sci U S A, 2010, 107(19): 8794-8799.
38.	Yoon S, Yu J, McDowell A, et al. Bile salt hydrolase-mediated inhibitory effect of Bacteroides ovatus on growth of Clostridium difficile. J Microbiol, 2017, 55(11): 892-899.
39.	Koh A, Molinaro A, Stahlman M, et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell, 2018, 175(4): 947-961.
40.	Iwakiri D, Zhou Li, Samanta M, et al. Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from Toll-like receptor 3. J Exp Med, 2009, 206(10): 2091-2099.
41.	Lopez-Otin C, Galluzzi L, Freije J M P, et al. Metabolic control of longevity. Cell, 2016, 166(4): 802-821.
42.	Liu Hu, Wang Ji, He Ting, et al. Butyrate: A double-edged sword for health?. Adv Nutr, 2018, 9(1): 21-29.
43.	Dent E, Martin F C, Bergman H, et al. Management of frailty: opportunities, challenges, and future directions. Lancet, 2019, 394(10206): 1376-1386.
44.	Haran J, Bucci V, Dutta P, et al. The nursing home elder microbiome stability and associations with age, frailty, nutrition and physical location. J Med Microbiol, 2018, 67(1): 40-51.
45.	Gaulke C A, Sharpton T J. The influence of ethnicity and geography on human gut microbiome composition. Nat Med, 2018, 24(10): 1495-1496.

1. 程志强, 马金秋. 中国人口老龄化的演变与应对之策. 学术交流, 2018(12): 101-109.
2. 董碧蓉. 老年衰弱综合征的研究进展. 中华保健医学杂志, 2014, 6(16): 417-420.
3. Clegg A, Young J, Iliffe S, et al. Frailty in elderly people. Lancet, 2013, 381(9868): 752-762.
4. Yoshida T, Tabony A M, Galvez S, et al. Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia. Int J Biochem Cell B, 2013, 45(10): 2322-2332.
5. Hwang H, Bowen B P, Lefort N, et al. Proteomics analysis of human skeletal muscle reveals novel abnormalities in obesity and type 2 diabetes. Diabetes, 2010, 59(1): 33-42.
6. Morley J E, Malmstrom T K, Rodriguez-manas L, et al. Frailty, sarcopenia and diabetes. J Am Med Dir Assoc, 2014, 15(12): 853-859.
7. Chen L K, Chen Y M, lin M H, et al. Care of elderly patients with diabetes mellitus: a focus on frailty. Ageing Res Rev, 2010, 9 Suppl 1: S18-22.
8. 田鹏, 杨宁, 郝秋奎, 等. 中国老年衰弱患病率的系统评价. 中国循证医学杂志, 2019, 19(6): 656-664.
9. Garcia-Esquinas E, Graciani A, Guallar-castillon P, et al. Diabetes and risk of frailty and its potential mechanisms: a prospective cohort study of older adults. J Am Med Dir Assoc, 2015, 16(9): 748-754.
10. Jackson M A, Jeffery I B, Beaumont M, et al. Signatures of early frailty in the gut microbiota. Genome Med, 2016, 8(1): 8.
11. van Tongeren S P, Slaets J P, Harmsen H J, et al. Fecal microbiota composition and frailty. Appl Environ Microbiol, 2005, 71(10): 6438-6442.
12. Biagi E, Franceschi C, Rampelli S, et al. Gut microbiota and extreme longevity. Curr Biol, 2016, 26(11): 1480-1485.
13. Ticinesi A, Nouvenne A, Cerundolo N, et al. Gut microbiota, muscle mass and function in aging: A focus on physical frailty and sarcopenia. Nutrients, 2019, 11(7): 1633.
14. Casati M, Ferri E, Azzolino D, et al. Gut microbiota and physical frailty through the mediation of sarcopenia. Exp Gerontol, 2019, 124: 110639.
15. Leduc-Gaudet J P, Picard M, Pelletier F S, et al. Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice. Oncotarget, 2015, 6(20): 17923-17937.
16. Pols T W H, Noriega L G, Nomura M, et al. The bile acid membrane receptor TGR5: a valuable metabolic target. Digest Dis, 2011, 29(1): 37-44.
17. Yatsunenko T, Rey F E, Manary M J, et al. Human gut microbiome viewed across age and geography. Nature, 2012, 486(7402): 222-227.
18. Buigues C, Fernandez-Garrido J, Pruimboom L, et al. Effect of a prebiotic formulation on frailty syndrome: A randomized, double-blind clinical trial. Int J Mol Sci, 2016, 17(6): 932.
19. Richard M L, Sokol H. The gut mycobiota: insights into analysis, environmental interactions and role in gastrointestinal diseases. Nat Rev Gastroenterol Hepatol, 2019, 16(6): 331-345.
20. Kultima J R, Coelho L P, Forslund K, et al. MOCAT2: a metagenomic assembly, annotation and profiling framework. Bioinformatics, 2016, 32(16): 2520-2523.
21. Zhu W, Lomsadze A, Borodovsky M. Ab initio gene identification in metagenomic sequences. Nucleic Acids Res, 2010, 38(12): e132.
22. Fu Limin, Niu Beifang, Zhu Zhengwei, et al. CD-HIT: accelerated for clustering the next-generation sequencing data. Bioinformatics, 2012, 28(23): 3150-3152.
23. Segata N, Waldron L, Ballarini A, et al. Metagenomic microbial community profiling using unique clade-specific marker genes. Nat Methods, 2012, 9(8): 811-814.
24. Sunagawa S, Mende D R, Zeller G, et al. Metagenomic species profiling using universal phylogenetic marker genes. Nat Methods, 2013, 10(12): 1196-1199.
25. Luo Weijun, Friedman M S, Shedden K, et al. GAGE: generally applicable gene set enrichment for pathway analysis. Bmc Bioinformatics, 2009, 10(1): 161.
26. Ticinesi A, Nouvenne A, Tana C, et al. The impact of intestinal microbiota on bio-medical research: definitions, techniques and physiology of a "new frontier". Acta Biomed, 2018, 89(9-S): 52-59.
27. Dejong E N, Surette M G, Bowdish D M E. The gut microbiota and unhealthy aging: Disentangling cause from consequence. Cell Host Microbe, 2020, 28(2): 180-189.
28. Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol, 2018, 15(9): 505-522.
29. Wu Hao, Tremaroli V, Schmidt C, et al. The gut microbiota in prediabetes and diabetes: A population-based cross-sectional study. Cell Metab, 2020, 32(3): 379-390.
30. Chow J, Tang H, Mazmanian S K. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol, 2011, 23(4): 473-480.
31. Gomez-Arango L F, Barrett H L, Wilkinson S A, et al. Low dietary fiber intake increases Collinsella abundance in the gut microbiota of overweight and obese pregnant women. Gut Microbes, 2018, 9(3): 189-201.
32. Cani P D, Possemiers S, Wiele T V, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut, 2009, 58(8): 1091-1103.
33. Ju Tingting, Kong J Y, Stothard P, et al. Defining the role of Parasutterella, a previously uncharacterized member of the core gut microbiota. ISME J, 2019, 13(6): 1520-1534.
34. Wang Qi, Wang Yunzhang, Lehto K, et al. Genetically-predicted life-long lowering of low-density lipoprotein cholesterol is associated with decreased frailty: A Mendelian randomization study in UK biobank. EBioMedicine, 2019, 45: 487-494.
35. Hemsworth G R, Thompson A J, Stepper J, et al. Structural dissection of a complex Bacteroides ovatus gene locus conferring xyloglucan metabolism in the human gut. Open Biol, 2016, 6(7): 160142.
36. Yang Chao, Mogno I, Contijoch E J, et al. Fecal IgA levels are determined by strain-level differences in Bacteroides ovatus and are modifiable by gut microbiota manipulation. Cell Host Microbe, 2020, 27(3): 467-475 e6.
37. Tokuhara D, Yuki Y, Nochi T, et al. Secretory IgA-mediated protection against V. cholerae and heat-labile enterotoxin-producing enterotoxigenic Escherichia coli by rice-based vaccine. Proc Natl Acad Sci U S A, 2010, 107(19): 8794-8799.
38. Yoon S, Yu J, McDowell A, et al. Bile salt hydrolase-mediated inhibitory effect of Bacteroides ovatus on growth of Clostridium difficile. J Microbiol, 2017, 55(11): 892-899.
39. Koh A, Molinaro A, Stahlman M, et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell, 2018, 175(4): 947-961.
40. Iwakiri D, Zhou Li, Samanta M, et al. Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from Toll-like receptor 3. J Exp Med, 2009, 206(10): 2091-2099.
41. Lopez-Otin C, Galluzzi L, Freije J M P, et al. Metabolic control of longevity. Cell, 2016, 166(4): 802-821.
42. Liu Hu, Wang Ji, He Ting, et al. Butyrate: A double-edged sword for health?. Adv Nutr, 2018, 9(1): 21-29.
43. Dent E, Martin F C, Bergman H, et al. Management of frailty: opportunities, challenges, and future directions. Lancet, 2019, 394(10206): 1376-1386.
44. Haran J, Bucci V, Dutta P, et al. The nursing home elder microbiome stability and associations with age, frailty, nutrition and physical location. J Med Microbiol, 2018, 67(1): 40-51.
45. Gaulke C A, Sharpton T J. The influence of ethnicity and geography on human gut microbiome composition. Nat Med, 2018, 24(10): 1495-1496.

Journal of Biomedical Engineering

Research of relationship between frailty and gut microbiota on middle-aged and the aged patients with diabetes

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