Long-term instability of the intestinal microbiome is associated with metabolic liver disease, low microbiota diversity, diabetes mellitus and impaired exocrine pancreatic function
Fabian Frost, Tim Kacprowski, Malte Rühlemann, Maik Pietzner, Corinna Bang, Andre Franke, Matthias Nauck, Uwe Völker, Henry Völzke, Marcus Dörr, Jan Baumbach, Matthias Sendler, Christian Schulz, Julia Mayerle, Frank U Weiss, Georg Homuth, Markus M Lerch, Fabian Frost, Tim Kacprowski, Malte Rühlemann, Maik Pietzner, Corinna Bang, Andre Franke, Matthias Nauck, Uwe Völker, Henry Völzke, Marcus Dörr, Jan Baumbach, Matthias Sendler, Christian Schulz, Julia Mayerle, Frank U Weiss, Georg Homuth, Markus M Lerch
Abstract
Objective: The intestinal microbiome affects the prevalence and pathophysiology of a variety of diseases ranging from inflammation to cancer. A reduced taxonomic or functional diversity of the microbiome was often observed in association with poorer health outcomes or disease in general. Conversely, factors or manifest diseases that determine the long-term stability or instability of the microbiome are largely unknown. We aimed to identify disease-relevant phenotypes associated with faecal microbiota (in-)stability.
Design: A total of 2564 paired faecal samples from 1282 participants of the population-based Study of Health in Pomerania (SHIP) were collected at a 5-year (median) interval and microbiota profiles determined by 16S rRNA gene sequencing. The changes in faecal microbiota over time were associated with highly standardised and comprehensive phenotypic data to determine factors related to microbiota (in-)stability.
Results: The overall microbiome landscape remained remarkably stable over time. The greatest microbiome instability was associated with factors contributing to metabolic syndrome such as fatty liver disease and diabetes mellitus. These, in turn, were associated with an increase in facultative pathogens such as Enterobacteriaceae or Escherichia/Shigella. Greatest stability of the microbiome was determined by higher initial alpha diversity, female sex, high household income and preserved exocrine pancreatic function. Participants who newly developed fatty liver disease or diabetes during the 5-year follow-up already displayed significant microbiota changes at study entry when the diseases were absent.
Conclusion: This study identifies distinct components of metabolic liver disease to be associated with instability of the intestinal microbiome, increased abundance of facultative pathogens and thus greater susceptibility toward dysbiosis-associated diseases.
Keywords: E. coli; colonic microflora; diabetes mellitus; fatty liver; pancreas.
Conflict of interest statement
Competing interests: None declared.
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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References
- Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 2016;14:e1002533. 10.1371/journal.pbio.1002533
- Zierer J, Jackson MA, Kastenmüller G, et al. . The fecal metabolome as a functional readout of the gut microbiome. Nat Genet 2018;50:790–5. 10.1038/s41588-018-0135-7
- Rastelli M, Knauf C, Cani PD. Gut microbes and health: a focus on the mechanisms linking microbes, obesity, and related disorders. Obesity 2018;26:792–800. 10.1002/oby.22175
- Tilg H, Mathurin P. Altered intestinal microbiota as a major driving force in alcoholic steatohepatitis. Gut 2016;65:728–9. 10.1136/gutjnl-2015-311014
- Chu H, Duan Y, Yang L, et al. . Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease. Gut 2019;68:359–70. 10.1136/gutjnl-2018-316307
- Yatsunenko T, Rey FE, Manary MJ, et al. . Human gut microbiome viewed across age and geography. Nature 2012;486:222–7. 10.1038/nature11053
- Frost F, Storck LJ, Kacprowski T, et al. . A structured weight loss program increases gut microbiota phylogenetic diversity and reduces levels of Collinsella in obese type 2 diabetics: a pilot study. PLoS One 2019;14:e0219489. 10.1371/journal.pone.0219489
- Vangay P, Johnson AJ, Ward TL, et al. . US immigration Westernizes the human gut microbiome. Cell 2018;175:962–72. e10. 10.1016/j.cell.2018.10.029
- Odamaki T, Kato K, Sugahara H, et al. . Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study. BMC Microbiol 2016;16:90. 10.1186/s12866-016-0708-5
- Tamburini S, Shen N, Wu HC, et al. . The microbiome in early life: implications for health outcomes. Nat Med 2016;22:713–22. 10.1038/nm.4142
- Völzke H, Alte D, Schmidt CO, et al. . Cohort profile: the study of health in Pomerania. Int J Epidemiol 2011;40:294–307. 10.1093/ije/dyp394
- Mayerle J, den Hoed CM, Schurmann C, et al. . Identification of genetic loci associated with Helicobacter pylori serologic status. JAMA 2013;309:1912–20. 10.1001/jama.2013.4350
- Frost F, Kacprowski T, Rühlemann M, et al. . Helicobacter pylori infection associates with fecal microbiota composition and diversity. Sci Rep 2019;9:20100. 10.1038/s41598-019-56631-4
- Frost F, Kacprowski T, Rühlemann M, et al. . Impaired exocrine pancreatic function associates with changes in intestinal microbiota composition and diversity. Gastroenterology 2019;156:1010–5. 10.1053/j.gastro.2018.10.047
- Frost F, Kacprowski T, Rühlemann MC, et al. . Functional abdominal pain and discomfort (IBS) is not associated with faecal microbiota composition in the general population. Gut 2019;68:1131.1–3. 10.1136/gutjnl-2018-316502
- Callahan BJ, McMurdie PJ, Rosen MJ, et al. . DADA2: high-resolution sample inference from illumina amplicon data. Nat Methods 2016;13:581–3. 10.1038/nmeth.3869
- Douglas GM, Maffei VJ, Zaneveld JR, et al. . PICRUSt2 for prediction of metagenome functions. Nat Biotechnol 2020;38:685–8. 10.1038/s41587-020-0548-6
- Levey AS, Stevens LA, Schmid CH, et al. . A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604–12. 10.7326/0003-4819-150-9-200905050-00006
- Luedemann J, Schminke U, Berger K, et al. . Association between behavior-dependent cardiovascular risk factors and asymptomatic carotid atherosclerosis in a general population. Stroke 2002;33:2929–35. 10.1161/01.STR.0000038422.57919.7F
- Winkler G, Döring A. Validation of a short qualitative food frequency list used in several German large scale surveys. Z Ernährungswiss 1998;37:234–41. 10.1007/PL00007377
- R Core Team R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2017.
- Oksanen J, Blanchet FG, Friendly M, et al. . Vegan: community ecology package. R package version 2.4-2, 2017. Available:
- Caspi R, Billington R, Fulcher CA, et al. . The MetaCyc database of metabolic pathways and enzymes. Nucleic Acids Res 2018;46:D633–9. 10.1093/nar/gkx935
- Wang J, Kurilshikov A, Radjabzadeh D, et al. . Meta-analysis of human genome-microbiome association studies: the MiBioGen Consortium initiative. Microbiome 2018;6:101. 10.1186/s40168-018-0479-3
- Thingholm LB, Rühlemann MC, Koch M, et al. . Obese individuals with and without type 2 diabetes show different gut microbial functional capacity and composition. Cell Host Microbe 2019;26:252–64. e10. 10.1016/j.chom.2019.07.004
- Tilg H, Cani PD, Mayer EA. Gut microbiome and liver diseases. Gut 2016;65:2035–44. 10.1136/gutjnl-2016-312729
- Cani PD, Van Hul M, diet M. Mediterranean diet, gut microbiota and health: when age and calories do not add up! Gut 2020;69:1167–8. 10.1136/gutjnl-2020-320781
- Wu H, Esteve E, Tremaroli V, 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;23:850–8. 10.1038/nm.4345
- Olivares M, Neyrinck AM, Pötgens SA, et al. . The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice. Diabetologia 2018;61:1838–48. 10.1007/s00125-018-4647-6
- Gomi H, Solomkin JS, Schlossberg D, et al. . Tokyo guidelines 2018: antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci 2018;25:3–16. 10.1002/jhbp.518
- Lee C-C, Chang I-J, Lai Y-C, et al. . Epidemiology and prognostic determinants of patients with bacteremic cholecystitis or cholangitis. Am J Gastroenterol 2007;102:563–9. 10.1111/j.1572-0241.2007.01095.x
- Li W, Chen H, Wu S, et al. . A comparison of pyogenic liver abscess in patients with or without diabetes: a retrospective study of 246 cases. BMC Gastroenterol 2018;18:144. 10.1186/s12876-018-0875-y
- Flores-Mireles AL, Walker JN, Caparon M, et al. . Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol 2015;13:269–84. 10.1038/nrmicro3432
- Samonis G, Karageorgopoulos DE, Kofteridis DP, et al. . Citrobacter infections in a general Hospital: characteristics and outcomes. Eur J Clin Microbiol Infect Dis 2009;28:61–8. 10.1007/s10096-008-0598-z
- Pedersen C, Ijaz UZ, Gallagher E, et al. . Fecal Enterobacteriales enrichment is associated with increased in vivo intestinal permeability in humans. Physiol Rep 2018;6:e13649. 10.14814/phy2.13649
- Cani PD, Amar J, Iglesias MA, et al. . Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56:1761–72. 10.2337/db06-1491
- Cani PD, Osto M, Geurts L, et al. . Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes 2012;3:279–88. 10.4161/gmic.19625
- Cani PD, Bibiloni R, Knauf C, et al. . Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470–81. 10.2337/db07-1403
- Cani PD, Possemiers S, Van de Wiele T, et al. . Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009;58:1091–103. 10.1136/gut.2008.165886
- Riedel C-U, Foata F, Philippe D, et al. . Anti-inflammatory effects of bifidobacteria by inhibition of LPS-induced NF-kappaB activation. World J Gastroenterol 2006;12:3729–35. 10.3748/wjg.v12.i23.3729
- Cani PD, Neyrinck AM, Fava F, et al. . Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia 2007;50:2374–83. 10.1007/s00125-007-0791-0
- Imhann F, Bonder MJ, Vich Vila A, et al. . Proton pump inhibitors affect the gut microbiome. Gut 2016;65:740–8. 10.1136/gutjnl-2015-310376
- Levine JM, D'Antonio CM. Elton revisited: a review of evidence linking diversity and invasibility. Oikos 1999;87:15 10.2307/3546992
- Horvat S, Rupnik M. Interactions Between Clostridioides difficile and Fecal Microbiota in in Vitro Batch Model: Growth, Sporulation, and Microbiota Changes. Front Microbiol 2018;9:1633. 10.3389/fmicb.2018.01633
- Ahuja M, Schwartz DM, Tandon M, et al. . Orai1-mediated antimicrobial secretion from pancreatic acini shapes the gut microbiome and regulates gut innate immunity. Cell Metab 2017;25:635–46. 10.1016/j.cmet.2017.02.007
- Ducheix S, Montagner A, Polizzi A, et al. . Dietary oleic acid regulates hepatic lipogenesis through a liver X receptor-dependent signaling. PLoS One 2017;12:e0181393. 10.1371/journal.pone.0181393
- Yamada S, Kamada N, Amiya T, et al. . Gut microbiota-mediated generation of saturated fatty acids elicits inflammation in the liver in murine high-fat diet-induced steatohepatitis. BMC Gastroenterol 2017;17:136. 10.1186/s12876-017-0689-3
- Lee JJ, Lambert JE, Hovhannisyan Y, et al. . Palmitoleic acid is elevated in fatty liver disease and reflects hepatic lipogenesis. Am J Clin Nutr 2015;101:34–43. 10.3945/ajcn.114.092262
- Cani PD Human gut microbiome: hopes, threats and promises. Gut 2018;67:1716–25. 10.1136/gutjnl-2018-316723
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