Biology & Philosophy

, 34:62 | Cite as

How causal are microbiomes? A comparison with the Helicobacter pylori explanation of ulcers

  • Kate E. LynchEmail author
  • Emily C. Parke
  • Maureen A. O’Malley
Part of the following topical collections:
  1. Target Article: How Causal are Microbiomes


Human microbiome research makes causal connections between entire microbial communities and a wide array of traits that range from physiological diseases to psychological states. To evaluate these causal claims, we first examine a well-known single-microbe causal explanation: of Helicobacter pylori causing ulcers. This apparently straightforward causal explanation is not so simple, however. It does not achieve a key explanatory standard in microbiology, of Koch’s postulates, which rely on manipulations of single-microorganism cultures to infer causal relationships to disease. When Koch’s postulates are framed by an interventionist causal framework, it is clearer what the H. pylori explanation achieves and where its explanatory strengths lie. After assessing this ‘simple’, single-microbe case, we apply the interventionist framework to two key areas of microbiome research, in which obesity and mental health states are purportedly explained by microbiomes. Despite the experimental data available, interventionist criteria for explanation show that many of the causal claims generated by microbiome research are weak or misleading. We focus on the stability, specificity and proportionality of proposed microbiome causal explanations, and evaluate how effectively these dimensions of causal explanation are achieved in some promising avenues of research. We suggest some conceptual and explanatory strategies to improve how causal claims about microbiomes are made.


Microbiome Causal explanation Helicobacter pylori Koch’s postulates Interventionism 



We thank Brett Calcott, Austen Ganley, David Kelley, John Matthewson, Sam Woolley, and the audience at PBDB 12 who provided crucial feedback on earlier versions of this manuscript, and acknowledge Pierrick Bourrat for earlier discussion of some of these ideas.


  1. Ait-Belgnaoui A et al (2012) Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats. Psychoneuroendocrinology 37:1885–1895CrossRefGoogle Scholar
  2. Arnold JW et al (2016) Emerging technologies for gut microbiome research. Trends Microbiol 24:887–901CrossRefGoogle Scholar
  3. Bercik P et al (2011) The intestinal microbiota affect central levels of brain-derived neurotropic factor and behaviour in mice. Gastroenterology 141:599–609.e3CrossRefGoogle Scholar
  4. Blaser MJ (1996) The bacteria behind ulcers. Sci Am 274:104–107CrossRefGoogle Scholar
  5. Blaser MJ (2014) The microbiome revolution. J Clin Investig 124:4162–4165CrossRefGoogle Scholar
  6. Bravo JA et al (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci 108:16050–16055CrossRefGoogle Scholar
  7. Buffie CG et al (2015) Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517:205CrossRefGoogle Scholar
  8. Calcott B (2017) Causal specificity and the instructive–permissive distinction. Biol Philos 32:481–505CrossRefGoogle Scholar
  9. Carter KC (2003) The rise of causal concepts of disease: case histories. Ashgate, FarnhamGoogle Scholar
  10. Chen D et al (2007) Does Helicobacter pylori infection per se cause gastric cancer or duodenal ulcer? Inadequate evidence in Mongolian gerbils and inbred mice. FEMS Immunol Med Microbiol 50:184–189CrossRefGoogle Scholar
  11. Cho I, Blaser MJ (2012) The human microbiome: at the interface of health and disease. Nat Rev Genet 13:260–270CrossRefGoogle Scholar
  12. Collins SM et al (2013) The adoptive transfer of behavioral phenotype via the intestinal microbiota: experimental evidence and clinical implications. Curr Opin Microbiol 16:240–245CrossRefGoogle Scholar
  13. Cox LM et al (2014) Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158:705–721CrossRefGoogle Scholar
  14. Duvallet C et al (2017) Meta-analysis of gut microbiome studies identifies disease-specific and shared responses. Nat Commun 8:1784CrossRefGoogle Scholar
  15. Fischbach MA (2018) Microbiome: focus on causation and mechanism. Cell 174:785–790CrossRefGoogle Scholar
  16. Fleissner CK et al (2010) Absence of intestinal microbiota does not protect mice from diet-induced obesity. Br J Nutr 104:919–929CrossRefGoogle Scholar
  17. Ford AC, Talley NJ (2009) Does Helicobacter pylori really cause duodenal ulcers? Yes. BMJ 339:b2784CrossRefGoogle Scholar
  18. Gilbert JA et al (2016) Microbiome-wide association studies link dynamic microbial consortia to disease. Nature 535:94–103CrossRefGoogle Scholar
  19. Gillies DA (2016) Establishing causality in medicine and Koch’s postulates. Intl J Hist Philos Med 6:10603Google Scholar
  20. Goodrich JK et al (2014a) Human genetics shape the gut microbiome. Cell 159:789–799CrossRefGoogle Scholar
  21. Goodrich JK et al (2014b) Conducting a microbiome study. Cell 158:250–262CrossRefGoogle Scholar
  22. Goodwin CS et al (1989) Transfer of Campylobacter pylori and Campylobacter mustelae to Helicobacter gen. nov. as Helicobacter pylori comb. nov. and Helicobacter mustelae comb. nov. respectively. Int J Syst Bacteriol 39:397–405CrossRefGoogle Scholar
  23. Graham DY et al (2009) African, Asia or Indian enigma, the East Asian Helicobacter pylori: facts or medical myths. J Dig Dis 10:77–84CrossRefGoogle Scholar
  24. Griffiths PE et al (2015) Measuring causal specificity. Philos Sci 82:529–555CrossRefGoogle Scholar
  25. Grinspan AM, Kelly CR (2015) Fecal microbiota transplantation for ulcerative colitis: not just yet. Gastroenterology 149:15–18CrossRefGoogle Scholar
  26. Grundy SM (1998) Multifactorial causation of obesity: implications for prevention. Am J Clin Nutr 67(Suppl):563S–572SCrossRefGoogle Scholar
  27. Hall EK et al (2018) Understanding how microbiomes influence the systems they inhabit. Nat Microbiol 3:977–982CrossRefGoogle Scholar
  28. Hamady M, Knight R (2009) Microbial community profiling for human microbiome projects: tools, techniques, and challenges. Genome Res 19:1141–1152CrossRefGoogle Scholar
  29. Hanage WP (2014) Microbiome science needs a healthy dose of scepticism. Nature 512:247–249CrossRefGoogle Scholar
  30. Harley ITW, Karp CL (2012) Obesity and the gut microbiome: striving for causality. Mol Metab 1:21–31CrossRefGoogle Scholar
  31. Hildebrandt MA et al (2009) High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 137:1716–1724CrossRefGoogle Scholar
  32. Hobsley M et al (2009) Does Helicobacter pylori really cause duodenal ulcers? No. BMJ 339:b2788CrossRefGoogle Scholar
  33. Hooi JKY et al (2017) Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis. Gastroenterology 153f:420–429CrossRefGoogle Scholar
  34. Hooks KB, O’Malley MA (2017) Dysbiosis and its discontents. mBio 8(5):e0149217CrossRefGoogle Scholar
  35. Hryckowian AJ et al (2018) Microbiota-accessible carbohydrates suppress Clostridium difficile infection in a murine model. Nat Microbiol 3:662–669CrossRefGoogle Scholar
  36. Human Microbiome Project Consortium (2012) Structure, function and diversity of the healthy human microbiome. Nature 486:207–214CrossRefGoogle Scholar
  37. Huss J (2014) Methodology and ontology in microbiome research. Biol Theor 9:392–400CrossRefGoogle Scholar
  38. Kelly JR et al (2016) Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res 82:109–118CrossRefGoogle Scholar
  39. Kelly JR et al (2017) Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects. Brain Behav Immun 61:50–59CrossRefGoogle Scholar
  40. Kendler KS (2005) “A gene for…”: the nature of gene action in psychiatric disorders. Am J Psychiatr 162:1243–1252CrossRefGoogle Scholar
  41. Kidd M, Modlin IM (1998) A century of Helicobacter pylori. Digestion 59:1–15CrossRefGoogle Scholar
  42. Kristensen NB et al (2016) Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: a systematic review of randomized controlled trials. Genome Med 8:52CrossRefGoogle Scholar
  43. Kusters JG et al (2006) Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev 19:449–490CrossRefGoogle Scholar
  44. Lawley TD, Walker AW (2013) Intestinal colonization resistance. Immunology 138:1–11CrossRefGoogle Scholar
  45. Levenstein S et al (2015) Psychological stress increases risk for peptic ulcer, regardless of Helicobacter pylori infection or use of nonsteroidal anti-inflammatory drugs. Clin Gastroenterol Hepatol 13:498–506CrossRefGoogle Scholar
  46. Ley RE et al (2006) Microbial ecology: human gut microbes associated with obesity. Nature 444:1022–1023CrossRefGoogle Scholar
  47. Lin D, Koskella B (2014) Friend and foe: factors influencing the movement of the bacterium Helicobacter pylori along the parasitism-mutualism continuum. Evol Appl 8:9–22CrossRefGoogle Scholar
  48. Liou AP et al (2013) Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med. CrossRefGoogle Scholar
  49. Lloyd-Price J et al (2016) The healthy human microbiome. Genome Med 8:51CrossRefGoogle Scholar
  50. Malfertheiner P et al (2009) Peptic ulcer disease. Lancet 374:1449–1461CrossRefGoogle Scholar
  51. Malfertheiner P et al (2014) Helicobacter pylori: perspectives and time trends. Nat Rev Gastroenterol Hepatol 11:628–638CrossRefGoogle Scholar
  52. Manor O, Borenstein E (2017) Systematic characterization and analysis of the taxonomic drivers of functional shifts in the human microbiome. Cell 21:254–267Google Scholar
  53. Marshall BJ (1995) Helicobacter pylori in peptic ulcer: Have Koch’s postulates been fulfilled? Ann Med 27:565–568CrossRefGoogle Scholar
  54. Marshall BJ (2005) Helicobacter connections (Nobel lecture, December 8, 2005). Reprinted in ChemMedChem (2006) 1:783–802CrossRefGoogle Scholar
  55. Marshall BJ, Warren JR (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 16:1311–1315CrossRefGoogle Scholar
  56. Marshall BJ et al (1985) Attempt to fulfil Koch’s postulates for pyloric Campylobacter. Med J Aust 142:436–439CrossRefGoogle Scholar
  57. Mayer EA et al (2014) Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci 34:15490–15496CrossRefGoogle Scholar
  58. McColl KEL et al (1993) A study of the pathogenesis of Helicobacter pylori negative chronic duodenal ulceration. Gut 34:762–768CrossRefGoogle Scholar
  59. Mitchell SD (2000) Dimensions of scientific law. Philos Sci 67:242–265CrossRefGoogle Scholar
  60. Mithieux G (2018) Gut microbiota and host metabolism: What relationship? Neuroendocrinology 106:352–356CrossRefGoogle Scholar
  61. Moayyedi P et al (2015) Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 149:102–109.e6CrossRefGoogle Scholar
  62. Momozawa Y et al (2011) Characterization of bacteria in biopsies of colon and stools by high throughput sequencing of the V2 region of bacterial 16S rRNA gene in human. PLoS ONE 6:e16952CrossRefGoogle Scholar
  63. Neville BA et al (2018) Commensal Koch’s postulates: establishing causation in human microbiota research. Curr Opin Microbiol 42:47–52CrossRefGoogle Scholar
  64. Nguyen TLA et al (2015) How informative is the mouse for human gut microbiota research? Dis Model Mech 8:1–16CrossRefGoogle Scholar
  65. O’Malley MA, Skillings DJ (2018) Methodological strategies in microbiome research and their explanatory implications. Persp Sci 26:239–265CrossRefGoogle Scholar
  66. Parke EC et al (2018) A cautionary note for claims about the microbiome’s impact on the “self”. PLoS Biol 16(9):e2006654CrossRefGoogle Scholar
  67. Pocheville A et al (2017) Comparing causes—an information-theoretic approach to specificity, proportionality and stability. In: Leitgeb H et al (eds) Proceedings of the 15th congress of logic, methodology and philosophy of science. College Publications, London, pp 250–275Google Scholar
  68. Rees T et al (2018) How the microbiome challenges our concept of self. PLoS Biol 16(2):e2005358CrossRefGoogle Scholar
  69. Reich T et al (1975) The multifactorial model of disease transmission: I. Description of the model and its use in psychiatry. Br J Psychiatry 127:1–10CrossRefGoogle Scholar
  70. Ridaura VK et al (2013) Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341:1241214CrossRefGoogle Scholar
  71. Ross LN (2018) Causal selection and the pathway concept. Philos Sci 85:551–572CrossRefGoogle Scholar
  72. Ross LN, Woodward JF (2016) Koch’s postulates: an interventionist perspective. Stud Hist Philos Biol Biomed Sci 59:35–46CrossRefGoogle Scholar
  73. Round JL, Mazmanian SK (2009) The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9:313–323CrossRefGoogle Scholar
  74. Sampson TR, Mazmanian SK (2015) Control of brain development, function, and behavior by the microbiome. Cell Host Microbe 17:565–576CrossRefGoogle Scholar
  75. Schwabe RF, Jobin C (2013) The microbiome and cancer. Nat Rev Genet 13:800–812Google Scholar
  76. Sender R et al (2016) Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164:337–340CrossRefGoogle Scholar
  77. Stein RR et al (2013) Ecological modeling from time-series inference: insight into dynamics and stability of intestinal microbiota. PLoS Comput Biol 9:e1003388CrossRefGoogle Scholar
  78. Surana NK, Kasper DL (2017) Moving beyond microbiome-wide associations to causal microbe identification. Nature 552(7684):244–247CrossRefGoogle Scholar
  79. Susser M (1991) What is a cause and how do we know one? A grammar for pragmatic epidemiology. Am J Epidemiol 133(7):635–648CrossRefGoogle Scholar
  80. Sze MA, Schloss PD (2016) Looking for a signal in the noise: revisiting obesity and the microbiome. mBio 7:e01018-16CrossRefGoogle Scholar
  81. Thagard P (1998) Explaining disease: correlations, causes, and mechanisms. Minds Mach 8:61–78CrossRefGoogle Scholar
  82. Truax AD et al (2018) The inhibitory innate immune sensor NLRP12 maintains a threshold against obesity by regulating gut microbiota homeostasis. Cell Host Microbe 24:364–378CrossRefGoogle Scholar
  83. Turnbaugh PJ et al (2008) Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3:213–223CrossRefGoogle Scholar
  84. Turnbaugh PJ et al (2009) A core gut microbiome in obese and lean twins. Nature 457:480–484CrossRefGoogle Scholar
  85. van Nood E et al (2013) Duodenal infusion of donor feces for recurrent Clostridium difficile. NEJM 368:407–415CrossRefGoogle Scholar
  86. van Zanten SJOV, Sherman PM (1994) Helicobacter pylori infection as a cause of gastritis, duodenal ulcer, gastric cancer and nonulcer dyspepsia: a systematic overview. Can Med Assoc J 150:177–185Google Scholar
  87. Vonaesch P et al (2018) Pathogens, microbiome and the host: emergence of the ecological Koch’s postulates. FEMS Microbiol Rev 42:273–292CrossRefGoogle Scholar
  88. Wang H et al (2016) Effect of probiotics on central nervous system functions in animals and humans: a systematic review. J Neurogastroenterol Motil 22:589–605CrossRefGoogle Scholar
  89. Woodward J (2003) Making things happen: a theory of causal explanation. OUP, OxfordGoogle Scholar
  90. Woodward J (2006) Some varieties of robustness. J Econ Methodol 13:219–240CrossRefGoogle Scholar
  91. Woodward J (2010) Causation in biology: stability, specificity, and the choice of levels of explanation. Biol Philos 25:287–318CrossRefGoogle Scholar
  92. Yablo S (1992) Mental causation. Philos Rev 101:245–280CrossRefGoogle Scholar
  93. Zmora N et al (2018) Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell 174:1388–1405.e21CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Philosophy and Charles Perkins CentreUniversity of SydneySydneyAustralia
  2. 2.Department of Biological SciencesMacquarie UniversitySydneyAustralia
  3. 3.Philosophy, School of HumanitiesUniversity of AucklandAucklandNew Zealand
  4. 4.School of History and Philosophy of ScienceUniversity of SydneySydneyAustralia

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