Opinion

The germ-organ theory of non-communicable diseases

  • Nature Reviews Microbiology volume 16, pages 103110 (2018)
  • doi:10.1038/nrmicro.2017.158
  • Download Citation
Published:

Abstract

Gut dysbiosis is associated with many non-communicable human diseases, but the mechanisms maintaining homeostasis remain incompletely understood. Recent insights suggest that during homeostasis, epithelial hypoxia limits oxygen availability in the colon, thereby maintaining a balanced microbiota that functions as a microbial organ, producing metabolites contributing to host nutrition, immune education and niche protection. Dysbiosis is characterized by a shift in the microbial community structure from obligate to facultative anaerobes, suggesting oxygen as an important ecological driver of microbial organ dysfunction. The ensuing disruption of gut homeostasis can lead to non- communicable disease because microbiota-derived metabolites are either depleted or generated at harmful concentrations. This Opinion article describes the concept that host control over the microbial ecosystem in the colon is critical for the composition and function of our microbial organ, which provides a theoretical framework for linking microorganisms to non-communicable diseases.

  • Subscribe to Nature Reviews Microbiology for full access:

    $265

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

  2. 2.

    et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

  3. 3.

    et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).

  4. 4.

    et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 13, 440–447 (2012).

  5. 5.

    et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159–166 (2014).

  6. 6.

    et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).

  7. 7.

    et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 22, 299–306 (2012).

  8. 8.

    et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 22, 292–298 (2012).

  9. 9.

    et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).

  10. 10.

    et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481 (2008).

  11. 11.

    et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013).

  12. 12.

    et al. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer's disease. Sci. Rep. 6, 30028 (2016).

  13. 13.

    & What is a pathogen? Toward a process view of host-parasite interactions. Virulence 5, 775–785 (2014).

  14. 14.

    & Microbiology: Ditch the term pathogen. Nature 516, 165–166 (2014).

  15. 15.

    & Nomenclature: Replace 'pathogens' with 'perceptogens'. Nature 518, 35 (2015).

  16. 16.

    , & What happened to Koch's postulates in diarrhea? Environ. Microbiol. (2017).

  17. 17.

    Gut microbiota — at the intersection of everything? Nat. Rev. Gastroenterol. Hepatol. 14, 321–322 (2017).

  18. 18.

    , , & Collateral damage: microbiota-derived metabolites and immune function in the antibiotic era. Cell Host Microbe 16, 156–163 (2014).

  19. 19.

    & The gut flora as a forgotten organ. EMBO Rep. 7, 688–693 (2006).

  20. 20.

    et al. Towards the human intestinal microbiota phylogenetic core. Environ. Microbiol. 11, 2574–2584 (2009).

  21. 21.

    , & The “Microflora Hypothesis” of allergic disease. Adv. Exp. Med. Biol. 635, 113–134 (2008).

  22. 22.

    & Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases. Curr. Opin. Infect. Dis. 22, 292–301 (2009).

  23. 23.

    & The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313–323 (2009).

  24. 24.

    in Microbial–Host Interaction: Tolerance versus Allergy. 64th Nestlé Nutrition Institute Workshop, Pediatric Program (eds Brandtzaeg, P., Isolauri, E. & Prescott, S. L.) 11–22 (Sydney, 2008).

  25. 25.

    , & The keystone-pathogen hypothesis. Nat. Rev. Microbiol. 10, 717–725 (2012).

  26. 26.

    et al. Distinct antimicrobial peptide expression determines host species-specific bacterial associations. Proc. Natl Acad. Sci. USA 110, E3730–E3738 (2013).

  27. 27.

    Lessons from a cooperative, bacterial-animal association: the Vibrio fischeri-Euprymna scolopes light organ symbiosis. Annu. Rev. Microbiol. 50, 591–624 (1996).

  28. 28.

    , & Consumption of human milk glycoconjugates by infant-associated bifidobacteria: mechanisms and implications. Microbiology 159, 649–664 (2013).

  29. 29.

    et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat. Immunol. 11, 76–83 (2010).

  30. 30.

    et al. R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease. J. Exp. Med. (2017).

  31. 31.

    et al. Microbiota-activated PPAR-γ-signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357, 570–575 (2017).

  32. 32.

    et al. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J. Exp. Med. 193, 1027–1034 (2001).

  33. 33.

    et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).

  34. 34.

    et al. The long-term stability of the human gut microbiota. Science 341, 1237439 (2013).

  35. 35.

    & The pyromaniac inside you: Salmonella metabolism in the host gut. Annu. Rev. Microbiol. 69, 31–48 (2015).

  36. 36.

    , , , & Survival and implantation of Escherichia coli in the intestinal tract. Infect. Immun. 39, 686–703 (1983).

  37. 37.

    , , & Short-chain fatty acids: ready for prime time? Nutr. Clin. Pract. 21, 351–366 (2006).

  38. 38.

    & Eating for two: how metabolism establishes interspecies interactions in the gut. Cell Host Microbe 10, 336–347 (2011).

  39. 39.

    , , , & Mechanisms of microbial hydrogen disposal in the human colon and implications for health and disease. Annu. Rev. Food Sci. Technol. 1, 363–395 (2010).

  40. 40.

    et al. Host-gut microbiota metabolic interactions. Science 336, 1262–1267 (2012).

  41. 41.

    et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 54, 2325–2340 (2013).

  42. 42.

    , & Butyrate and the colonocyte. Production, absorption, metabolism, and therapeutic implications. Adv. Exp. Med. Biol. 427, 123–134 (1997).

  43. 43.

    et al. Butyrate affects differentiation, maturation and function of human monocyte-derived dendritic cells and macrophages. Clin. Exp. Immunol. 130, 245–255 (2002).

  44. 44.

    , , , & Butyrate inhibits functional differentiation of human monocyte-derived dendritic cells. Cell. Immunol. 253, 54–58 (2008).

  45. 45.

    et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

  46. 46.

    et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

  47. 47.

    et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

  48. 48.

    et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

  49. 49.

    , , & The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc. Natl Acad. Sci. USA 111, 2247–2252 (2014).

  50. 50.

    et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).

  51. 51.

    Dysbiosis in inflammatory bowel diseases: the oxygen hypothesis. ISME J. 7, 1256–1261 (2013).

  52. 52.

    , & Oxygen as a driver of gut dysbiosis. Free Radic. Biol. Med. 105, 93–101 (2017).

  53. 53.

    et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 487, 104–108 (2012).

  54. 54.

    et al. Western diet induces dysbiosis with increased E coli in CEABAC10 mice, alters host barrier function favouring AIEC colonisation. Gut 63, 116–124 (2014).

  55. 55.

    , & Co-trimoxazole impairs colonization resistance in healthy volunteers. J. Antimicrob. Chemother. 30, 685–691 (1992).

  56. 56.

    , , & Alterations in composition and diversity of the intestinal microbiota in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol. Motil. 24, 521–530 (2012).

  57. 57.

    et al. Microbial community analysis reveals high level phylogenetic alterations in the overall gastrointestinal microbiota of diarrhoea-predominant irritable bowel syndrome sufferers. BMC Gastroenterol. 9, 95 (2009).

  58. 58.

    et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 13, R79 (2012).

  59. 59.

    et al. The intestinal microbiota plays a role in Salmonella-induced colitis independent of pathogen colonization. PLoS ONE 6, e20338 (2011).

  60. 60.

    , , & Intestinal microbial profiles in extremely preterm infants with and without necrotizing enterocolitis. Acta Paediatr. 102, 129–136 (2013).

  61. 61.

    et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338, 120–123 (2012).

  62. 62.

    et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 204 (2007).

  63. 63.

    et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339, 708–711 (2013).

  64. 64.

    et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8, 292–300 (2010).

  65. 65.

    et al. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467, 426–429 (2010).

  66. 66.

    et al. Intestinal microbiota shifts towards elevated commensal Escherichia coli loads abrogate colonization resistance against Campylobacter jejuni in mice. PLoS ONE 7, e35988 (2012).

  67. 67.

    , & Effect of streptomycin on susceptibility of intestinal tract to experimental Salmonella infection. Proc. Soc. Exp. Biol. Med. 86, 132–137 (1954).

  68. 68.

    Studies on the habitation of pathogenic Escherichia coli in the intestinal tract of mice. I. Comparative experiments on the habitation of each type of resistant pathogenic Escherichia coli under an administration of streptomycin [Japanese]. Paediatr. Jpn. 65, 385–393 (1961).

  69. 69.

    Studies on the habitation of pathogenic Escherichia coli in the intestinal tract of mice. II. Experimental inoculation of type 055 Escherichia coli after long-term administration of streptomycin [Japanese]. Paediatr. Jpn. 65, 394–399 (1961).

  70. 70.

    , & Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol. 33, 496–503 (2015).

  71. 71.

    Antibacterial mechanisms of the mouse gut. II. The role of Eh and volatile fatty acids in the normal gut. Br. J. Exp. Pathol. 44, 209–219 (1963).

  72. 72.

    et al. Neutrophil elastase alters the murine gut microbiota resulting in enhanced Salmonella colonization. PLoS ONE 7, e49646 (2012).

  73. 73.

    et al. A multi-omic view of host-pathogen-commensal interplay in -mediated intestinal infection. PLoS ONE 8, e67155 (2013).

  74. 74.

    et al. Depletion of butyrate-producing Clostridia from the gut microbiota drives an aerobic luminal expansion of Salmonella. Cell Host Microbe 19, 443–454 (2016).

  75. 75.

    et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 17, 662–671 (2015).

  76. 76.

    et al. A bioassay to measure energy metabolism in mouse colonic crypts, organoids, and sorted stem cells. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G1–G9 (2015).

  77. 77.

    et al. Microbial respiration and formate oxidation as metabolic signatures of inflammation-associated dysbiosis. Cell Host Microbe 21, 208–219 (2017).

  78. 78.

    et al. Virulence factors enhance Citrobacter rodentium expansion through aerobic respiration. Science 353, 1249–1253 (2016).

  79. 79.

    et al. Critical roles of Notch and Wnt/β-catenin pathways in the regulation of hyperplasia and/or colitis in response to bacterial infection. Infect. Immun. 80, 3107–3121 (2012).

  80. 80.

    et al. Novel changes in NF-κB activity during progression and regression phases of hyperplasia: role of MEK, ERK, and p38. J. Biol. Chem. 285, 33485–33498 (2010).

  81. 81.

    et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517, 205–208 (2015).

  82. 82.

    et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 17, 49–60 (2013).

  83. 83.

    , , & Contribution of Salmonella typhimurium virulence factors to diarrheal disease in calves. Infect. Immun. 67, 4879–4885 (1999).

  84. 84.

    et al. Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40, 66–77 (2014).

  85. 85.

    et al. Genetic and metabolic signals during acute enteric bacterial infection alter the microbiota and drive progression to chronic inflammatory disease. Cell Host Microbe 19, 21–31 (2016).

  86. 86.

    et al. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502, 96–99 (2013).

  87. 87.

    et al. Host-mediated sugar oxidation promotes post-antibiotic pathogen expansion. Nature 534, 697–699 (2016).

  88. 88.

    , & Clostridium difficile colitis. N. Engl. J. Med. 330, 257–262 (1994).

  89. 89.

    & Bile salts and glycine as cogerminants for Clostridium difficile spores. J. Bacteriol. 190, 2505–2512 (2008).

  90. 90.

    et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat. Commun. 5, 3114 (2014).

  91. 91.

    Efficiency of various bile salt preparations for stimulation of Clostridium difficile spore germination. J. Clin. Microbiol. 18, 1017–1019 (1983).

  92. 92.

    et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013).

  93. 93.

    et al. Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G310–G319 (2014).

  94. 94.

    et al. Association between dietary patterns and plasma biomarkers of obesity and cardiovascular disease risk. Am. J. Clin. Nutr. 73, 61–67 (2001).

  95. 95.

    et al. Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota. Proc. Natl Acad. Sci. USA 111, 4268–4273 (2014).

  96. 96.

    , , & Uncovering the trimethylamine-producing bacteria of the human gut microbiota. Microbiome 5, 54 (2017).

  97. 97.

    , , & The evolution of the host microbiome as an ecosystem on a leash. Nature 548, 43–51 (2017).

  98. 98.

    , & From homeostasis to pathology: decrypting microbe-host symbiotic signals in the intestinal crypt. Philos. Trans. R. Soc. Lond. B. Biol. Sci. (2016).

  99. 99.

    Louis Pasteur (1822–1895). Microbes Infect. 5, 553–560 (2003).

  100. 100.

    Etudes Sur La Maladie Des Vers A Soie. Vol. 1,2 (Gauthier-Villars, 1870).

  101. 101.

    On the etiology of leprosy. Br. Foreign Med. Chir. Rev. 55, 459–489 (1875).

  102. 102.

    Massenhafte entwickelung von amöben im dickdarm. Arch. Pathol. Anat. Physiol. 65, 196–211 (1875).

  103. 103.

    Untersuchungen über Die aetiologie der milzbrandkrankheit, begründet auf der entwicklungsgeschichte des Bacillus anthracis. Beiträge Biol. Pflanzen 2, 277–308 (1877).

  104. 104.

    Die organismen in den organen bei typhus abdominalis [German]. Virchows Arch. 81, 58–74 (1880).

  105. 105.

    Note sur la maladie nouvelle provoquee par la salive d'un enfant mort de la rage [French]. C. R. Acad. Sci. 92, 159–165 (1881).

  106. 106.

    A fatal form of septicaemia, produced by the injection of human saliva. An experimental research. Bull. Nat. Board Health USA 2, 781–783 (1881).

  107. 107.

    Die aetiologie der tuberkulose. Berliner Klinische Wochenschrift 15, 221–230 (1882).

  108. 108.

    Der zweite bericht der deutschen cholerakommission. Dt. Med. Wochenschr. 9, 743–744 (1883).

  109. 109.

    Ueber die cholerabakterien. Dt. Med. Wochenschr. 10, 725–728 (1884).

  110. 110.

    Zur ätiologie des abdominaltyphus. Mitteilungen Kaiserlichen Gesundheitsamt 2, 372–420 (1884).

  111. 111.

    Untersuchungen über die bedeutung der mikroorganismen für die entstehung der diphtherie beim menschen, bei der taube und beim kalbe. Mitth. a. d. Kaiserl. Gesundheitsamtes 2, 421–499 (1884).

  112. 112.

    Ueber infectiösen tetanus. Dt. Med. Wochenschr. 10, 842–844 (1884).

  113. 113.

    La peste bubonique à Hong-Kong. Ann. l'Institut Pasteur 8, 662–667 (1894).

  114. 114.

    The bacillus of bubonic plague. Lancet 144, 428–430 (1894).

  115. 115.

    Ueber den dysenterie-bacillus (Bacillus dysenteriae). Zentralbl Bakteriol Orig 24, 913–918 (1898).

  116. 116.

    Contribution à l'étude de la diphtérie Ann. Inst. Pasteur 2, 421–499 (1888).

  117. 117.

    Über lösliche, durch aseptische autolyse erhaltene giftstoffe von ruhr- und typhus-bazillen. Dtsch. Med. Wochenschr. 29, 26–28 (1903).

  118. 118.

    & Ueber freie receptoren von typhus- und dysenteriebazillen und über das dysenterietoxin. Dtsch. Med. Wochenschr. 29, 61–62 (1903).

  119. 119.

    & Ueber das zustandekommen der diphtherie — immunität und der tetanus — immunität bei tieren. Dt. Med. Wochenschr. 16, 1113–1114 (1890).

  120. 120.

    Untersuchungen über das zustandekommen de diphtherie — immunität bei tieren. Dt. Med. Wochenschr. 16, 1145–1148 (1890).

  121. 121.

    , & Summary report of the experiments conducted at Pouilly-le-Fort, near Melun, on the anthrax vaccination, 1881. C. R. Acad. Sci. 92, 1378–1383 (1881).

  122. 122.

    Methode pour prevenir l rage apres morsure. C. R. Acad. Sci. 101, 765–772 (1885).

  123. 123.

    & Experimentele untersuchungen zur frage der schutzimpfungen des menschen gegen den typhus abdominalis. Dtsch. Med. Wochenschr. 22, 735–737 (1896).

  124. 124.

    et al. Low-oxygen tensions found in Salmonella-infected gut tissue boost Salmonella replication in macrophages by impairing antimicrobial activity and augmenting Salmonella virulence. Cell. Microbiol. 17, 1833–1847 (2015).

Download references

Acknowledgements

Work in the authors' laboratory was supported by public health service grants AI112445, AI112949 and AI096528 (A.J.B.).

Author information

Affiliations

  1. Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, California 95616, USA.

    • Mariana X. Byndloss
    •  & Andreas J. Bäumler

Authors

  1. Search for Mariana X. Byndloss in:

  2. Search for Andreas J. Bäumler in:

Contributions

M.X.B. and A.J.B. substantially contributed to the discussion of content and review and editing of the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Andreas J. Bäumler.