Abstract
The current ‘Darwinian’ synthesis of the hygiene (or ‘Old Friends’) hypothesis suggests that the increase in chronic inflammatory disorders that started in Europe in the mid-19th century and progressed until the late 20th century is at least partly attributable to immunodysregulation resulting from lack of exposure to microorganisms that were tasked by co-evolutionary processes with establishing the ‘normal’ background levels of immunoregulation, a role that they perform in concert with the normal microbiota. This is an example of ‘evolved dependence’. The relevant organisms co-evolved with mammals, already accompanied early hominids in the Paleolithic era and are associated with animals, mud and faeces. These organisms often establish stable carrier states, or are encountered continuously in primitive environments as ‘pseudocommensals’ from mud and water. These organisms were not lost during the first epidemiological transition, which might even have resulted in increased exposure to them. However, the crucial organisms are lost progressively as populations undergo the second epidemiological transition (modern urban environment). Recently evolved sporadic ‘childhood infections’ are not likely to have evolved immunoregulatory roles, and epidemiology supports this contention. The consequences of the loss of the Old Friends and distortion of the microbiota are aggravated by other modern environmental changes that also lead to enhanced inflammatory responses (obesity, vitamin D deficiency, pollution (dioxins), etc.). The range of chronic inflammatory disorders affected may be larger than had been assumed (allergies, autoimmunity, inflammatory bowel disease, but also coeliac disease, food allergy, vascular disease, some cancers, and depression/anxiety when accompanied by raised inflammatory cytokines).
References
1.
Strachan DP: Hay fever, hygiene, and household size. BMJ 1989;299:1259–1260.
2.
Dunder T, Tapiainen T, Pokka T, Uhari M: Infections in child day care centers and later development of asthma, allergic rhinitis, and atopic dermatitis: prospective follow-up survey 12 years after controlled randomized hygiene intervention. Arch Pediatr Adolesc Med 2007;161:972–977.
3.
Rook GAW, Stanford JL: Give us this day our daily germs. Immunol Today 1998;19:113–116.
4.
Bach JF: The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347:911–920.
5.
Wildin RS, Smyk-Pearson S, Filipovich AH: Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. J Med Genet 2002;39:537–545.
6.
De Mazancourt C, Loreau M, Dieckmann U: Understanding mutualism when there is adaptation to the partner. J Ecol 2005;93:305–314.
7.
Jeon KW: Development of cellular dependence on infective organisms: micrurgical studies in amoebas. Science 1972;176:1122–1123.
8.
Armelagos GJ, Brown PJ, Turner B: Evolutionary, historical and political economic perspectives on health and disease. Soc Sci Med 2005;61:755–765.
9.
Van Blerkom LM: Role of viruses in human evolution. Am J Phys Anthropol 2003;37 (suppl):14–46.
10.
De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, Collini S, Pieraccini G, Lionetti P: Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 2010;107:14691–14696.
11.
Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, Xavier RJ, Teixeira MM, Mackay CR: Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009;461:1282–1286.
12.
Dos Santos VM, Muller M, de Vos WM: Systems biology of the gut: the interplay of food, microbiota and host at the mucosal interface. Curr Opin Biotechnol 2010;21:1–12.
13.
Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G, Grangette C, Vasquez N, Pochart P, Trugnan G, Thomas G, Blottiere HM, Dore J, Marteau P, Seksik P, Langella P: Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 2008;105:16731–16736.
14.
Kalliomaki M, Collado MC, Salminen S, Isolauri E: Early differences in fecal microbiota composition in children may predict overweight. Am J Clin Nutr 2008;87:534–538.
15.
Reyes A, Haynes M, Hanson N, Angly FE, Heath AC, Rohwer F, Gordon JI: Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature 2010;466:334–338.
16.
Pelosi U, Porcedda G, Tiddia F, Tripodi S, Tozzi AE, Panetta V, Pintor C, Matricardi PM: The inverse association of salmonellosis in infancy with allergic rhinoconjunctivitis and asthma at school age: a longitudinal study. Allergy 2005;60:626–630.
17.
Matricardi PM, Rosmini F, Riondino S, Fortini M, Ferrigno L, Rapicetta M, Bonini S: Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma; epidemiological study. BMJ 2000;320:412–417.
18.
Umetsu DT, McIntire JJ, DeKruyff RH: TIM-1, hepatitis A virus and the hygiene theory of atopy: association of TIM-1 with atopy. J Pediatr Gastroenterol Nutr 2005;40 (suppl 1):S43.
19.
Seiskari T, Kondrashova A, Viskari H, Kaila M, Haapala AM, Aittoniemi J, Virta M, Hurme M, Uibo R, Knip M, Hyoty H: Allergic sensitization and microbial load – a comparison between Finland and Russian Karelia. Clin Exp Immunol 2007;148:47–52.
20.
Yazdanbakhsh M, Wahyuni S: The role of helminth infections in protection from atopic disorders. Curr Opin Allergy Clin Immunol 2005;5:386–391.
21.
Correale J, Farez M: Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol 2007;61:97–108.
22.
Correale J, Farez M, Razzitte G: Helminth infections associated with multiple sclerosis induce regulatory B cells. Ann Neurol 2008;64:187–199.
23.
Walk ST, Blum AM, Ewing SA, Weinstock JV, Young VB: Alteration of the murine gut microbiota during infection with the parasitic helminth Heligmosomoides polygyrus. Inflamm Bowel Dis 2010;16:1841–1849.
24.
Whitlock DR, Feelisch M: Soil bacteria, nitrite, and the skin; in Rook GAW (eds): The Hygiene Hypothesis and Darwinian Medicine. Basel, Birkhäuser, 2009, p 103–116.
25.
Donnet-Hughes A, Perez PF, Dore J, Leclerc M, Levenez F, Benyacoub J, Serrant P, Segura-Roggero I, Schiffrin EJ: Potential role of the intestinal microbiota of the mother in neonatal immune education. Proc Nutr Soc 2010;69:407–415.
26.
Zivkovic AM, German JB, Lebrilla CB, Mills DA: Microbes and Health Sackler Colloquium: Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci USA, Epub ahead of print.
27.
Zuany-Amorim C, Sawicka E, Manlius C, Le Moine A, Brunet LR, Kemeny DM, Bowen G, Rook G, Walker C: Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 2002;8:625–629.
28.
Ricklin-Gutzwiller ME, Reist M, Peel JE, Seewald W, Brunet LR, Roosje PJ: Intradermal injection of heat-killed Mycobacterium vaccae in dogs with atopic dermatitis: a multicentre pilot study. Vet Dermatol 2007;18:87–93.
29.
Friberg IM, Bradley JE, Jackson JA: Macroparasites, innate immunity and immunoregulation: developing natural models. Trends Parasitol 2010;26:540–549.
30.
Rook GAW: The broader implications of the hygiene hypothesis. Immunology 2009;126:3–11.
31.
Correale J, Farez M: Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol 2007;61:97–108.
32.
Van Die I, Cummings RD: Glycan gimmickry by parasitic helminths: a strategy for modulating the host immune response? Glycobiology 2010;20:2–12.
33.
Grainger JR, Smith KA, Hewitson JP, McSorley HJ, Harcus Y, Filbey KJ, Finney CAM, Greenwood EJD, Knox DP, Wilson MS, Belkaid Y, Rudensky AY, Maizels RM: Helminth secretions induce de novo T-cell Foxp3 expression and regulatory function through the TGF-I pathway. J Exp Med 2010;207:2331–2341.
34.
Hang L, Setiawan T, Blum AM, Urban J, Stoyanoff K, Arihiro S, Reinecker HC, Weinstock JV: Heligmosomoides polygyrus infection can inhibit colitis through direct interaction with innate immunity. J Immunol 2010;185:3184–3189.
35.
Umetsu DT, DeKruyff RH: Microbes, apoptosis and TIM-1 in the development of asthma. Clin Exp Immunol 2010;160:125–129.
36.
Ehlers S, Rook GAW: The role of bacterial and parasitic infections in chronic inflammatory disorders and autoimmunity; in Kaufmann SH, Rouse BT, Sacks DL (eds): Immunology of Infectious Diseases. Washington, American Society for Microbiology, 2011, pp 521–535.
37.
Round JL, Mazmanian SK: The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 2009;9:313–323.
38.
Kohashi O, Kohashi Y, Takahashi T, Ozawa A, Shigematsu N: Reverse effect of Gram-positive bacteria vs. Gram-negative bacteria on adjuvant-induced arthritis in germ-free rats. Microbiol Immunol 1985;29:487–497.
39.
Lee YK, Menezes JS, Umesaki Y, Mazmanian SK: Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA, Epub ahead of print.
40.
Schnoeller C, Rausch S, Pillai S, Avagyan A, Wittig BM, Loddenkemper C, Hamann A, Hamelmann E, Lucius R, Hartmann S: A helminth immunomodulator reduces allergic and inflammatory responses by induction of IL-10-producing macrophages. J Immunol 2008;180:4265–4272.
41.
Ivanov II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB, Littman DR: Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 2008;4:337–349.
42.
Iliev ID, Mileti E, Matteoli G, Chieppa M, Rescigno M: Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning. Mucosal Immunol 2009;2:340–350.
43.
Cash HL, Whitham CV, Behrendt CL, Hooper LV: Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 2006;313:1126–1130.
44.
Erdman SE, Rao VP, Olipitz W, Taylor CL, Jackson EA, Levkovich T, Lee CW, Horwitz BH, Fox JG, Ge Z, Poutahidis T: Unifying roles for regulatory T cells and inflammation in cancer. Int J Cancer 2010;126:1651–1665.
45.
Van Baarlen P, Troost FJ, van Hemert S, van der Meer C, de Vos WM, de Groot PJ, Hooiveld GJ, Brummer RJ, Kleerebezem M: Differential NF-ĸB pathways induction by Lactobacillus plantarum in the duodenum of healthy humans correlating with immune tolerance. Proc Natl Acad Sci USA 2009;106:2371–2376.
46.
Foligne B, Zoumpopoulou G, Dewulf J, Ben Younes A, Chareyre F, Sirard JC, Pot B, Grangette C: A key role of dendritic cells in probiotic functionality. PLoS One 2007;2:e313.
47.
Fumagalli M, Pozzoli U, Cagliani R, Comi GP, Riva S, Clerici M, Bresolin N, Sironi M: Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions. J Exp Med 2009;206:1395–1408.
48.
Barnes KC, Grant AV, Gao P: A review of the genetic epidemiology of resistance to parasitic disease and atopic asthma: common variants for common phenotypes? Curr Opin Allergy Clin Immunol 2005;5:379–385.
49.
Fredericks CA, Drabant EM, Edge MD, Tillie JM, Hallmayer J, Ramel W, Kuo JR, Mackey S, Gross JJ, Dhabhar FS: Healthy young women with serotonin transporter SS polymorphism show a pro-inflammatory bias under resting and stress conditions. Brain Behav Immun 2010;24:350–357.
50.
Smith AM, Rahman FZ, Hayee B, Graham SJ, Marks DJ, Sewell GW, Palmer CD, Wilde J, Foxwell BM, Gloger IS, Sweeting T, Marsh M, Walker AP, Bloom SL, Segal AW: Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn’s disease. J Exp Med 2009;206:1883–1897.
51.
Riedler J, Braun-Fahrlander C, Eder W, Schreuer M, Waser M, Maisch S, Carr D, Schierl R, Nowak D, von Mutius E: Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 2001;358:1129–1133.
52.
Peters M, Kauth M, Scherner O, Gehlhar K, Steffen I, Wentker P, von Mutius E, Holst O, Bufe A: Arabinogalactan isolated from cowshed dust extract protects mice from allergic airway inflammation and sensitization. J Allergy Clin Immunol 2010;126:648–656. e1–4.
53.
Von Mutius E: 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: farm lifestyles and the hygiene hypothesis. Clin Exp Immunol 2010;160:130–135.
54.
Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI: A core gut microbiome in obese and lean twins. Nature 2009;457:480–484.
55.
Collins SM, Bercik P: The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 2009;136:2003–2014.
56.
Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, Adikibi T, Pridgeon C, Dallman M, Loke TK, Robinson DS, Barrat FJ, O’Garra A, Lavender P, Lee TH, Corrigan C, Hawrylowicz CM: Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest 2006;116:146–155.
57.
Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B: The aryl hydrocarbon receptor links Th17-cell-mediated autoimmunity to environmental toxins. Nature 2008;453:106–109.
58.
Zaccone P, Fehervari Z, Jones FM, Sidobre S, Kronenberg M, Dunne DW, Cooke A: Schistosoma mansoni antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes. Eur J Immunol 2003;33:1439–1449.
59.
Summers RW, Elliott DE, Urban JF Jr, Thompson R, Weinstock JV: Trichuris suis therapy in Crohn’s disease. Gut 2005;54:87–90.
60.
Blount D, Hooi D, Feary J, Venn A, Telford G, Brown A, Britton J, Pritchard D: Immunological profiles of subjects recruited for a randomized, placebo-controlled clinical trial of hookworm infection. Am J Trop Med Hyg 2009;81:911–916.
61.
Summers RW, Elliott DE, Urban JF Jr, Thompson RA, Weinstock JV: Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology 2005;128:825–832.
62.
Rook GAW, Dalgleish A: Infection, immunoregulation and cancer. Immunol Rev 2010 (in press).
63.
Raison CL, Lowry CA, Rook GAW: Inflammation, sanitation and consternation: loss of contact with co-evolved, tolerogenic micro-organisms and the pathophysiology and treatment of major depression. Arch Gen Psychiatry 2010 (in press).
64.
Yan F, Polk DB: Probiotics: progress toward novel therapies for intestinal diseases. Curr Opin Gastroenterol 2010;26:95–101.
© 2011 S. Karger AG, Basel
2011
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
