Diet promotes dysbiosis and colitis in susceptible hosts

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Diet promotes dysbiosis and colitis in susceptible hosts

  1. 1. NEWS & VIEWS GUT MICROBIOTADiet promotes dysbiosis and colitisin susceptible hostsR. Balfour SartorNew findings demonstrate novel interactions between diet, bacteria, genetic susceptibility and immuneresponses in IBD. Milk fat increases production of taurocholine-conjugated bile acids, which promotes growthof sulphate-reducing bacteria that cause immune-mediated colitis in susceptible mice. These observations willguide human studies that might improve dietary advice for patients with IBD.Sartor, R. B. Nat. Rev. Gastroenterol. Hepatol. 9, 561–562 (2012); published online 14 August 2012; doi:10.1038/nrgastro.2012.157Physicians are poorly equipped to answer one bacterial community structure.4 Ingestion of of milk-fat consumption also increased theof the questions most frequently posed by saturated milk fat (37% of consumed calories) incidence and aggressiveness of experimen‑patients with Crohn’s disease and ulcerative by mice selectively expanded a population of tal colitis and proinflammatory cytokinecolitis: how should I alter my diet to control normally low abundance sulphate-reducing production in IL‑10-deficient mice, but hadmy disease?1 Many patients are convinced Deltaproteobacteria, of which Bilophilia no detrimental effect on wild-type mice.that diet affects their disease course and wadsworthia is prototypical. Isocaloric con­ Expansion of the B. wadsworthia popu­lationsymptoms, and consequently alter their food sumption of polyunsaturated fat (safflower was dependent on increased concentrationsintake on the basis of their personal experi‑ oil) altered faecal bacterial profiles in the of taurine-conjugated bile acids as a resultences.2 Evolving dietary patterns are plausi‑ mice, but did not promote growth of Delta­ of ingestion of milk fat. As its name implies,ble environmental mediators of the increased proteobacteria or B. wadsworthia. High levels B. wadsworthia—and other functionallyincidence of IBD in the second half of the20th century in North America and WesternEurope, and of the more recent explosion inincidence of these diseases in Asian, Eastern LiverEuropean and South American countries thathave adopted Western lifestyle practices.3 GallbladderNow, in elegantly designed experiments inmice, Devkota and colleagues4 convincingly Milk fat Taurine-conjugateddemon­strate that ingesting saturated milk fat bile acidspromotes more aggressive colitis in IL‑10-deficient mice, by expanding a normally rare Bilophilia wadsworthia growthbacterial population that induces pathogenicT‑helper‑1 (TH1) immune responses. The investigators carefully dissected howconsuming milk fat indirectly altered the Macrophage Antigen IL-12 p40 Taurine IL-6Figure 1 | Diet promotes dysbiosis and colitis ▶ deconjugationin susceptible hosts. Milk fat stimulatesproduction of taurine-conjugated bile acids, Dendriticwhich in turn increases intraluminal growth of cellBilophilia wadsworthia. This organism thenstimulates production of immune cytokines bymacrophages and dendritic cells, which then Antigen presentationstimulate bacterial-antigen-specific TH1 cells Colitisto secrete IFN‑γ that causes colitis. Analternative pathway that might be involved,hence the question mark, is B. wadsworthia Hydrogen sulphide TH1deconjugation of taurine leading to hydrogen cellsulphide formation that possibly disrupts the ?mucosal barrier and inhibits colonic epithelial Disruption of mucosal barrier, IFN-γ inhibition of butyrate metabolism IL-6metabolism. Abbreviations: IFN, interferon; IL,interleukin; TH1, T‑helper‑1.NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY VOLUME 9  |  OCTOBER 2012  |  561 © 2012 Macmillan Publishers Limited. All rights reserved
  2. 2. NEWS & VIEWSsimilar bacterial species containing the dis‑ includ­ing B. wadsworthia, metabolize diet­ary recommendations to their patients. To realizesimatory sulphite reductase A gene (dsrA)— sul­phur to produce hydrogen sulphide. These this goal, however, essential translationalflourish in the presence of taurocholate metabolites have important physiological and clinical studies must be performed to(tauro­ holic acid, a sulphur-containing bile c effects on the intestine—butyrate is an essen‑ verify whether B. wadsworthia and relatedacid) owing to their ability to reduce sulphur, tial energy source for the distal colonocyte sulphate-­reducing Deltaproteobacteria definewhich generates hydrogen sulphide. Growth and hydrogen sulphide damages mucosal IBD subsets in patients and whether alteringof B. wadsworthia in selectively colonized integrity and inhibits butyrate metabolism.9 milk-fat intake influences human microbiota(mono­associated) gnotobiotic Il10–/– mice Induction of taurocholic acid secretion by community profiles and, most importantly,required exogenous taurocholine in the consumption of milk fat provides metabolic IBD disease activity. By stimulating suchabsence of milk-fat consumption, and tauro­ substrates for sulphate-reducing bacte‑ clinical and translational investigations, thecholine-­fed mono­associated Il10–/– mice rial species. Finally, dietary carbohydrates innovative study by Devkota et al.4 coulddeveloped colitis and had increased IFN‑γ rapidly alter gene expression in gut bacteria, ultimately influence clinical care and evenproduction. Thus, ingestion of saturated including mucolytic enzyme activity that can provide a dietary guide to prevent disease inmilk fat promotes a progression of events that diminish mucosal protection by decreasing genetically at-risk individuals. Meanwhile,culminates in potentiated risk of colitis in a the mucus barrier as a result of bacterial from the broader perspective, these resultssusceptible host (Figure 1). Milk fats increase utilization of host mucus glycans.10 validate a renewed mandate to better under‑the amount of taurine-conjugated bile acids Complete understanding of the progres‑ stand the influence of the Western dietthat promote growth and metabolic activ‑ sive events described by Devkota and col‑ on the pathogenesis of rapidly increasingity of sulphate-reducing, bile-acid-tolerant leagues4 will require mechanistic studies. A immune-mediated diseases and, in a globalbac­ erial species, such as B. wadsworthia, t primary unresolved question is the relative context, the mechanisms by which dietwhich in turn stimulate pathogenic immune contribution of bacterial-antigen-induced affects the composition and function of theresponses in genetically susceptible hosts. TH1 responses versus the toxic effects of enteric microbiota. The inherent complexity of this disease hydrogen sulphide and other B. wadsworthia Department of Medicine, Division ofmodel, in which environmental (dietary), metabolites on the mucosal barrier. IFN‑γ Gastroenterology and Hepatology, University ofmicro­ ial, immunological and genetic vari­ b production by CD4 + T cells co-cultured North Carolina at Chapel Hill, CB #7032, Room 7039, Biomolecular Building, Chapel Hill,ables interact to cause inflammation, might with dendritic cells that have been exposed NC 27599‑7032, USA.help explain several unresolved clini­ al c to B. wadsworthia lysate demonstrates that rbs@med.unc.eduobservations in patients with IBD. Incom­ this organism can activate aggressive effector Competing interestsplete disease penetrance in mono­ ygo­ ic z t T cells.4 The potentially toxic role of hydro‑ The author declares no competing interests.twins, rapid changes in disease inci­ ence, d gen sulphide on the epithelium barrier can be 1. Brown, A. C., Rampertab, S. D. & Mullin, G. E.asym­ etric geographical distribution and m most definitively addressed by selective colo‑ Existing dietary guidelines for Crohn’s diseasereacti­ ation of clinical activity after long v nization of Il10–/– mice with B. wadsworthia and ulcerative colitis. Expert Rev. Gastroenterol.quies­cent periods strongly implicate environ­ strains lacking dsrA. The component of milk Hepatol. 5, 411–425 (2011).mental influences in IBD, but character­ fat that induces hepatic production of tauro‑ 2. Zallot, C. et al. Dietary beliefs and behavior among inflammatory bowel disease patients.izing these influences and the mecha­ ismsn cholic acid needs to be determined, and dose Inflamm. Bowel Dis. http://dx.doi.org/by which they affect disease suscepti­ i­ b response studies of dietary milk fat should be 10.1002/ibd.22965.lity has been challenging.5 In parallel, our performed to elucidate whether consump‑ 3. Molodecky, N. A. et al. Increasing incidence and prevalence of the inflammatory bowel diseasesunder­ tanding of the influence of diet on s tion of low-fat milk alters Deltaproteobacteria with time, based on systematic review.inflam­ ation, microbiota composition and m populations and induces colitis. The effect of Gastroenterology 142, 46–54 (2012).bac­ erial function has lagged consider­ bly t a milk-fat consumption on other TH1-mediated 4. Devkota, S. et al. Dietary‑fat‑induced taurocholic acid promotes pathobiont expansion and colitisbehind the widespread belief of patients conditions such as coeliac disease, rheuma‑ in Il10–/– mice. Nature 487, 104–108 (2012).that dietary consumption influences their toid arthritis, psoriasis and multiple sclerosis 5. Molodecky, N. A., Panaccione, R., Ghosh, S.,sy­ ptoms and disease activity.2 m needs to be addressed. Most importantly, the Barkema, H. W. & Kaplan, G. G. Challenges Enteric microbiota are firmly implicated clinical implications of these observations in associated with identifying the environmental determinants of the inflammatory bowelin the pathogenesis of IBD,6 and food and a mouse model must be pursued in humans. diseases. Inflamm. Bowel Dis. 17, 1792–1799bacteria are most probably integrally linked The Devkota et al.4 study identifies a puta‑ (2011).in the development of the disease.7 Diet can tive immunologically active commensal 6. Sartor, R. B. Microbial influences in inflammatory bowel diseases. Gastroenterologyinfluence enteric bacteria in several ways. pathobiont that could serve as a diagnostic 134, 577–594 (2008).Sustained consumption of foods high in fat biomarker for clinically relevant subsets of 7. Albenberg, L. G., Lewis, J. D. & Wu, G. D. Foodand low in fibre is associated with a different patients with IBD and as a target for thera‑ and the gut microbiota in inflammatory bowelbacterial profile, a Bacteroides enterotype, peutic interventions, including selective diseases: a critical connection. Curr. Opin. Gastroenterol. 28, 314–320 (2012).compared with individuals consuming high- anti­ iotics, dietary manipulation or novel b 8. Wu, G. D. et al. Linking long-term dietaryfibre, low-fat diets, who exhibit a Prevotella inhibitors of sulphite reductase activity or patterns with gut microbial enterotypes. Scienceenterotype.8 In addition, dietary substrates taurine conjugation of bile acids. Interestingly, 334, 105–108 (2011). 9. Carbonero, F., Benefiel, A. C. & Gaskins, H. R.profoundly influence bacterial metabolism. B. wadsworthia and other sulphate-reducing Contributions of the microbial hydrogenFor example, nonabsorbed dietary fibre bacteria are normally found in the intestines economy to colonic homeostasis. Nat. Rev.and prebiotic compounds such as inulin are of healthy humans, and their populations are Gastroenterol. Hepatol. http://dx.doi.org/ 10.1038/nrgastro.2012.85.metabolized by colonic bacteria to produce increased in patients with ulcerative colitis.9 10. Sonnenburg, J. L. et al. Glycan foraging in vivo byshort-chain fatty acids, including butyrate. These innovative observations could poten‑ an intestine-adapted bacterial symbiont.More­ ver, sulphate-reducing bacteria, o tially help guide clinicians in providing better Science 307, 1955–1959 (2005).562  |  OCTOBER 2012  |  VOLUME 9 www.nature.com/nrgastro © 2012 Macmillan Publishers Limited. All rights reserved

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