Marked changes in socio-economic status, cultural traditions, population growth and agriculture are affecting diets worldwide. Understanding how our diet and nutritional status influence the composition and dynamic operations of our gut microbial communities, and the innate and adaptive arms of our immune system, represents an area of scientific need, opportunity and challenge. The insights gleaned should help to address several pressing global health problems.
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Whitacre, P. T., Fagen, A. P., Husbands, J. L. & Sharples, F. E. Implementing the New Biology: Decadal Challenges Linking Food, Energy, and the Environment (National Research Council of The National Academies of Science, 2010).
Muegge, B. et al. Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science 332, 970–974 (2011).
Goodman, A. L. et al. Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice. Proc. Natl Acad. Sci. USA 108, 6252–6257 (2011). This report highlights the use of gnotobiotic mice containing a transplanted human gut microbiome for studying the dynamic interactions between diet and the microbial community.
Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).
Bryce, J., Boschi-Pinto, C., Shibuya, K. & Black, R. E. WHO estimates of the causes of death in children. Lancet 365, 1147–1152 (2005).
Bhutta, Z. A. et al. What works? Interventions for maternal and child undernutrition and survival. Lancet 371, 417–440 (2008).
Barker, D. J. Adult consequences of fetal growth restriction. Clin. Obstet. Gynecol. 49, 270–283 (2006).
Wikoff, W. R. et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl Acad. Sci. USA 106, 3698–3703 (2009).
Martin, F. P. et al. Probiotic modulation of symbiotic gut microbial–host metabolic interactions in a humanized microbiome mouse model. Mol. Syst. Biol. 4, 157 (2008).
Wright, J. D., Kennedy-Stephenson, J., Wang, C. Y., McDowell, M. A. & Johnson, C. L. Trends in intake of energy and macronutrients — United States, 1971–2000. MMWR Morb. Mortal. Wkly Rep. 53, 80–82 (2004).
Chase, J. M. Stochastic community assembly causes higher biodiversity in more productive environments. Science 328, 1388–1391 (2010).
Koenig, J. E. et al. Succession of microbial consortia in the developing infant gut microbiome. Proc. Natl Acad. Sci. USA 108, 4578–4585 (2011).
Perry, G. H. et al. Diet and the evolution of human amylase gene copy number variation. Nature Genet. 39, 1256–1260 (2007).
Hehemann, J. H. et al. Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota. Nature 464, 908–912 (2010).
La Cava, A. & Matarese, G. The weight of leptin in immunity. Nature Rev. Immunol. 4, 371–379 (2004).
Lord, G. M. et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897–901 (1998).
De Rosa, V. et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity 26, 241–255 (2007).
Guo, X. et al. Leptin signaling in intestinal epithelium mediates resistance to enteric infection by Entamoeba histolytica. Mucosal Immunol. 4, 294–303 (2011). This study demonstrates the role of leptin-receptor signalling in protecting the intestinal epithelium against infection and damage by the enteropathogen E. histolytica.
Backhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).
Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).
Fox, C. J., Hammerman, P. S. & Thompson, C. B. Fuel feeds function: energy metabolism and the T-cell response. Nature Rev. Immunol. 5, 844–852 (2005).
Michalek, R. D. & Rathmell, J. C. The metabolic life and times of a T-cell. Immunol. Rev. 236, 190–202 (2010).
Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).
Lupton, J. R. Microbial degradation products influence colon cancer risk: the butyrate controversy. J. Nutr. 134, 479–482 (2004).
Bird, J. J. et al. Helper T cell differentiation is controlled by the cell cycle. Immunity 9, 229–237 (1998).
Peng, L., He, Z., Chen, W., Holzman, I. R. & Lin, J. Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier. Pediatr. Res. 61, 37–41 (2007).
Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).
Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547 (2011). References 27 and 28 demonstrate how microbiota-derived short-chain fatty acids help to modulate immune responses and susceptibility to enteropathogen invasion.
Kim, G. W., Gocevski, G., Wu, C. J. & Yang, X. J. Dietary, metabolic, and potentially environmental modulation of the lysine acetylation machinery. Int. J. Cell Biol. 2010, 632739 (2010).
Nguyen, M. T. et al. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J. Biol. Chem. 282, 35279–35292 (2007).
Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).
Thomson, A. W., Turnquist, H. R. & Raimondi, G. Immunoregulatory functions of mTOR inhibition. Nature Rev. Immunol. 9, 324–337 (2009).
Nakamura, T. et al. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell 140, 338–348 (2010).
Stockinger, B. Beyond toxicity: aryl hydrocarbon receptor-mediated functions in the immune system. J. Biol. 8, 61 (2009).
Glass, C. K. & Ogawa, S. Combinatorial roles of nuclear receptors in inflammation and immunity. Nature Rev. Immunol. 6, 44–55 (2006).
Araki, K., Youngblood, B. & Ahmed, R. The role of mTOR in memory CD8 T-cell differentiation. Immunol. Rev. 235, 234–243 (2010).
Esser, C., Rannug, A. & Stockinger, B. The aryl hydrocarbon receptor in immunity. Trends Immunol. 30, 447–454 (2009).
Mezrich, J. D. et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185, 3190–3198 (2010).
Platzer, B. et al. Aryl hydrocarbon receptor activation inhibits in vitro differentiation of human monocytes and Langerhans dendritic cells. J. Immunol. 183, 66–74 (2009).
Quintana, F. J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).
Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).
Bronte, V. & Zanovello, P. Regulation of immune responses by L-arginine metabolism. Nature Rev. Immunol. 5, 641–654 (2005).
Mellor, A. L. & Munn, D. H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nature Rev. Immunol. 4, 762–774 (2004).
Munn, D. H. et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22, 633–642 (2005).
Allen, R. H. & Stabler, S. P. Identification and quantitation of cobalamin and cobalamin analogues in human feces. Am. J. Clin. Nutr. 87, 1324–1335 (2008).
Goodman, A. L. et al. Identifying genetic determinants needed to establish a human gut symbiont in its habitat. Cell Host Microbe 6, 279–289 (2009).
Anderson, P. J. et al. One pathway can incorporate either adenine or dimethylbenzimidazole as an α-axial ligand of B12 cofactors in Salmonella enterica. J. Bacteriol. 190, 1160–1171 (2008).
Curtale, F., Pokhrel, R. P., Tilden, R. L. & Higashi, G. Intestinal helminths and xerophthalmia in Nepal. A case control study. J. Trop. Pediatr. 41, 334–337 (1995).
Sommer, A., Tarwotjo, I. & Katz, J. Increased risk of xerophthalmia following diarrhea and respiratory disease. Am. J. Clin. Nutr. 45, 977–980 (1987).
Cha, H. R. et al. Downregulation of Th17 cells in the small intestine by disruption of gut flora in the absence of retinoic acid. J. Immunol. 184, 6799–6806 (2010). This study shows how a single micronutrient, vitamin A, modulates host immune responses through its effects on the composition of the intestinal microbiota.
Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).
Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009). References 51 and 52 are seminal studies identifying a single member of the intestinal microbiota that drives the differentiation of intestinal T H 17 cells.
Schaible, U. E. & Kaufmann, S. H. Iron and microbial infection. Nature Rev. Microbiol. 2, 946–953 (2004).
Reddy, B. S., Pleasants, J. R. & Wostmann, B. S. Effect of intestinal microflora on iron and zinc metabolism, and on activities of metalloenzymes in rats. J. Nutr. 102, 101–107 (1972).
Werner, T. et al. Depletion of luminal iron alters the gut microbiota and prevents Crohn's disease-like ileitis. Gut 60, 325–333 (2011).
Ley, R. E. Obesity and the human microbiome. Curr. Opin. Gastroenterol. 26, 5–11 (2010).
Turnbaugh, P. J., Backhed, F., Fulton, L. & Gordon, J. I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213–223 (2008).
Mandard, S. et al. The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity. J. Biol. Chem. 281, 934–944 (2006).
Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010). This paper links changes in the configuration of the intestinal microbiota in Tlr5 -deficient mice to inflammation and development of metabolic syndrome.
Gregor, M. F. & Hotamisligil, G. S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2011).
Kintscher, U. et al. T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler. Thromb. Vasc. Biol. 28, 1304–1310 (2008).
Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nature Med. 15, 921–929 (2009).
Zuniga, L. A. et al. IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J. Immunol. 185, 6947–6959 (2010).
Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nature Med. 15, 930–939 (2009).
Uysal, K. T., Wiesbrock, S. M., Marino, M. W. & Hotamisligil, G. S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389, 610–614 (1997).
Wen, L. et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109–1113 (2008).
Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).
Brun, P. et al. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G518–G525 (2007).
Shi, H. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006).
Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).
Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108, 4615–4622 (2011).
Valm, A. M. et al. Systems-level analysis of microbial community organization through combinatorial labeling and spectral imaging. Proc. Natl Acad. Sci. USA 108, 4152–4157 (2011).
Golden, M. H. Oedematous malnutrition. Br. Med. Bull. 54, 433–444 (1998).
Ferreira, R. B., Antunes, L. C. & Finlay, B. B. Should the human microbiome be considered when developing vaccines? PLoS Pathogens 6, e1001190 (2010).
Campbell, D. I. et al. Chronic T cell-mediated enteropathy in rural west African children: relationship with nutritional status and small bowel function. Pediatr. Res. 54, 306–311 (2003).
Humphrey, J. H. Child undernutrition, tropical enteropathy, toilets, and handwashing. Lancet 374, 1032–1035 (2009). This is an excellent review of the relationship between environmental enteropathy and malnutrition.
Guerrant, R. L., Oria, R. B., Moore, S. R., Oria, M. O. & Lima, A. A. Malnutrition as an enteric infectious disease with long-term effects on child development. Nutr. Rev. 66, 487–505 (2008).
World Health Organization. Meeting of the immunization Strategic Advisory Group of Experts, April 2009 — conclusions and recommendations. Wkly Epidemiol. Rec. 84, 220–236 (2009).
Grassly, N. C. et al. Mucosal immunity after vaccination with monovalent and trivalent oral poliovirus vaccine in India. J. Infect. Dis. 200, 794–801 (2009).
Lagos, R. et al. Effect of small bowel bacterial overgrowth on the immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR. J. Infect. Dis. 180, 1709–1712 (1999).
Nemes, E. et al. Gluten intake interferes with the humoral immune response to recombinant hepatitis B vaccine in patients with celiac disease. Pediatrics 121, e1570–e1576 (2008).
Menendez-Corrada, R., Nettleship, E. & Santiago-Delpin, E. A. HLA and tropical sprue. Lancet 2, 1183–1185 (1986).
Ghoshal, U. C. et al. Tropical sprue is associated with contamination of small bowel with aerobic bacteria and reversible prolongation of orocecal transit time. J. Gastroenterol. Hepatol. 18, 540–547 (2003).
Hayes, K. S. et al. Exploitation of the intestinal microflora by the parasitic nematode Trichuris muris. Science 328, 1391–1394 (2010). This study demonstrates the co-evolution of bacterial and eukaryotic components of the microbiota and its effect on host immunity.
Faith, J. J., McNulty, N. P., Rey, F. E. & Gordon, J. I. Predicting a human gut microbiota's response to diet in gnotobiotic mice. Science doi:10.1126/science.1206025 (19 May 2011).
Gaboriau-Routhiau, V., Raibaud, P., Dubuquoy, C. & Moreau, M. C. Colonization of gnotobiotic mice with human gut microflora at birth protects against Escherichia coli heat-labile enterotoxin-mediated abrogation of oral tolerance. Pediatr. Res. 54, 739–746 (2003).
Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).
Liu, G., Yang, K., Burns, S., Shrestha, S. & Chi, H. The S1P1-mTOR axis directs the reciprocal differentiation of TH1 and Treg cells. Nature Immunol. 11, 1047–1056 (2010).
Procaccini, C. et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33, 929–941 (2010).
Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004).
Siddiqui, K. R. & Powrie, F. CD103+ GALT DCs promote Foxp3+ regulatory T cells. Mucosal Immunol. 1, S34–S38 (2008).
Ertesvag, A., Engedal, N., Naderi, S. & Blomhoff, H. K. Retinoic acid stimulates the cell cycle machinery in normal T cells: involvement of retinoic acid receptor-mediated IL-2 secretion. J. Immunol. 169, 5555–5563 (2002).
Iwata, M., Eshima, Y. & Kagechika, H. Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors. Int. Immunol. 15, 1017–1025 (2003).
Lemire, J. M., Adams, J. S., Sakai, R. & Jordan, S. C. 1α,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J. Clin. Invest. 74, 657–661 (1984).
Mora, J. R., Iwata, M. & von Andrian, U. H. Vitamin effects on the immune system: vitamins A and D take centre stage. Nature Rev. Immunol. 8, 685–698 (2008).
Daniel, C., Sartory, N. A., Zahn, N., Radeke, H. H. & Stein, J. M. Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile. J. Pharmacol. Exp. Ther. 324, 23–33 (2008).
Wang, T. T. et al. 1,25-Dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J. Immunol. 173, 2909–2912 (2004).
Sigmundsdottir, H. et al. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nature Immunol. 8, 285–293 (2007).
Oh, D. Y. et al. GPR120 is an ω-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010).
Atarashi, K. et al. ATP drives lamina propria TH17 cell differentiation. Nature 455, 808–812 (2008).
We are grateful to members of our laboratory, plus our colleagues C. Semenkovich and A. Shaw for many discussions. Work cited from our laboratory was supported by grants from the National Institutes of Health (DK30292, DK70977 and DK078669), the Crohn's and Colitis Foundation of America and the Bill and Melinda Gates Foundation.
The authors declare no competing financial interests.
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Kau, A., Ahern, P., Griffin, N. et al. Human nutrition, the gut microbiome and the immune system. Nature 474, 327–336 (2011). https://doi.org/10.1038/nature10213
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