Immunity, microbiota and kidney disease


The recognition that intestinal microbiota exert profound effects on human health has led to major advances in our understanding of disease processes. Studies over the past 20 years have shown that host components, including components of the host immune system, shape the microbial community. Pathogenic alterations in commensal microorganisms contribute to disease manifestations that are generally considered to be noncommunicable, such as inflammatory bowel disease, diabetes mellitus and liver disease, through a variety of mechanisms, including effects on host immunity. More recent studies have shed new light on how the immune system and microbiota might also drive the pathogenesis of renal disorders. In this Review, we discuss the latest insights into the mechanisms regulating the microbiome composition, with a focus both on genetics and environmental factors, and describe how commensal microorganisms calibrate innate and adaptive immune responses to affect the activation threshold for pathogenic stimulations. We discuss the mechanisms that lead to intestinal epithelial barrier inflammation and the relevance of certain bacteria to the pathogenesis of two common kidney-based disorders: hypertension and renal stone disease. Limitations of current approaches to microbiota research are also highlighted, emphasizing the need to move beyond studies of correlation to causation.

Key points

  • The gut microbiota influences the host through reciprocal interactions with the host immune system.

  • Imbalances in the microbiota (dysbiosis) lead to epithelial barrier dysfunction and translocation of toxic compounds to the systemic circulation.

  • Hypertension and kidney stone disease might be linked to compositional or functional changes in the gut microbiome.

  • Novel research methods are being established to identify causal microorganisms that drive disease progression.

  • Understanding the crosstalk between immunity, the microbiota and the kidney has potential for the development of innovative, paradigm-shifting treatment strategies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Regulation of gut microbial composition by host mechanisms.
Fig. 2: Microorganism-derived factors influence immunity.
Fig. 3: The gut–kidney axis in blood pressure regulation and kidney stone disease.
Fig. 4: Approaches for assessing the causality of microbiome constituents in kidney disease.


  1. 1.

    Levin, A. et al. Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy. Lancet 390, 1888–1917 (2017).

    PubMed  Google Scholar 

  2. 2.

    Thompson, S. et al. Cause of death in patients with reduced kidney function. J. Am. Soc. Nephrol. 26, 2504–2511 (2015).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Jha, V. et al. Understanding kidney care needs and implementation strategies in low- and middle-income countries: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 90, 1164–1174 (2016).

    PubMed  Google Scholar 

  4. 4.

    Abboud, H. & Henrich, W. L. Clinical practice. Stage IV chronic kidney disease. N. Engl. J. Med. 362, 56–65 (2010).

    PubMed  Google Scholar 

  5. 5.

    Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

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

    Google Scholar 

  7. 7.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Dejea, C. M. et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359, 592–597 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Zheng, P. et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol. Psychiatry 21, 786–796 (2016).

    CAS  PubMed  Google Scholar 

  10. 10.

    The Integrative HMP (iHMP) Research Network Consortium. The Integrative Human Microbiome Project: dynamic analysis of microbiome-host omics profiles during periods of human health and disease. Cell Host Microbe 16, 276–289 (2014).

    Google Scholar 

  11. 11.

    Kuntz, T. M. & Gilbert, J. A. Introducing the microbiome into precision medicine. Trends Pharmacol. Sci. 38, 81–91 (2017).

    CAS  PubMed  Google Scholar 

  12. 12.

    Zou, J. et al. Fiber-mediated nourishment of gut microbiota protects against diet-induced obesity by restoring IL-22-mediated colonic health. Cell Host Microbe 23, 41–53 (2018).

    CAS  PubMed  Google Scholar 

  13. 13.

    Chung, H. et al. Gut immune maturation depends on colonization with a host-specific microbiota. Cell 149, 1578–1593 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Mao, K. et al. Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 554, 255–259 (2018).

    CAS  PubMed  Google Scholar 

  15. 15.

    Moghadamrad, S. et al. Attenuated portal hypertension in germ-free mice: Function of bacterial flora on the development of mesenteric lymphatic and blood vessels. Hepatology 61, 1685–1695 (2015).

    CAS  PubMed  Google Scholar 

  16. 16.

    Geuking, M. B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (2011).

    CAS  PubMed  Google Scholar 

  17. 17.

    Hapfelmeier, S. et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 328, 1705–1709 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Wiedermann, C. J. et al. Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck study. J. Am. Coll. Cardiol. 34, 1975–1981 (1999).

    CAS  PubMed  Google Scholar 

  20. 20.

    McIntyre, C. W. et al. Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease. Clin. J. Am. Soc. Nephrol. 6, 133–141 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Poesen, R. et al. Associations of soluble CD14 and endotoxin with mortality, cardiovascular disease, and progression of kidney disease among patients with CKD. Clin. J. Am. Soc. Nephrol. 10, 1525–1533 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Sender, R., Fuchs, S. & Milo, R. Revised estimates for the number of human and bacteria cells in the body. PLOS Biol. 14, e1002533 (2016).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Gill, S. R. et al. Metagenomic analysis of the human distal gut microbiome. Science 312, 1355–1359 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Koenig, J. E. et al. Succession of microbial consortia in the developing infant gut microbiome. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4578–4585 (2011).

    CAS  PubMed  Google Scholar 

  26. 26.

    Stappenbeck, T. S. & Virgin, H. W. Accounting for reciprocal host-microbiome interactions in experimental science. Nature 534, 191–199 (2016).

    CAS  PubMed  Google Scholar 

  27. 27.

    Azad, M. B. et al. Infant gut microbiota and the hygiene hypothesis of allergic disease: impact of household pets and siblings on microbiota composition and diversity. Allergy Asthma Clin. Immunol. 9, 15 (2013).

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Hasegawa, K. et al. Household siblings and nasal and fecal microbiota in infants. Pediatr. Int. 59, 473–481 (2017).

    CAS  PubMed  Google Scholar 

  29. 29.

    Shukla, S. K. et al. The nasal microbiota of dairy farmers is more complex than oral microbiota, reflects occupational exposure, and provides competition for staphylococci. PLOS ONE 12, e0183898 (2017).

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Fall, T. et al. Early exposure to dogs and farm animals and the risk of childhood asthma. JAMA Pediatr. 169, e153219 (2015).

    PubMed  Google Scholar 

  31. 31.

    Strachan, D. P. Hay fever, hygiene, and household size. BMJ 299, 1259–1260 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    CAS  Google Scholar 

  33. 33.

    Sonnenburg, E. D. et al. Diet-induced extinctions in the gut microbiota compound over generations. Nature 529, 212–215 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Suez, J. et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514, 181–186 (2014).

    CAS  Google Scholar 

  35. 35.

    Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92–96 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Gum, J. R. et al. Molecular cloning of human intestinal mucin (MUC2) cDNA. Identification of the amino terminus and overall sequence similarity to prepro-von Willebrand factor. J. Biol. Chem. 269, 2440–2446 (1994).

    CAS  PubMed  Google Scholar 

  37. 37.

    Atuma, C., Strugala, V., Allen, A. & Holm, L. The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo. Am. J. Physiol. Gastrointest. Liver Physiol. 280, G922–G929 (2001).

    CAS  PubMed  Google Scholar 

  38. 38.

    Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008).

    CAS  PubMed  Google Scholar 

  39. 39.

    Kim, J. J. & Khan, W. I. Goblet cells and mucins: role in innate defense in enteric infections. Pathogens 2, 55–70 (2013).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Birchenough, G. M., Nystrom, E. E., Johansson, M. E. & Hansson, G. C. A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion. Science 352, 1535–1542 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Wlodarska, M. et al. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156, 1045–1059 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Nowarski, R. et al. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163, 1444–1456 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Ragland, S. A. & Criss, A. K. From bacterial killing to immune modulation: recent insights into the functions of lysozyme. PLOS Pathog. 13, e1006512 (2017).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Cash, H. L., Whitham, C. V., Behrendt, C. L. & Hooper, L. V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Qu, X. D. & Lehrer, R. I. Secretory phospholipase A2 is the principal bactericide for staphylococci and other gram-positive bacteria in human tears. Infect. Immun. 66, 2791–2797 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Koduri, R. S. et al. Bactericidal properties of human and murine groups I, II, V, X, and XII secreted phospholipases A2. J. Biol. Chem. 277, 5849–5857 (2002).

    CAS  PubMed  Google Scholar 

  47. 47.

    Holly, M. K. & Smith, J. G. Paneth cells during viral infection and pathogenesis. Viruses 10, 225 (2018).

    PubMed Central  Google Scholar 

  48. 48.

    Hooper, L. V., Stappenbeck, T. S., Hong, C. V. & Gordon, J. I. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nat. Immunol. 4, 269–273 (2003).

    CAS  PubMed  Google Scholar 

  49. 49.

    Rumio, C. et al. Degranulation of paneth cells via toll-like receptor 9. Am. J. Pathol. 165, 373–381 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Foureau, D. M. et al. TLR9-dependent induction of intestinal alpha-defensins by Toxoplasma gondii. J. Immunol. 184, 7022–7029 (2010).

    CAS  PubMed  Google Scholar 

  51. 51.

    Selsted, M. E. & Ouellette, A. J. Mammalian defensins in the antimicrobial immune response. Nat. Immunol. 6, 551–557 (2005).

    CAS  PubMed  Google Scholar 

  52. 52.

    Carvalho, F. A., Aitken, J. D., Vijay-Kumar, M. & Gewirtz, A. T. Toll-like receptor-gut microbiota interactions: perturb at your own risk! Annu. Rev. Physiol. 74, 177–198 (2012).

    CAS  PubMed  Google Scholar 

  53. 53.

    Vaishnava, S., Behrendt, C. L., Ismail, A. S., Eckmann, L. & Hooper, L. V. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc. Natl Acad. Sci. USA 105, 20858–20863 (2008).

    CAS  PubMed  Google Scholar 

  54. 54.

    Shulzhenko, N. et al. Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nat. Med. 17, 1585–1593 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Palm, N. W. et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158, 1000–1010 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Slack, E., Balmer, M. L., Fritz, J. H. & Hapfelmeier, S. Functional flexibility of intestinal IgA - broadening the fine line. Front. Immunol. 3, 100 (2012).

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Pabst, O. New concepts in the generation and functions of IgA. Nat. Rev. Immunol. 12, 821–832 (2012).

    CAS  PubMed  Google Scholar 

  58. 58.

    Mantis, N. J. & Forbes, S. J. Secretory IgA: arresting microbial pathogens at epithelial borders. Immunol. Invest. 39, 383–406 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Lycke, N., Erlandsson, L., Ekman, L., Schon, K. & Leanderson, T. Lack of J chain inhibits the transport of gut IgA and abrogates the development of intestinal antitoxic protection. J. Immunol. 163, 913–919 (1999).

    CAS  PubMed  Google Scholar 

  60. 60.

    Forbes, S. J., Eschmann, M. & Mantis, N. J. Inhibition of Salmonella enterica serovar typhimurium motility and entry into epithelial cells by a protective antilipopolysaccharide monoclonal immunoglobulin A antibody. Infect. Immun. 76, 4137–4144 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Vijay-Kumar, M. et al. Deletion of TLR5 results in spontaneous colitis in mice. J. Clin. Invest. 117, 3909–3921 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Singh, V. et al. Microbiota-dependent hepatic lipogenesis mediated by stearoyl CoA desaturase 1 (SCD1) promotes metabolic syndrome in TLR5-deficient mice. Cell. Metab. 22, 983–996 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Seregin, S. S. et al. NLRP6 protects Il10(−/−) mice from colitis by limiting colonization of akkermansia muciniphila. Cell Rep. 19, 733–745 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Levy, M. et al. Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163, 1428–1443 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Galvez, E. J. C., Iljazovic, A., Gronow, A., Flavell, R. & Strowig, T. Shaping of intestinal microbiota in Nlrp6- and Rag2-deficient mice depends on community structure. Cell Rep. 21, 3914–3926 (2017).

    CAS  PubMed  Google Scholar 

  68. 68.

    Ubeda, C. et al. Familial transmission rather than defective innate immunity shapes the distinct intestinal microbiota of TLR-deficient mice. J. Exp. Med. 209, 1445–1456 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Lemire, P. et al. The NLR protein NLRP6 does not impact gut microbiota composition. Cell Rep. 21, 3653–3661 (2017).

    CAS  PubMed  Google Scholar 

  70. 70.

    Mamantopoulos, M. et al. Nlrp6- and ASC-dependent inflammasomes do not shape the commensal gut microbiota composition. Immunity 47, 339–348 (2017).

    CAS  PubMed  Google Scholar 

  71. 71.

    Wostmann, B. S., Larkin, C., Moriarty, A. & Bruckner-Kardoss, E. Dietary intake, energy metabolism, and excretory losses of adult male germfree Wistar rats. Lab. Anim. Sci. 33, 46–50 (1983).

    CAS  PubMed  Google Scholar 

  72. 72.

    Stecher, B. et al. Comparison of Salmonella enterica serovar Typhimurium colitis in germfree mice and mice pretreated with streptomycin. Infect. Immun. 73, 3228–3241 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Gordon, H. A. Morphological and physiological characterization of germfree life. Ann. NY Acad. Sci. 78, 208–220 (1959).

    CAS  PubMed  Google Scholar 

  74. 74.

    Reinhardt, C. et al. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 483, 627–631 (2012).

    CAS  PubMed  Google Scholar 

  75. 75.

    Surana, N. K. & Kasper, D. L. Deciphering the tete-a-tete between the microbiota and the immune system. J. Clin. Invest. 124, 4197–4203 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    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).

    CAS  PubMed  Google Scholar 

  77. 77.

    Ochoa-Reparaz, J. et al. Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J. Immunol. 185, 4101–4108 (2010).

    CAS  PubMed  Google Scholar 

  78. 78.

    Ochoa-Reparaz, J. et al. A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol. 3, 487–495 (2010).

    CAS  PubMed  Google Scholar 

  79. 79.

    Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008).

    CAS  PubMed  Google Scholar 

  81. 81.

    Shen, Y. et al. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe 12, 509–520 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Dasgupta, S., Erturk-Hasdemir, D., Ochoa-Reparaz, J., Reinecker, H. C. & Kasper, D. L. Plasmacytoid dendritic cells mediate anti-inflammatory responses to a gut commensal molecule via both innate and adaptive mechanisms. Cell Host Microbe 15, 413–423 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    An, D. et al. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell 156, 123–133 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Hoverstad, T. & Midtvedt, T. Short-chain fatty acids in germfree mice and rats. J. Nutr. 116, 1772–1776 (1986).

    CAS  PubMed  Google Scholar 

  85. 85.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Tan, J. K., McKenzie, C., Marino, E., Macia, L. & Mackay, C. R. Metabolite-sensing G protein-coupled receptors-facilitators of diet-related immune regulation. Annu. Rev. Immunol. 35, 371–402 (2017).

    CAS  PubMed  Google Scholar 

  87. 87.

    Le Poul, E. et al. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J. Biol. Chem. 278, 25481–25489 (2003).

    PubMed  Google Scholar 

  88. 88.

    Macia, L. et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6, 6734 (2015).

    CAS  PubMed  Google Scholar 

  89. 89.

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

    CAS  PubMed  Google Scholar 

  90. 90.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Park, J. et al. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol. 8, 80–93 (2015).

    CAS  PubMed  Google Scholar 

  92. 92.

    Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Flannigan, K. L. & Denning, T. L. Segmented filamentous bacteria-induced immune responses: a balancing act between host protection and autoimmunity. Immunology 154, 537–546 (2018).

    CAS  Google Scholar 

  94. 94.

    Atarashi, K. et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163, 367–380 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    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).

    CAS  PubMed  Google Scholar 

  96. 96.

    Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Ivanov, I. I. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337–349 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Lei, Z. et al. EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins. Dev. Biol. 371, 136–145 (2012).

    CAS  PubMed  Google Scholar 

  99. 99.

    Laukoetter, M. G. et al. JAM-A regulates permeability and inflammation in the intestine in vivo. J. Exp. Med. 204, 3067–3076 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Tanaka, H. et al. Intestinal deletion of Claudin-7 enhances paracellular organic solute flux and initiates colonic inflammation in mice. Gut 64, 1529–1538 (2015).

    CAS  PubMed  Google Scholar 

  101. 101.

    Michielan, A. & D’Inca, R. Intestinal permeability in inflammatory bowel disease: pathogenesis, clinical evaluation, and therapy of leaky gut. Mediators Inflamm. 2015, 628157 (2015).

    PubMed  PubMed Central  Google Scholar 

  102. 102.

    Zeissig, S. et al. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut 56, 61–72 (2007).

    CAS  PubMed  Google Scholar 

  103. 103.

    Ma, T. Y. et al. TNF-alpha-induced increase in intestinal epithelial tight junction permeability requires NF-kappa B activation. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G367–G376 (2004).

    CAS  PubMed  Google Scholar 

  104. 104.

    Adams, R. B., Planchon, S. M. & Roche, J. K. IFN-gamma modulation of epithelial barrier function. Time course, reversibility, and site of cytokine binding. J. Immunol. 150, 2356–2363 (1993).

    CAS  PubMed  Google Scholar 

  105. 105.

    Al-Sadi, R., Ye, D., Dokladny, K. & Ma, T. Y. Mechanism of IL-1beta-induced increase in intestinal epithelial tight junction permeability. J. Immunol. 180, 5653–5661 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Howe, K. L., Reardon, C., Wang, A., Nazli, A. & McKay, D. M. Transforming growth factor-beta regulation of epithelial tight junction proteins enhances barrier function and blocks enterohemorrhagic Escherichia coli O157:H7-induced increased permeability. Am. J. Pathol. 167, 1587–1597 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Suenaert, P. et al. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. Am. J. Gastroenterol. 97, 2000–2004 (2002).

    CAS  PubMed  Google Scholar 

  108. 108.

    Suenaert, P. et al. Hyperresponsiveness of the mucosal barrier in Crohn’s disease is not tumor necrosis factor-dependent. Inflamm. Bowel Dis. 11, 667–673 (2005).

    PubMed  Google Scholar 

  109. 109.

    Martinez-Medina, M. 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).

    PubMed  Google Scholar 

  110. 110.

    Thaiss, C. A. et al. Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science 359, 1376–1383 (2018).

    CAS  PubMed  Google Scholar 

  111. 111.

    Sturniolo, G. C. et al. Effect of zinc supplementation on intestinal permeability in experimental colitis. J. Lab. Clin. Med. 139, 311–315 (2002).

    CAS  PubMed  Google Scholar 

  112. 112.

    Roy, S. K. et al. Impact of zinc supplementation on intestinal permeability in Bangladeshi children with acute diarrhoea and persistent diarrhoea syndrome. J. Pediatr. Gastroenterol. Nutr. 15, 289–296 (1992).

    CAS  PubMed  Google Scholar 

  113. 113.

    Sturniolo, G. C., Di Leo, V., Ferronato, A., D’Odorico, A. & D’Inca, R. Zinc supplementation tightens “leaky gut” in Crohn’s disease. Inflamm. Bowel Dis. 7, 94–98 (2001).

    CAS  PubMed  Google Scholar 

  114. 114.

    Alam, A. N., Sarker, S. A., Wahed, M. A., Khatun, M. & Rahaman, M. M. Enteric protein loss and intestinal permeability changes in children during acute shigellosis and after recovery: effect of zinc supplementation. Gut 35, 1707–1711 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Venkatraman, A., Ramakrishna, B. S., Pulimood, A. B., Patra, S. & Murthy, S. Increased permeability in dextran sulphate colitis in rats: time course of development and effect of butyrate. Scand. J. Gastroenterol. 35, 1053–1059 (2000).

    CAS  PubMed  Google Scholar 

  116. 116.

    Mariadason, J. M., Barkla, D. H. & Gibson, P. R. Effect of short-chain fatty acids on paracellular permeability in Caco-2 intestinal epithelium model. Am. J. Physiol. 272, G705–G712 (1997).

    CAS  PubMed  Google Scholar 

  117. 117.

    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).

    CAS  PubMed  Google Scholar 

  118. 118.

    Vernia, P. et al. Topical butyrate improves efficacy of 5-ASA in refractory distal ulcerative colitis: results of a multicentre trial. Eur. J. Clin. Invest. 33, 244–248 (2003).

    CAS  PubMed  Google Scholar 

  119. 119.

    Finnie, I. A., Dwarakanath, A. D., Taylor, B. A. & Rhodes, J. M. Colonic mucin synthesis is increased by sodium butyrate. Gut 36, 93–99 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Barcelo, A. et al. Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon. Gut 46, 218–224 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Ulluwishewa, D. et al. Regulation of tight junction permeability by intestinal bacteria and dietary components. J. Nutr. 141, 769–776 (2011).

    CAS  PubMed  Google Scholar 

  122. 122.

    Patel, R. M. et al. Probiotic bacteria induce maturation of intestinal claudin 3 expression and barrier function. Am. J. Pathol. 180, 626–635 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Garcia Vilela, E. et al. Influence of Saccharomyces boulardii on the intestinal permeability of patients with Crohn’s disease in remission. Scand. J. Gastroenterol. 43, 842–848 (2008).

    PubMed  Google Scholar 

  124. 124.

    Zakostelska, Z. et al. Lysate of probiotic Lactobacillus casei DN-114 001 ameliorates colitis by strengthening the gut barrier function and changing the gut microenvironment. PLOS ONE 6, e27961 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Baez, S. & Gordon, H. A. Tone and reactivity of vascular smooth muscle in germfree rat mesentery. J. Exp. Med. 134, 846–856 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Yang, T. et al. Gut dysbiosis is linked to hypertension. Hypertension 65, 1331–1340 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Adnan, S. et al. Alterations in the gut microbiota can elicit hypertension in rats. Physiol. Genom. 49, 96–104 (2017).

    CAS  Google Scholar 

  128. 128.

    Marques, F. Z. et al. High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice. Circulation 135, 964–977 (2017).

    CAS  Google Scholar 

  129. 129.

    Chang, A. J., Ortega, F. E., Riegler, J., Madison, D. V. & Krasnow, M. A. Oxygen regulation of breathing through an olfactory receptor activated by lactate. Nature 527, 240–244 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Pluznick, J. L. et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc. Natl Acad. Sci. USA 110, 4410–4415 (2013).

    CAS  PubMed  Google Scholar 

  131. 131.

    Nutting, C. W., Islam, S., Ye, M. H., Batlle, D. C. & Daugirdas, J. T. The vasorelaxant effects of acetate: role of adenosine, glycolysis, lyotropism, and pHi and Cai 2+. Kidney Int. 41, 166–174 (1992).

    CAS  PubMed  Google Scholar 

  132. 132.

    Mell, B. et al. Evidence for a link between gut microbiota and hypertension in the Dahl rat. Physiol. Genom. 47, 187–197 (2015).

    CAS  Google Scholar 

  133. 133.

    Pluznick, J. L. Gut microbiota in renal physiology: focus on short-chain fatty acids and their receptors. Kidney Int. 90, 1191–1198 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Wilck, N. et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Santisteban, M. M. et al. Hypertension-linked pathophysiological alterations in the gut. Circ. Res. 120, 312–323 (2017).

    CAS  PubMed  Google Scholar 

  136. 136.

    Stewart, D. C. et al. Hypertension-linked mechanical changes of rat gut. Acta Biomater. 45, 296–302 (2016).

    PubMed  PubMed Central  Google Scholar 

  137. 137.

    Yoo, H. H., Kim, I. S., Yoo, D. H. & Kim, D. H. Effects of orally administered antibiotics on the bioavailability of amlodipine: gut microbiota-mediated drug interaction. J. Hypertens. 34, 156–162 (2016).

    CAS  PubMed  Google Scholar 

  138. 138.

    Saksena, S. et al. Upregulation of P-glycoprotein by probiotics in intestinal epithelial cells and in the dextran sulfate sodium model of colitis in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G1115–G1123 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Scales, C. D. et al. Prevalence of kidney stones in the United States. Eur. Urol. 62, 160–165 (2012).

    PubMed  PubMed Central  Google Scholar 

  140. 140.

    Romero, V., Akpinar, H. & Assimos, D. G. Kidney stones: a global picture of prevalence, incidence, and associated risk factors. Rev. Urol. 12, e86–96 (2010).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Alexander, R. T. et al. Kidney stones and cardiovascular events: a cohort study. Clin. J. Am. Soc. Nephrol. 9, 506–512 (2014).

    PubMed  Google Scholar 

  142. 142.

    Kittanamongkolchai, W. et al. The changing incidence and presentation of urinary stones over 3 decades. Mayo Clin. Proc. 93, 291–299 (2018).

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    Zhe, M. & Hang, Z. Nephrolithiasis as a risk factor of chronic kidney disease: a meta-analysis of cohort studies with 4,770,691 participants. Urolithiasis 45, 441–448 (2016).

    PubMed  Google Scholar 

  144. 144.

    Ferraro, P. M. et al. History of kidney stones and the risk of coronary heart disease. JAMA 310, 408–415 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Asplin, J. R., Parks, J. H. & Coe, F. L. Dependence of upper limit of metastability on supersaturation in nephrolithiasis. Kidney Int. 52, 1602–1608 (1997).

    CAS  PubMed  Google Scholar 

  146. 146.

    Bergsland, K. J., Zisman, A. L., Asplin, J. R., Worcester, E. M. & Coe, F. L. Evidence for net renal tubule oxalate secretion in patients with calcium kidney stones. Am. J. Physiol. Renal Physiol. 300, F311–F318 (2011).

    CAS  PubMed  Google Scholar 

  147. 147.

    Coe, F. L., Worcester, E. M. & Evan, A. P. Idiopathic hypercalciuria and formation of calcium renal stones. Nat. Rev. Nephrol. 12, 519–533 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Coe, F. L., Evan, A. P., Lingeman, J. E. & Worcester, E. M. Plaque and deposits in nine human stone diseases. Urol. Res. 38, 239–247 (2010).

    PubMed  PubMed Central  Google Scholar 

  149. 149.

    Ticinesi, A. et al. Understanding the gut-kidney axis in nephrolithiasis: an analysis of the gut microbiota composition and functionality of stone formers. Gut 67, 2097–2106 (2018).

    CAS  PubMed  Google Scholar 

  150. 150.

    Stern, J. M. et al. Evidence for a distinct gut microbiome in kidney stone formers compared to non-stone formers. Urolithiasis 44, 399–407 (2016).

    PubMed  Google Scholar 

  151. 151.

    Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Kronman, M. P., Zaoutis, T. E., Haynes, K., Feng, R. & Coffin, S. E. Antibiotic exposure and IBD development among children: a population-based cohort study. Pediatrics 130, e794–e803 (2012).

    PubMed  PubMed Central  Google Scholar 

  153. 153.

    Mitre, E. et al. Association between use of acid-suppressive medications and antibiotics during infancy and allergic diseases in early childhood. JAMA Pediatr. 172, e180315 (2018).

    PubMed  PubMed Central  Google Scholar 

  154. 154.

    Tasian, G. E. et al. Oral antibiotic exposure and kidney stone disease. J. Am. Soc. Nephrol. 29, 1731–1740 (2018).

    PubMed  Google Scholar 

  155. 155.

    Pfau, A. & Knauf, F. Update on nephrolithiasis: core curriculum 2016. Am. J. Kidney Dis. 68, 973–985 (2016).

    PubMed  Google Scholar 

  156. 156.

    Hatch, M. Gut microbiota and oxalate homeostasis. Ann. Transl Med. 5, 36 (2017).

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    Knight, J., Deora, R., Assimos, D. G. & Holmes, R. P. The genetic composition of Oxalobacter formigenes and its relationship to colonization and calcium oxalate stone disease. Urolithiasis 41, 187–196 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Al-Wahsh, I., Wu, Y. & Liebman, M. Acute probiotic ingestion reduces gastrointestinal oxalate absorption in healthy subjects. Urol. Res. 40, 191–196 (2012).

    PubMed  Google Scholar 

  159. 159.

    Turroni, S. et al. Oxalate-degrading activity in Bifidobacterium animalis subsp. lactis: impact of acidic conditions on the transcriptional levels of the oxalyl coenzyme A (CoA) decarboxylase and formyl-CoA transferase genes. Appl. Environ. Microbiol. 76, 5609–5620 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Mehta, M., Goldfarb, D. S. & Nazzal, L. The role of the microbiome in kidney stone formation. Int. J. Surg. 36, 607–612 (2016).

    PubMed  PubMed Central  Google Scholar 

  161. 161.

    Klimesova, K., Whittamore, J. M. & Hatch, M. Bifidobacterium animalis subsp. lactis decreases urinary oxalate excretion in a mouse model of primary hyperoxaluria. Urolithiasis 43, 107–117 (2015).

    CAS  PubMed  Google Scholar 

  162. 162.

    Hatch, M. et al. Oxalobacter sp. reduces urinary oxalate excretion by promoting enteric oxalate secretion. Kidney Int. 69, 691–698 (2006).

    CAS  PubMed  Google Scholar 

  163. 163.

    Sidhu, H. et al. Direct correlation between hyperoxaluria/oxalate stone disease and the absence of the gastrointestinal tract-dwelling bacterium Oxalobacter formigenes: possible prevention by gut recolonization or enzyme replacement therapy. J. Am. Soc. Nephrol. 10 (Suppl. 14), 334–340 (1999).

    CAS  PubMed  Google Scholar 

  164. 164.

    Hatch, M. & Freel, R. W. A human strain of Oxalobacter (HC-1) promotes enteric oxalate secretion in the small intestine of mice and reduces urinary oxalate excretion. Urolithiasis 41, 379–384 (2013).

    CAS  PubMed  Google Scholar 

  165. 165.

    Hatch, M., Freel, R. W. & Vaziri, N. D. Regulatory aspects of oxalate secretion in enteric oxalate elimination. J. Am. Soc. Nephrol. 10 (Suppl. 14), 324–328 (1999).

    CAS  PubMed  Google Scholar 

  166. 166.

    Knauf, F. et al. Net intestinal transport of oxalate reflects passive absorption and SLC26A6-mediated secretion. J. Am. Soc. Nephrol. 22, 2247–2255 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Jiang, Z. et al. Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6. Nat. Genet. 38, 474–478 (2006).

    CAS  PubMed  Google Scholar 

  168. 168.

    Freel, R. W., Hatch, M., Green, M. & Soleimani, M. Ileal oxalate absorption and urinary oxalate excretion are enhanced in Slc26a6 null mice. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G719–G728 (2006).

    CAS  PubMed  Google Scholar 

  169. 169.

    Arvans, D. et al. Oxalobacter formigenes-derived bioactive factors stimulate oxalate transport by intestinal epithelial cells. J. Am. Soc. Nephrol. 28, 876–887 (2017).

    CAS  PubMed  Google Scholar 

  170. 170.

    Mulay, S. R. et al. Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in C57BL/6 mice. Am. J. Physiol. Renal Physiol. 310, F785–F795 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Knauf, F. et al. NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy. Kidney Int. 84, 895–901 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Mulay, S. R. et al. Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1beta secretion. J. Clin. Invest. 123, 236–246 (2013).

    CAS  PubMed  Google Scholar 

  173. 173.

    Kim, S. M. et al. Hyperuricemia-induced NLRP3 activation of macrophages contributes to the progression of diabetic nephropathy. Am. J. Physiol. Renal Physiol. 308, F993–F1003 (2015).

    CAS  PubMed  Google Scholar 

  174. 174.

    Prencipe, G. et al. Inflammasome activation by cystine crystals: implications for the pathogenesis of cystinosis. J. Am. Soc. Nephrol. 25, 1163–1169 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Ludwig-Portugall, I. et al. An NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice. Kidney Int. 90, 525–539 (2016).

    CAS  PubMed  Google Scholar 

  176. 176.

    Gilbert, J. A. et al. Microbiome-wide association studies link dynamic microbial consortia to disease. Nature 535, 94–103 (2016).

    CAS  Google Scholar 

  177. 177.

    Surana, N. K. & Kasper, D. L. Moving beyond microbiome-wide associations to causal microbe identification. Nature 552, 244–247 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    Rosen, C. E. & Palm, N. W. Navigating the microbiota seas: triangulation finds a way forward. Cell Host Microbe 23, 1–3 (2018).

    CAS  PubMed  Google Scholar 

  179. 179.

    Poesen, R. et al. The influence of CKD on colonic microbial metabolism. J. Am. Soc. Nephrol. 27, 1389–1399 (2016).

    CAS  PubMed  Google Scholar 

  180. 180.

    Mondot, S. & Lepage, P. The human gut microbiome and its dysfunctions through the meta-omics prism. Ann. NY Acad. Sci. 1372, 9–19 (2016).

    PubMed  Google Scholar 

  181. 181.

    Rosen, C. E. & Palm, N. W. Functional classification of the gut microbiota: the key to cracking the microbiota composition code: functional classifications of the gut microbiota reveal previously hidden contributions of indigenous gut bacteria to human health and disease. Bioessays 39, 1700032 (2017).

    Google Scholar 

  182. 182.

    Wyatt, R. J. & Julian, B. A. IgA nephropathy. N. Engl. J. Med. 368, 2402–2414 (2013).

    CAS  PubMed  Google Scholar 

  183. 183.

    Barratt, J., Smith, A. C., Molyneux, K. & Feehally, J. Immunopathogenesis of IgAN. Semin. Immunopathol. 29, 427–443 (2007).

    CAS  PubMed  Google Scholar 

  184. 184.

    Kiryluk, K. et al. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat. Genet. 46, 1187–1196 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    Fellstrom, B. C. et al. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet 389, 2117–2127 (2017).

    PubMed  Google Scholar 

  186. 186.

    Dong, J. Y. et al. Effect of probiotic fermented milk on blood pressure: a meta-analysis of randomised controlled trials. Br. J. Nutr. 110, 1188–1194 (2013).

    CAS  PubMed  Google Scholar 

  187. 187.

    Khalesi, S., Sun, J., Buys, N. & Jayasinghe, R. Effect of probiotics on blood pressure: a systematic review and meta-analysis of randomized, controlled trials. Hypertension 64, 897–903 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188.

    Hatch, M., Gjymishka, A., Salido, E. C., Allison, M. J. & Freel, R. W. Enteric oxalate elimination is induced and oxalate is normalized in a mouse model of primary hyperoxaluria following intestinal colonization with Oxalobacter. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G461–G469 (2011).

    CAS  PubMed  Google Scholar 

  189. 189.

    Milliner, D., Hoppe, B. & Groothoff, J. A randomised Phase II/III study to evaluate the efficacy and safety of orally administered Oxalobacter formigenes to treat primary hyperoxaluria. Urolithiasis 46, 313–323 (2018).

    CAS  PubMed  Google Scholar 

  190. 190.

    Goldfarb, D. S., Modersitzki, F. & Asplin, J. R. A randomized, controlled trial of lactic acid bacteria for idiopathic hyperoxaluria. Clin. J. Am. Soc. Nephrol. 2, 745–749 (2007).

    PubMed  Google Scholar 

  191. 191.

    Lieske, J. C. et al. Diet, but not oral probiotics, effectively reduces urinary oxalate excretion and calcium oxalate supersaturation. Kidney Int. 78, 1178–1185 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


F.K. is supported by the Deutsche Forschungsgemeinschaft (DFG; project KN 1148/2-1 and CRC 1365 Renoprotection), the Oxalosis and Hyperoxaluria Foundation and TRENAL, a thematic network grant of the Deutscher Akademischer Austauschdienst (DAAD). J.R.B. is supported by an American Cancer Society Postdoctoral Fellowship (PF-17-237-01-DMC). R.A.F. is supported by the Howard Hughes Medical Institute.

Reviewer information

Nature Reviews Nephrology thanks C. M. Higueras, C. Kurts, L. Nazzal and other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information




F.K. and J.R.B. researched data for the article and wrote the article. All authors contributed substantially to discussion of the article’s content and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Richard A. Flavell.

Ethics declarations

Competing interests

R.A.F. is a scientific consultant to GlaxoSmithKline and Zie Labs and a founder, shareholder and advisor to SMOC Therapeutics Inc. The other authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Paneth cells

Epithelial cells localized in the glands of the small intestine. Microscopically, they are characterized by large eosinophilic granules that occupy the cytoplasm and contain antimicrobial compounds critical for host defence.


Epithelial cells found in the small intestine. Microscopically, they are characterized by microvilli found on the apical membrane. Enterocytes are responsible for the absorption or secretion of molecules from or into the intestine.

Macrophage foam cells

Monocyte-derived macrophages that clear oxidized lipids and in this process develop into lipid-laden foam cells. These cells are components of atherosclerotic plaques and have been implicated in the pathogenesis of atherosclerotic disease.

Coprophagic animals

Animals that eat faeces, which facilitates the transmission of microbiomes between individual animals.

Goblet cells

Epithelial cells found in various organs. Goblet cells secrete mucus, a viscous fluid composed primarily of proteins called mucins.

T helper 2 (TH2) cells

Specialized population of T cells that orchestrate protective type 2 immune responses to pathogens such as parasites as well as tissue repair. TH2 cells have also been implicated in diseases such as asthma.

Pathogen-associated molecular patterns

(PAMPs). Highly conserved groups of molecular motifs detected by pattern recognition receptor (PRR)-bearing cells of the innate immune system.

Natural killer T (NKT) cells

Subset of T cells that express both a T cell receptor, a classical component of adaptive immunity, and surface receptors for natural killer cells, which are characteristic of innate immunity.

Immune exclusion

Process of clearing pathogenic microorganisms. Secretory immunoglobulin A (IgA) has a central role in this process by blocking antigens and pathogenic microorganisms from the intestinal lumen.


Enclosed areas for live animals in a semi-natural environment for observation or studies.

Histone deacetylases

(HDACs). Class of enzymes that remove acetyl groups. HDACs regulate access to DNA by modulating chromatin and thereby cellular processes. HDACs are also involved in immunity by, for example, regulating CD4+ T cells.

Paracellular transport

Transfer of molecules or solutes across the epithelium by passing through the intercellular space between cells. This route of transport can be enhanced if junctional proteins are displaced or have altered expression.

Transcellular transport

Transfer of molecules or solutes across the epithelium by passing through the cell. This route of transport is mediated by specialized proteins that transport from the lumen to the blood (absorption) or from the blood to the lumen (secretion).


Direct genetic analysis of entire microbial communities to provide information on microbial diversity.


Characterization of all the protein samples recovered from environmental sources.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Knauf, F., Brewer, J.R. & Flavell, R.A. Immunity, microbiota and kidney disease. Nat Rev Nephrol 15, 263–274 (2019).

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing