Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Macrophages in intestinal homeostasis and inflammatory bowel disease

Nature Reviews Gastroenterology & Hepatology volume 20, pages 538–553 (2023)Cite this article

Subjects

Abstract

Macrophages are essential for the maintenance of intestinal homeostasis, yet appear to be drivers of inflammation in the context of inflammatory bowel disease (IBD). How these peacekeepers become powerful aggressors in IBD is still unclear, but technological advances have revolutionized our understanding of many facets of their biology. In this Review, we discuss the progress made in understanding the heterogeneity of intestinal macrophages, the functions they perform in gut health and how the environment and origin can control the differentiation and longevity of these cells. We describe how these processes might change in the context of chronic inflammation and how aberrant macrophage behaviour contributes to IBD pathology, and discuss how therapeutic approaches might target dysregulated macrophages to dampen inflammation and promote mucosal healing. Finally, we set out key areas in the field of intestinal macrophage biology for which further investigation is warranted.

Key points

  • Advances in single-cell RNA sequencing and fate-mapping mouse models have uncovered the heterogeneity of intestinal macrophages.

  • Intestinal macrophage subsets in discrete niches have distinct functions and replenishment kinetics from monocytes.

  • Dysregulated monocytes and macrophages are a characteristic feature of intestinal inflammation.

  • The environmental signals and downstream molecular pathways governing monocyte-to-macrophage differentiation in health and how these change in inflammation remain poorly understood.

  • Understanding the molecular dialogue between macrophage subsets and other immune cells and their niche will enable macrophage dysfunction to be targeted in inflammatory bowel disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Heterogeneity, niche interactions and functions of intestinal macrophage subsets in the healthy intestine.
Fig. 2: Monocyte to macrophage differentiation in the intestine in health and inflammation.
Fig. 3: Macrophage involvement in intestinal inflammation.

Similar content being viewed by others

References

  1. Mowat, A. M. & Agace, W. W. Regional specialization within the intestinal immune system. Nat. Rev. Immunol. 14, 667–685 (2014).

    CAS  PubMed  Google Scholar 

  2. Fiocchi, C. What is ‘physiological’ intestinal inflammation and how does it differ from ‘pathological’ inflammation? Inflamm. Bowel Dis. 14, S77–S78 (2008).

    PubMed  Google Scholar 

  3. Martin, J. C. et al. Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy. Cell 178, 1493–1508.e20 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Kaplan, G. G. & Windsor, J. W. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 18, 56–66 (2021).

    PubMed  Google Scholar 

  5. Ng, S. C. et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390, 2769–2778 (2017).

    PubMed  Google Scholar 

  6. Coward, S. et al. Past and future burden of inflammatory bowel diseases based on modeling of population-based data. Gastroenterology 156, 1345–1353.e4 (2019).

    PubMed  Google Scholar 

  7. Jones, G.-R. et al. IBD prevalence in Lothian, Scotland, derived by capture–recapture methodology. Gut 68, 1953–1960 (2019).

    PubMed  Google Scholar 

  8. Mulder, K. et al. Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease. Immunity 54, 1883–1900.e5 (2021).

    CAS  PubMed  Google Scholar 

  9. Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. & Hill, A. M. M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 164, 6166–6173 (2000).

    CAS  PubMed  Google Scholar 

  10. Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23–35 (2003).

    CAS  PubMed  Google Scholar 

  11. Nahrendorf, M. & Swirski, F. K. Abandoning M1/M2 for a network model of macrophage function. Circ. Res. 119, 414–417 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Domanska, D. et al. Single-cell transcriptomic analysis of human colonic macrophages reveals niche-specific subsets. J. Exp. Med. 219, e20211846 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Tamoutounour, S. et al. CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1-inducing role of mesenteric lymph node macrophages during colitis. Eur. J. Immunol. 42, 3150–3166 (2012).

    CAS  PubMed  Google Scholar 

  14. Shaw, T. N. et al. Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression. J. Exp. Med. 215, 1507–1518 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. De Schepper, S. et al. Self-maintaining gut macrophages are essential for intestinal homeostasis. Cell 175, 400–415.e13 (2018).

    PubMed  Google Scholar 

  16. Zigmond, E. et al. Ly6C hi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 37, 1076–1090 (2012).

    CAS  PubMed  Google Scholar 

  17. Bain, C. C. et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat. Immunol. 15, 929–937 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bain, C. C. et al. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol. 6, 498–510 (2013).

    CAS  PubMed  Google Scholar 

  19. Kamada, N. et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis. J. Clin. Invest. 118, 2269–2280 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Thiesen, S. et al. CD14hiHLA-DRdim macrophages, with a resemblance to classical blood monocytes, dominate inflamed mucosa in Crohn’s disease. J. Leukoc. Biol. 95, 531–541 (2013).

    PubMed  Google Scholar 

  21. Jones, G.-R. et al. Dynamics of colon monocyte and macrophage activation during colitis. Front. Immunol. 9, 2764 (2018).

    PubMed  PubMed Central  Google Scholar 

  22. Gabanyi, I. et al. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell 164, 378–391 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Muller, P. A. et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300–313 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Matheis, F. et al. Adrenergic signaling in muscularis macrophages limits infection-induced neuronal loss. Cell 180, 64–78.e16 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Matusiak, M. et al. A spatial map of human macrophage niches links tissue location with function. Preprint at bioRxiv https://doi.org/10.1101/2022.08.18.504434 (2022).

  26. Kang, B. et al. Commensal microbiota drive the functional diversification of colon macrophages. Mucosal Immunol. 13, 216–229 (2020).

    CAS  PubMed  Google Scholar 

  27. Asano, K. et al. Intestinal CD169+ macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes. Nat. Commun. 6, 7802 (2015).

    CAS  PubMed  Google Scholar 

  28. Hapfelmeier, S. et al. Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent step in ΔinvG S. Typhimurium colitis. J. Exp. Med. 205, 437–450 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kumawat, A. K. et al. Expression and characterization of αvβ5 integrin on intestinal macrophages. Eur. J. Immunol. 48, 1181–1187 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Cummings, R. J. et al. Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs. Nature 539, 565–569 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Lacy-Hulbert, A. et al. Ulcerative colitis and autoimmunity induced by loss of myeloid αv integrins. Proc. Natl Acad. Sci. USA 104, 15823–15828 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. D’Angelo, F. et al. Macrophages promote epithelial repair through hepatocyte growth factor secretion. Clin. Exp. Immunol. 174, 60–72 (2013).

    PubMed  PubMed Central  Google Scholar 

  33. Cosín-Roger, J. et al. The activation of Wnt signaling by a STAT6-dependent macrophage phenotype promotes mucosal repair in murine IBD. Mucosal Immunol. 9, 986–998 (2016).

    PubMed  Google Scholar 

  34. Saha, S. et al. Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury. Nat. Commun. 7, 13096 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2011).

    CAS  PubMed  Google Scholar 

  36. Sehgal, A. et al. The role of CSF1R-dependent macrophages in control of the intestinal stem-cell niche. Nat. Commun. 9, 1272 (2018).

    PubMed  PubMed Central  Google Scholar 

  37. Pull, S. L., Doherty, J. M., Mills, J. C., Gordon, J. I. & Stappenbeck, T. S. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl Acad. Sci. USA 102, 99–104 (2005).

    CAS  PubMed  Google Scholar 

  38. Chikina, A. S. et al. Macrophages maintain epithelium integrity by limiting fungal product absorption. Cell 183, 411–428.e16 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Rivollier, A., He, J., Kole, A., Valatas, V. & Kelsall, B. L. Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon. J. Exp. Med. 209, 139–155 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Murai, M. et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat. Immunol. 10, 1178–1184 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zigmond, E. et al. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity 40, 720–733 (2014).

    CAS  PubMed  Google Scholar 

  42. Morhardt, T. L. et al. IL-10 produced by macrophages regulates epithelial integrity in the small intestine. Sci. Rep. 9, 1223 (2019).

    PubMed  PubMed Central  Google Scholar 

  43. Kayama, H. et al. Intestinal CX3C chemokine receptor 1high (CX3CR1high) myeloid cells prevent T-cell-dependent colitis. Proc. Natl Acad. Sci. USA 109, 5010–5015 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Hadis, U. et al. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity 34, 237–246 (2011).

    CAS  PubMed  Google Scholar 

  45. Denning, T. L., Wang, Y. C., Patel, S. R., Williams, I. R. & Pulendran, B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat. Immunol. 8, 1086–1094 (2007).

    CAS  PubMed  Google Scholar 

  46. Shaw, M. H., Kamada, N., Kim, Y.-G. & Núñez, G. Microbiota-induced IL-1β, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine. J. Exp. Med. 209, 251–258 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Panea, C. et al. Intestinal monocyte-derived macrophages control commensal-specific Th17 responses. Cell Rep. 12, 1314–1324 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ruder, B., Atreya, R. & Becker, C. Tumour necrosis factor alpha in intestinal homeostasis and gut related diseases. Int. J. Mol. Sci. 20, E1887 (2019).

    Google Scholar 

  49. Diehl, G. E. et al. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells. Nature 494, 116–120 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Bravo-Blas, A. et al. Salmonella enterica serovar Typhimurium travels to mesenteric lymph nodes both with host cells and autonomously. J. Immunol. 202, 260–267 (2019).

    CAS  PubMed  Google Scholar 

  51. Honda, M. et al. Perivascular localization of macrophages in the intestinal mucosa is regulated by Nr4a1 and the microbiome. Nat. Commun. 11, 1329 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Suh, S. H. et al. Gut microbiota regulates lacteal integrity by inducing VEGF-C in intestinal villus macrophages. EMBO Rep. 20, e46927 (2019).

    PubMed  PubMed Central  Google Scholar 

  53. Rao, M. & Gershon, M. D. The bowel and beyond: the enteric nervous system in neurological disorders. Nat. Rev. Gastroenterol. Hepatol. 13, 517–528 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Farzaei, M. H., Bahramsoltani, R., Abdollahi, M. & Rahimi, R. The role of visceral hypersensitivity in irritable bowel syndrome: pharmacological targets and novel treatments. J. Neurogastroenterol. Motil. 22, 558–574 (2016).

    PubMed  PubMed Central  Google Scholar 

  55. Pendse, M. et al. Macrophages regulate gastrointestinal motility through complement component 1q. Preprint at bioRxiv https://doi.org/10.1101/2022.01.27.478097 (2022).

  56. Luo, J. et al. TRPV4 channel signaling in macrophages promotes gastrointestinal motility via direct effects on smooth muscle cells. Immunity 49, 107–119.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Chiaranunt, P. et al. Microbial energy metabolism fuels a CSF2-dependent intestinal macrophage niche within tertiary lymphoid organs. Preprint at bioRxiv https://doi.org/10.1101/2022.03.23.485563 (2022).

  58. Kim, Y.-I. et al. CX3CR1+ macrophages and CD8+ T cells control intestinal IgA production. J. Immunol. 201, 1287–1294 (2018).

    CAS  PubMed  Google Scholar 

  59. Koscsó, B. et al. Gut-resident CX3CR1hi macrophages induce tertiary lymphoid structures and IgA response in situ. Sci. Immunol. 5, eaax0062 (2020).

    PubMed  PubMed Central  Google Scholar 

  60. Da Silva, C., Wagner, C., Bonnardel, J., Gorvel, J.-P. & Lelouard, H. The Peyer’s patch mononuclear phagocyte system at steady state and during infection. Front. Immunol. 8, 1254 (2017).

    PubMed  PubMed Central  Google Scholar 

  61. van Furth, R. et al. The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull. World Health Organ. 46, 845–852 (1972).

    PubMed  PubMed Central  Google Scholar 

  62. Tarling, J. D., Lin, H. S. & Hsu, S. Self-renewal of pulmonary alveolar macrophages: evidence from radiation chimera studies. J. Leukoc. Biol. 42, 443–446 (1987).

    CAS  PubMed  Google Scholar 

  63. Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).

    CAS  PubMed  Google Scholar 

  64. Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

    CAS  PubMed  Google Scholar 

  65. Hoeffel, G. et al. C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).

    PubMed  Google Scholar 

  68. Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

    CAS  PubMed  Google Scholar 

  69. Sheng, J., Ruedl, C. & Karjalainen, K. Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity 43, 382–393 (2015).

    CAS  PubMed  Google Scholar 

  70. Chen, Q., Nair, S. & Ruedl, C. Microbiota regulates the turnover kinetics of gut macrophages in health and inflammation. Life Sci. Alliance 5, e202101178 (2022).

    CAS  PubMed  Google Scholar 

  71. Liu, Z. et al. Fate mapping via Ms4a3-expression history traces monocyte-derived cells. Cell 178, 1509–1525.e19 (2019).

    CAS  PubMed  Google Scholar 

  72. Gensollen, T. et al. Embryonic macrophages function during early life to determine invariant natural killer T cell levels at barrier surfaces. Nat. Immunol. 22, 699–710 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Fenton, T. M. et al. Single-cell characterisation of mononuclear phagocytes in the human intestinal mucosa. Preprint at bioRxiv https://doi.org/10.1101/2021.03.28.437379 (2021).

  74. Bujko, A. et al. Transcriptional and functional profiling defines human small intestinal macrophage subsets. J. Exp. Med. 215, 441–458 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Schridde, A. et al. Tissue-specific differentiation of colonic macrophages requires TGFβ receptor-mediated signaling. Mucosal Immunol. 10, 1387–1399 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Bain, C. C. et al. Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities. Nat. Commun. 7, ncomms11852 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Kanitakis, J., Morelon, E., Petruzzo, P., Badet, L. & Dubernard, J.-M. Self-renewal capacity of human epidermal Langerhans cells: observations made on a composite tissue allograft. Exp. Dermatol. 20, 145–146 (2011).

    CAS  PubMed  Google Scholar 

  79. Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Rosshart, S. P. et al. Laboratory mice born to wild mice have natural microbiota and model human immune responses. Science 365, eaaw4361 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Grubišić, V. et al. Enteric glia modulate macrophage phenotype and visceral sensitivity following inflammation. Cell Rep. 32, 108100 (2020).

    PubMed  PubMed Central  Google Scholar 

  82. Bogunovic, M. et al. Origin of the lamina propria dendritic cell network. Immunity 31, 513–525 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Mortha, A. et al. Neutralizing anti-granulocyte macrophage-colony stimulating factor autoantibodies recognize post-translational glycosylations on granulocyte macrophage-colony stimulating factor years before diagnosis and predict complicated Crohn’s disease. Gastroenterology 163, 659–670 (2022).

    CAS  PubMed  Google Scholar 

  84. Ueda, Y. et al. Commensal microbiota induce LPS hyporesponsiveness in colonic macrophages via the production of IL-10. Int. Immunol. 22, 953–962 (2010).

    CAS  PubMed  Google Scholar 

  85. El Sayed, S. et al. CCR2 promotes monocyte recruitment and intestinal inflammation in mice lacking the interleukin-10 receptor. Sci. Rep. 12, 452 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Shouval, D. S. et al. Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity 40, 706–719 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Hoshi, N. et al. MyD88 signalling in colonic mononuclear phagocytes drives colitis in IL-10-deficient mice. Nat. Commun. 3, 1120 (2012).

    PubMed  Google Scholar 

  88. Takeda, K. et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10, 39–49 (1999).

    CAS  PubMed  Google Scholar 

  89. Bernshtein, B. et al. IL-23-producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven proinflammatory epithelial cell response. Sci. Immunol. 4, eaau6571 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Francesca, V. M. et al. Neuro- immune crosstalk in the enteric nervous system from early postnatal development to adulthood. Preprint at bioRxiv https://doi.org/10.1101/2022.05.12.491517 (2022).

  92. Niess, J. H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005).

    CAS  PubMed  Google Scholar 

  93. Chieppa, M., Rescigno, M., Huang, A. Y. & Germain, R. N. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 203, 2841–2852 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Bernardo, D. et al. Human intestinal pro-inflammatory CD11chighCCR2+CX3CR1+ macrophages, but not their tolerogenic CD11c−CCR2−CX3CR1− counterparts, are expanded in inflammatory bowel disease. Mucosal Immunol. 11, 1114–1126 (2018).

    CAS  PubMed  Google Scholar 

  95. Ishifune, C. et al. Differentiation of CD11c+CX3CR1+ cells in the small intestine requires Notch signaling. Proc. Natl Acad. Sci. USA 111, 5986–5991 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. A-Gonzalez, N. et al. Phagocytosis imprints heterogeneity in tissue-resident macrophages. J. Exp. Med. 214, 1281–1296 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Scott, N. A. et al. Macrophage metabolism in the intestine is compartment specific and regulated by the microbiota. Immunology 166, 138–152 (2022).

    CAS  PubMed  Google Scholar 

  98. Scott, N. A. et al. Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis. Sci. Transl. Med. 10, eaao4755 (2018).

    PubMed  PubMed Central  Google Scholar 

  99. Okawa, T., Nagai, M. & Hase, K. Dietary intervention impacts immune cell functions and dynamics by inducing metabolic rewiring. Front. Immunol. 11, 623989 (2020).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Alex, S. et al. Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating peroxisome proliferator-activated receptor γ. Mol. Cell Biol. 33, 1303–1316 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Marinelli, L. et al. Identification of the novel role of butyrate as AhR ligand in human intestinal epithelial cells. Sci. Rep. 9, 643 (2019).

    PubMed  PubMed Central  Google Scholar 

  103. Chng, S. H. et al. Ablating the aryl hydrocarbon receptor (AhR) in CD11c+ cells perturbs intestinal epithelium development and intestinal immunity. Sci. Rep. 6, 23820 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Erkelens, M. N. et al. Intestinal macrophages balance inflammatory expression profiles via vitamin A and dectin-1-mediated signaling. Front. Immunol. 11, 551 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Miranda, P. M. et al. High salt diet exacerbates colitis in mice by decreasing Lactobacillus levels and butyrate production. Microbiome 6, 57 (2018).

    PubMed  PubMed Central  Google Scholar 

  106. Rohm, T. V. et al. Obesity in humans is characterized by gut inflammation as shown by pro-inflammatory intestinal macrophage accumulation. Front. Immunol. 12, 668654 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Rohm, T. V. et al. Targeting colonic macrophages improves glycemic control in high-fat diet-induced obesity. Commun. Biol. 5, 370 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Scott, C. L. et al. The transcription factor ZEB2 is required to maintain the tissue-specific identities of macrophages. Immunity 49, 312–325.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Hantisteanu, S. et al. Runx3 prevents spontaneous colitis by directing the differentiation of anti-inflammatory mononuclear phagocytes. PLoS ONE 15, e0233044 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Corbin, A. L. et al. IRF5 guides monocytes toward an inflammatory CD11c+ macrophage phenotype and promotes intestinal inflammation. Sci. Immunol. 5, eaax6085 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Moura Silva, H. et al. c-MAF-dependent perivascular macrophages regulate diet-induced metabolic syndrome. Sci. Immunol. 6, eabg7506 (2021).

    PubMed  Google Scholar 

  112. Heresbach, D. et al. Frequency and significance of granulomas in a cohort of incident cases of Crohn’s disease. Gut 54, 215–222 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Baillie, J. K. et al. Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease. PLoS Genet. 13, e1006641 (2017).

    PubMed  PubMed Central  Google Scholar 

  114. Lesage, S. et al. CARD15/NOD2 mutational analysis and genotype–phenotype correlation in 612 patients with inflammatory bowel disease. Am. J. Hum. Genet. 70, 845–857 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Watanabe, T., Kitani, A. & Strober, W. NOD2 regulation of Toll-like receptor responses and the pathogenesis of Crohn’s disease. Gut 54, 1515–1518 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Nayar, S. et al. A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn’s disease. Nature 593, 275–281 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Lapaquette, P., Glasser, A.-L., Huett, A., Xavier, R. J. & Darfeuille-Michaud, A. Crohn’s disease-associated adherent-invasive E. coli are selectively favoured by impaired autophagy to replicate intracellularly. Cell Microbiol. 12, 99–113 (2010).

    CAS  PubMed  Google Scholar 

  118. Lapaquette, P., Bringer, M.-A. & Darfeuille-Michaud, A. Defects in autophagy favour adherent-invasive Escherichia coli persistence within macrophages leading to increased pro-inflammatory response. Cell Microbiol. 14, 791–807 (2012).

    CAS  PubMed  Google Scholar 

  119. Dige, A. et al. Soluble CD163, a specific macrophage activation marker, is decreased by anti-TNF-α antibody treatment in active inflammatory bowel disease. Scand. J. Immunol. 80, 417–423 (2014).

    CAS  PubMed  Google Scholar 

  120. Vos, A. C. W. et al. Anti-tumor necrosis factor-α antibodies induce regulatory macrophages in an Fc region-dependent manner. Gastroenterology 140, 221–230 (2011).

    CAS  PubMed  Google Scholar 

  121. Schleier, L. et al. Non-classical monocyte homing to the gut via α4β7 integrin mediates macrophage-dependent intestinal wound healing. Gut 69, 252–263 (2020).

    CAS  PubMed  Google Scholar 

  122. Delfini, M., Stakenborg, N., Viola, M. F. & Boeckxstaens, G. Macrophages in the gut: masters in multitasking. Immunity 55, 1530–1548 (2022).

    CAS  PubMed  Google Scholar 

  123. Na, Y. R., Stakenborg, M., Seok, S. H. & Matteoli, G. Macrophages in intestinal inflammation and resolution: a potential therapeutic target in IBD. Nat. Rev. Gastroenterol. Hepatol. 16, 531–543 (2019).

    CAS  PubMed  Google Scholar 

  124. Rugtveit, J. et al. Respiratory burst of intestinal macrophages in inflammatory bowel disease is mainly caused by CD14+L1+ monocyte derived cells. Gut 37, 367–373 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Rugtveit, J. et al. Cytokine profiles differ in newly recruited and resident subsets of mucosal macrophages from inflammatory bowel disease. Gastroenterology 112, 1493–1505 (1997).

    CAS  PubMed  Google Scholar 

  126. Grimm, M. C. et al. Direct evidence of monocyte recruitment to inflammatory bowel disease mucosa. J. Gastroenterol. Hepatol. 10, 387–395 (1995).

    CAS  PubMed  Google Scholar 

  127. Ogino, T. et al. Increased Th17-inducing activity of CD14+ CD163low myeloid cells in intestinal lamina propria of patients with Crohn’s disease. Gastroenterology 145, 1380–1391.e1 (2013).

    CAS  PubMed  Google Scholar 

  128. Kelley, N., Jeltema, D., Duan, Y. & He, Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int. J. Mol. Sci. 20, E3328 (2019).

    Google Scholar 

  129. Mao, L. et al. Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease. J. Clin. Invest. 128, 1793–1806 (2018).

    PubMed  PubMed Central  Google Scholar 

  130. Kiesler, P., Fuss, I. J. & Strober, W. Experimental models of inflammatory bowel diseases. Cell Mol. Gastroenterol. Hepatol. 1, 154–170 (2015).

    PubMed  PubMed Central  Google Scholar 

  131. Pariente, B. et al. Validation and update of the Lémann index to measure cumulative structural bowel damage in Crohn’s disease. Gastroenterology 161, 853–864.e13 (2021).

    PubMed  Google Scholar 

  132. Beaugerie, L., Seksik, P., Nion-Larmurier, I., Gendre, J.-P. & Cosnes, J. Predictors of Crohn’s disease. Gastroenterology 130, 650–656 (2006).

    PubMed  Google Scholar 

  133. Henriksen, M. et al. Clinical course in Crohn’s disease: results of a five-year population-based follow-up study (the IBSEN study). Scand. J. Gastroenterol. 42, 602–610 (2007).

    PubMed  Google Scholar 

  134. Desalegn, G. & Pabst, O. Inflammation triggers immediate rather than progressive changes in monocyte differentiation in the small intestine. Nat. Commun. 10, 3229 (2019).

    PubMed  PubMed Central  Google Scholar 

  135. Schippers, A. et al. β7-Integrin exacerbates experimental DSS-induced colitis in mice by directing inflammatory monocytes into the colon. Mucosal Immunol. 9, 527–538 (2016).

    CAS  PubMed  Google Scholar 

  136. Seo, S.-U. et al. Distinct commensals induce interleukin-1β via NLRP3 inflammasome in inflammatory monocytes to promote intestinal inflammation in response to injury. Immunity 42, 744–755 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Bain, C. C., Oliphant, C. J., Thomson, C. A., Kullberg, M. C. & Mowat, A. M. Proinflammatory role of monocyte-derived CX3CR1int macrophages in Helicobacter hepaticus-induced colitis. Infect. Immun. 86, e00579-17 (2018).

    PubMed  PubMed Central  Google Scholar 

  138. Arnold, I. C. et al. CD11c+ monocyte/macrophages promote chronic Helicobacter hepaticus-induced intestinal inflammation through the production of IL-23. Mucosal Immunol. 9, 352–363 (2015).

    PubMed  PubMed Central  Google Scholar 

  139. Weber, B., Saurer, L., Schenk, M., Dickgreber, N. & Mueller, C. CX3CR1 defines functionally distinct intestinal mononuclear phagocyte subsets which maintain their respective functions during homeostatic and inflammatory conditions. Eur. J. Immunol. 41, 773–779 (2011).

    CAS  PubMed  Google Scholar 

  140. Platt, A. M., Bain, C. C., Bordon, Y., Sester, D. P. & Mowat, A. M. An independent subset of TLR expressing CCR2-dependent macrophages promotes colonic inflammation. J. Immunol. 184, 6843–6854 (2010).

    CAS  PubMed  Google Scholar 

  141. Varol, C. et al. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity 31, 502–512 (2009).

    CAS  PubMed  Google Scholar 

  142. Shouval, D. S. et al. Interleukin 1β mediates intestinal inflammation in mice and patients with interleukin 10 receptor deficiency. Gastroenterology 151, 1100–1104 (2016).

    CAS  PubMed  Google Scholar 

  143. West, N. R. et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat. Med. 23, 579–589 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Sawada, K. & Shimoyama, T. Therapeutic cytapheresis for inflammatory bowel disease. Ther. Apher. 2, 90–92 (1998).

    CAS  PubMed  Google Scholar 

  145. Shimoyama, T. et al. Safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active ulcerative colitis: a multicenter study. J. Clin. Apher. 16, 1–9 (2001).

    CAS  PubMed  Google Scholar 

  146. Hibi, T. et al. Treating ulcerative colitis by Adacolumn therapeutic leucocytapheresis: clinical efficacy and safety based on surveillance of 656 patients in 53 centres in Japan. Dig. Liver Dis. 41, 570–577 (2009).

    CAS  PubMed  Google Scholar 

  147. Sands, B. E. et al. A randomised, double-blind, sham-controlled study of granulocyte/monocyte apheresis for moderate to severe Crohn’s disease. Gut 62, 1288–1294 (2013).

    PubMed  Google Scholar 

  148. Sands, B. E. et al. A randomized, double-blind, sham-controlled study of granulocyte/monocyte apheresis for active ulcerative colitis. Gastroenterology 135, 400–409 (2008).

    CAS  PubMed  Google Scholar 

  149. Aychek, T. et al. IL-23-mediated mononuclear phagocyte crosstalk protects mice from Citrobacter rodentium-induced colon immunopathology. Nat. Commun. 6, 6525 (2015).

    CAS  PubMed  Google Scholar 

  150. Schreiber, H. A. et al. Intestinal monocytes and macrophages are required for T cell polarization in response to Citrobacter rodentium. J. Exp. Med. 210, 2025–2039 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Kim, Y. G. et al. The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes. Immunity 34, 769–780 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Dunay, I. R., Fuchs, A. & Sibley, L. D. Inflammatory monocytes but not neutrophils are necessary to control infection with Toxoplasma gondii in mice. Infect. Immun. 78, 1564–1570 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Grainger, J. R. et al. Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection. Nat. Med. 19, 713–721 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Griseri, T., McKenzie, B. S., Schiering, C. & Powrie, F. Dysregulated hematopoietic stem and progenitor cell activity promotes interleukin-23-driven chronic intestinal inflammation. Immunity 37, 1116–1129 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Caër, C. et al. TREM-1+ macrophages define a pathogenic cell subset in the intestine of Crohn’s disease patients. J. Crohn’s Colitis 15, 1346–1361 (2021).

    Google Scholar 

  156. Nakanishi, Y., Sato, T., Takahashi, K. & Ohteki, T. IFN-γ-dependent epigenetic regulation instructs colitogenic monocyte/macrophage lineage differentiation in vivo. Mucosal Immunol. 11, 871–880 (2018).

    CAS  PubMed  Google Scholar 

  157. Castro-Dopico, T. et al. GM-CSF calibrates macrophage defense and wound healing programs during intestinal infection and inflammation. Cell Rep. 32, 107857 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Weber, B. et al. TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. PLoS Pathog. 10, e1003900 (2014).

    PubMed  PubMed Central  Google Scholar 

  159. Askenase, M. H. et al. Bone-marrow-resident NK cells prime monocytes for regulatory function during infection. Immunity 42, 1130–1142 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Aschenbrenner, D. et al. Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance. Gut 70, 1023–1036 (2021).

    CAS  PubMed  Google Scholar 

  161. O’Neill, L. A. J., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).

    PubMed  PubMed Central  Google Scholar 

  162. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Kim, Y.-E. et al. HIF-1α activation in myeloid cells accelerates dextran sodium sulfate-induced colitis progression in mice. Dis. Model. Mech. 11, dmm033241 (2018).

    PubMed  PubMed Central  Google Scholar 

  164. Macias-Ceja, D. C. et al. Succinate receptor mediates intestinal inflammation and fibrosis. Mucosal Immunol. 12, 178–187 (2019).

    CAS  PubMed  Google Scholar 

  165. Kolho, K.-L., Pessia, A., Jaakkola, T., de Vos, W. M. & Velagapudi, V. Faecal and serum metabolomics in paediatric inflammatory bowel disease. J. Crohns Colitis 11, 321–334 (2017).

    PubMed  Google Scholar 

  166. Sido, B., Seel, C., Hochlehnert, A., Breitkreutz, R. & Dröge, W. Low intestinal glutamine level and low glutaminase activity in Crohn’s disease: a rational for glutamine supplementation? Dig. Dis. Sci. 51, 2170–2179 (2006).

    CAS  PubMed  Google Scholar 

  167. Ren, W. et al. Serum amino acids profile and the beneficial effects of L-arginine or L-glutamine supplementation in dextran sulfate sodium colitis. PLoS ONE 9, e88335 (2014).

    PubMed  PubMed Central  Google Scholar 

  168. Chu, C.-C., Hou, Y.-C., Pai, M.-H., Chao, C.-J. & Yeh, S.-L. Pretreatment with alanyl-glutamine suppresses T-helper-cell-associated cytokine expression and reduces inflammatory responses in mice with acute DSS-induced colitis. J. Nutr. Biochem. 23, 1092–1099 (2012).

    CAS  PubMed  Google Scholar 

  169. Rath, M., Müller, I., Kropf, P., Closs, E. I. & Munder, M. Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front. Immunol. 5, 532 (2014).

    PubMed  PubMed Central  Google Scholar 

  170. Singh, K. et al. Dietary arginine regulates severity of experimental colitis and affects the colonic microbiome. Front. Cell Infect. Microbiol. 9, 66 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Wuggenig, P. et al. Loss of the branched-chain amino acid transporter CD98hc alters the development of colonic macrophages in mice. Commun. Biol. 3, 130 (2020).

    PubMed  PubMed Central  Google Scholar 

  172. Duffin, R. et al. Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell–IL-22 axis. Science 351, 1333–1338 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Na, Y. R. et al. Prostaglandin E2 receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation. Gut 70, 2249–2260 (2021).

    CAS  PubMed  Google Scholar 

  174. Miyoshi, H. et al. Prostaglandin E2 promotes intestinal repair through an adaptive cellular response of the epithelium. EMBO J. 36, 5–24 (2017).

    CAS  PubMed  Google Scholar 

  175. Glas, J. et al. PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn’s disease and affect NF-κB and XBP1 binding sites. PLoS ONE 7, e52873 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Rani, R., Smulian, A. G., Greaves, D. R., Hogan, S. P. & Herbert, D. R. TGF-beta limits IL-33 production and promotes the resolution of colitis through regulation of macrophage function. Eur. J. Immunol. 41, 2000–2009 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Yurdagul, A. et al. Macrophage metabolism of apoptotic cell-derived arginine promotes continual efferocytosis and resolution of injury. Cell Metab. 31, 518–533.e10 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Ikeda, N. et al. Emergence of immunoregulatory Ym1+Ly6Chi monocytes during recovery phase of tissue injury. Sci. Immunol. 3, eaat0207 (2018).

    PubMed  Google Scholar 

  179. Gaiani, F. et al. Monocytes from infliximab-resistant patients with Crohn’s disease exhibit a disordered cytokine profile. Sci. Rep. 10, 12238 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Salvador, P. et al. CD16+ macrophages mediate fibrosis in inflammatory bowel disease. J. Crohns Colitis 12, 589–599 (2018).

    PubMed  Google Scholar 

  181. Kennedy, N. A. et al. Association between level of fecal calprotectin and progression of Crohn’s disease. Clin. Gastroenterol. Hepatol. 17, 2269–2276.e4 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Plevris, N. et al. Normalization of fecal calprotectin within 12 months of diagnosis is associated with reduced risk of disease progression in patients with Crohn’s disease. Clin. Gastroenterol. Hepatol. 19, 1835–1844.e6 (2021).

    PubMed  Google Scholar 

  183. Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Seno, H. et al. Efficient colonic mucosal wound repair requires Trem2 signaling. Proc. Natl Acad. Sci. USA 106, 256–261 (2009).

    CAS  PubMed  Google Scholar 

  185. Elmentaite, R. et al. Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease. Dev. Cell 55, 771–783.e5 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Han, L. et al. Single cell transcriptomics identifies a signaling network coordinating endoderm and mesoderm diversification during foregut organogenesis. Nat. Commun. 11, 4158 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Elmentaite, R. et al. Cells of the human intestinal tract mapped across space and time. Nature 597, 250–255 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Smillie, C. S. et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 178, 714–730.e22 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Krljanac, B. et al. RELMα-expressing macrophages protect against fatal lung damage and reduce parasite burden during helminth infection. Sci. Immunol. 4, eaau3814 (2019).

    CAS  PubMed  Google Scholar 

  190. Singh, S. B., Davis, A. S., Taylor, G. A. & Deretic, V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438–1441 (2006).

    CAS  PubMed  Google Scholar 

  191. Nguyen, H. T. T., Lapaquette, P., Bringer, M.-A. & Darfeuille-Michaud, A. Autophagy and Crohn’s disease. J. Innate Immun. 5, 434–443 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Gettler, K. et al. Prioritizing Crohn’s disease genes by integrating association signals with gene expression implicates monocyte subsets. Genes Immun. 20, 577–588 (2019).

    PubMed  PubMed Central  Google Scholar 

  193. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Franke, A. et al. Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat. Genet. 42, 292–294 (2010).

    CAS  PubMed  Google Scholar 

  195. Kim, K. W. et al. In vivo structure/function and expression analysis of the CX3C chemokine fractalkine. Blood 118, e156–e167 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Mortha, A. et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014).

    PubMed  PubMed Central  Google Scholar 

  197. Mikkelsen, H. B., Garbarsch, C., Tranum-Jensen, J. & Thuneberg, L. Macrophages in the small intestinal muscularis externa of embryos, newborn and adult germ-free mice. J. Mol. Histol. 35, 377–387 (2004).

    CAS  PubMed  Google Scholar 

  198. Schlitzer, A. et al. IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38, 970–983 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).

    CAS  PubMed  Google Scholar 

  200. Schulthess, J. et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity 50, 432–445.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Smith, P. D. et al. Intestinal macrophages and response to microbial encroachment. Mucosal Immunol. 4, 31–42 (2010).

    PubMed  Google Scholar 

Download references

Acknowledgements

All authors are funded by the Wellcome Trust/Royal Society in the form of a PhD studentship (L.M.H.; 222356/Z/21/Z), Clinical Career Development Fellowship (G.-R.J.; 220725/Z/20/Z) and a Sir Henry Dale Fellowship (C.C.B.; 206234/Z/17/Z).

Author information

Author notes

  1. These authors contributed equally: Lizi M. Hegarty, Gareth-Rhys Jones.

Authors and Affiliations

  1. Centre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh BioQuarter, Queen’s Medical Research Institute, Edinburgh, UK

    Lizi M. Hegarty, Gareth-Rhys Jones & Calum C. Bain

Authors
  1. Lizi M. Hegarty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gareth-Rhys Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Calum C. Bain
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Calum C. Bain.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Gastroenterology & Hepatology thanks Yi Rang Na, Rodney Newberry, Claudia Cavelti-Weder and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hegarty, L.M., Jones, GR. & Bain, C.C. Macrophages in intestinal homeostasis and inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 20, 538–553 (2023). https://doi.org/10.1038/s41575-023-00769-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41575-023-00769-0

This article is cited by

Search

Advanced search

Quick links

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