{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T22:34:59Z","timestamp":1792708499578,"version":"4.5.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T00:00:00Z","timestamp":1620777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Chronic low-grade inflammation is a hallmark of obesity and associated with cardiovascular complications. However, it remains unclear where this inflammation starts. As the gut is constantly exposed to food, gut microbiota, and metabolites, we hypothesized that mucosal immunity triggers an innate inflammatory response in obesity. We characterized five distinct macrophage subpopulations (P1-P5) along the gastrointestinal tract and blood monocyte subpopulations (classical, non-classical, intermediate), which replenish intestinal macrophages, in non-obese (BMI&amp;lt;27kg\/m\n                    <jats:sup>2<\/jats:sup>\n                    ) and obese individuals (BMI&amp;gt;32kg\/m\n                    <jats:sup>2<\/jats:sup>\n                    ). To elucidate factors that potentially trigger gut inflammation, we correlated these subpopulations with cardiovascular risk factors and lifestyle behaviors. In obese individuals, we found higher pro-inflammatory macrophages in the stomach, duodenum, and colon. Intermediate blood monocytes were also increased in obesity, suggesting enhanced recruitment to the gut. We identified unhealthy lifestyle habits as potential triggers of gut and systemic inflammation (i.e., low vegetable intake, high processed meat consumption, sedentary lifestyle). Cardiovascular risk factors other than body weight did not affect the innate immune response. Thus, obesity in humans is characterized by gut inflammation as shown by accumulation of pro-inflammatory intestinal macrophages, potentially\n                    <jats:italic>via<\/jats:italic>\n                    recruited blood monocytes. Understanding gut innate immunity in human obesity might open up new targets for immune-modulatory treatments in metabolic disease.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2021.668654","type":"journal-article","created":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T02:30:38Z","timestamp":1620786638000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":60,"title":["Obesity in Humans Is Characterized by Gut Inflammation as Shown by Pro-Inflammatory Intestinal Macrophage Accumulation"],"prefix":"10.3389","volume":"12","author":[{"given":"Theresa V.","family":"Rohm","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regula","family":"Fuchs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahel L.","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zora","family":"Baumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela J. T.","family":"Bosch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romano","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny","family":"Labes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Langer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia B.","family":"Pilz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan H.","family":"Niess","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarik","family":"Delko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr","family":"Hruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Cavelti-Weder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00410","article-title":"Human Intestinal Mononuclear Phagocytes in Health and Inflammatory Bowel Disease","volume":"11","author":"Caer","year":"2020","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3738","article-title":"Regional Specialization Within the Intestinal Immune System","volume":"14","author":"Mowat","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2967","article-title":"Constant Replenishment From Circulating Monocytes Maintains the Macrophage Pool in the Intestine of Adult Mice","volume":"15","author":"Bain","year":"2014","journal-title":"Nat Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02035","article-title":"Human Monocyte Subsets and Phenotypes in Major Chronic Inflammatory Diseases","volume":"10","author":"Kapellos","year":"2019","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/mi.2012.89","article-title":"Resident and Pro-Inflammatory Macrophages in the Colon Represent Alternative Context-Dependent Fates of the Same Ly6Chi Monocyte Precursors","volume":"6","author":"Bain","year":"2013","journal-title":"Mucosal Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201242847","article-title":"CD64 Distinguishes Macrophages From Dendritic Cells in the Gut and Reveals the Th1-inducing Role of Mesenteric Lymph Node Macrophages During Colitis","volume":"42","author":"Tamoutounour","year":"2012","journal-title":"Eur J Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.10.004","article-title":"Origins and Functional Specialization of Macrophages and of Conventional and Monocyte-Derived Dendritic Cells in Mouse Skin","volume":"39","author":"Tamoutounour","year":"2013","journal-title":"Immunity"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2017.22","article-title":"Diversity and Functions of Intestinal Mononuclear Phagocytes","volume":"10","author":"Joeris","year":"2017","journal-title":"Mucosal Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ni1511","article-title":"Lamina Propria Macrophages and Dendritic Cells Differentially Induce Regulatory and Interleukin 17-Producing T Cell Responses","volume":"8","author":"Denning","year":"2007","journal-title":"Nat Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.01.016","article-title":"Intestinal Tolerance Requires Gut Homing and Expansion of FoxP3+ Regulatory T Cells in the Lamina Propria","volume":"34","author":"Hadis","year":"2011","journal-title":"Immunity"},{"key":"B11","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1172\/JCI200519229","article-title":"Human Intestinal Macrophages Display Profound Inflammatory Anergy Despite Avid Phagocytic and Bacteriocidal Activity","volume":"115","author":"Smythies","year":"2005","journal-title":"J Clin Invest"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20170057","article-title":"Transcriptional and Functional Profiling Defines Human Small Intestinal Macrophage Subsets","volume":"215","author":"Bujko","year":"2018","journal-title":"J Exp Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20101387","article-title":"Inflammation Switches the Differentiation Program of Ly6Chi Monocytes From Antiinflammatory Macrophages to Inflammatory Dendritic Cells in the Colon","volume":"209","author":"Rivollier","year":"2012","journal-title":"J Exp Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.05.019","article-title":"Gr1(+) Inflammatory Monocytes are Required for Mucosal Resistance to the Pathogen Toxoplasma Gondii","volume":"29","author":"Dunay","year":"2008","journal-title":"Immunity"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3189","article-title":"Inflammatory Monocytes Regulate Pathologic Responses to Commensals During Acute Gastrointestinal Infection","volume":"19","author":"Grainger","year":"2013","journal-title":"Nat Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200319246","article-title":"Obesity is Associated With Macrophage Accumulation in Adipose Tissue","volume":"112","author":"Weisberg","year":"2003","journal-title":"J Clin Invest"},{"key":"B17","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.cmet.2016.07.009","article-title":"Colonic Pro-inflammatory Macrophages Cause Insulin Resistance in an Intestinal Ccl2\/Ccr2-Dependent Manner","volume":"24","author":"Kawano","year":"2016","journal-title":"Cell Metab"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00098.2010","article-title":"Propensity to High-Fat Diet-Induced Obesity in Rats is Associated With Changes in the Gut Microbiota and Gut Inflammation","volume":"299","author":"de La Serre","year":"2010","journal-title":"Am J Physiol Gastrointestinal liver Physiol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e12191","DOI":"10.1371\/journal.pone.0012191","article-title":"High-Fat Diet: Bacteria Interactions Promote Intestinal Inflammation Which Precedes and Correlates With Obesity and Insulin Resistance in Mouse","volume":"5","author":"Ding","year":"2010","journal-title":"PloS One"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.2337\/db18-283-OR","article-title":"Targeting Intestinal Macrophages as a Potential Therapeutic Option in Obesity","volume":"67","author":"Rohm","year":"2018","journal-title":"Diabetes"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-02-258558","article-title":"Nomenclature of Monocytes and Dendritic Cells in Blood","volume":"116","author":"Ziegler-Heitbrock","year":"2010","journal-title":"Blood"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/medsci6040116","article-title":"Microbiota in the Gastrointestinal Tract","volume":"6","author":"Dieterich","year":"2018","journal-title":"Med Sci (Basel)"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jand.2012.12.016","article-title":"Update of the Healthy Eating Index: Hei-2010","volume":"113","author":"Guenther","year":"2013","journal-title":"J Acad Nutr Diet"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1001\/jama.282.22.2131","article-title":"Elevated C-reactive Protein Levels in Overweight and Obese Adults","volume":"282","author":"Visser","year":"1999","journal-title":"JAMA"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.03.001","article-title":"Regulation of Obesity-Related Insulin Resistance With Gut Anti-Inflammatory Agents","volume":"21","author":"Luck","year":"2015","journal-title":"Cell Metab"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.05.020","article-title":"Jejunal T Cell Inflammation in Human Obesity Correlates With Decreased Enterocyte Insulin Signaling","volume":"22","author":"Monteiro-Sepulveda","year":"2015","journal-title":"Cell Metab"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1177\/44.7.8675993","article-title":"Lamina Propria Macrophages in the Human Gastrointestinal Mucosa: Their Distribution, Immunohistological Phenotype, and Function","volume":"44","author":"Nagashima","year":"1996","journal-title":"J Histochem Cytochem"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-018-0030-7","article-title":"Human Intestinal Pro-Inflammatory CD11c(high)CCR2(+)CX3CR1(+) Macrophages, But Not Their Tolerogenic CD11c(-)CCR2(-)CX3CR1(-) Counterparts, are Expanded in Inflammatory Bowel Disease","volume":"11","author":"Bernardo","year":"2018","journal-title":"Mucosal Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0113021","article-title":"CD14(Hi)HLA-DR(dim) Macrophages, With a Resemblance to Classical Blood Monocytes, Dominate Inflamed Mucosa in Crohn\u2019s Disease","volume":"95","author":"Thiesen","year":"2014","journal-title":"J Leukoc Biol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1152\/physrev.00045.2009","article-title":"Gut Microbiota in Health and Disease","volume":"90","author":"Sekirov","year":"2010","journal-title":"Physiol Rev"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1172\/JCI34610","article-title":"Unique CD14 Intestinal Macrophages Contribute to the Pathogenesis of Crohn Disease Via IL-23\/IFN-gamma Axis","volume":"118","author":"Kamada","year":"2008","journal-title":"J Clin Invest"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2017.104","article-title":"IFN-Gamma-Dependent Epigenetic Regulation Instructs Colitogenic Monocyte\/Macrophage Lineage Differentiation In Vivo","volume":"11","author":"Nakanishi","year":"2018","journal-title":"Mucosal Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.05.011","article-title":"Bone-Marrow-Resident NK Cells Prime Monocytes for Regulatory Function During Infection","volume":"42","author":"Askenase","year":"2015","journal-title":"Immunity"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.08.025","article-title":"Dysregulated Hematopoietic Stem and Progenitor Cell Activity Promotes interleukin-23-driven Chronic Intestinal Inflammation","volume":"37","author":"Griseri","year":"2012","journal-title":"Immunity"},{"key":"B35","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.cell.2017.12.013","article-title":"Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming","volume":"172","author":"Christ","year":"2018","journal-title":"Cell"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehp308","article-title":"Monocyte Heterogeneity in Obesity and Subclinical Atherosclerosis","volume":"31","author":"Rogacev","year":"2010","journal-title":"Eur Heart J"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.111.230979","article-title":"Cd14dimCD16+ and CD14+CD16+ Monocytes in Obesity and During Weight Loss: Relationships With Fat Mass and Subclinical Atherosclerosis","volume":"31","author":"Poitou","year":"2011","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.7.3536","article-title":"The Proinflammatory CD14+CD16+DR++ Monocytes are a Major Source of TNF","volume":"168","author":"Belge","year":"2002","journal-title":"J Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402655","article-title":"Profiling of the Three Circulating Monocyte Subpopulations in Human Obesity","volume":"194","author":"Devevre","year":"2015","journal-title":"J Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"27634","DOI":"10.1038\/srep27634","article-title":"Diet-Dependent, Microbiota-Independent Regulation of IL-10-producing Lamina Propria Macrophages in the Small Intestine","volume":"6","author":"Ochi","year":"2016","journal-title":"Sci Rep"},{"key":"B41","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1053\/j.gastro.2008.09.062","article-title":"Dietary Histidine Ameliorates Murine Colitis by Inhibition of Proinflammatory Cytokine Production From Macrophages","volume":"136","author":"Andou","year":"2009","journal-title":"Gastroenterology"},{"key":"B42","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1038\/s42003-020-0842-3","article-title":"Loss of the Branched-Chain Amino Acid Transporter CD98hc Alters the Development of Colonic Macrophages in Mice","volume":"3","author":"Wuggenig","year":"2020","journal-title":"Commun Biol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/nature05414","article-title":"An Obesity-Associated Gut Microbiome With Increased Capacity for Energy Harvest","volume":"444","author":"Turnbaugh","year":"2006","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1093\/nutrit\/nuw067","article-title":"Role of Short-Chain Fatty Acids in Colonic Inflammation, Carcinogenesis, and Mucosal Protection and Healing","volume":"75","author":"van der Beek","year":"2017","journal-title":"Nutr Rev"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3109\/00365521.2015.1134649","article-title":"Reduced Numbers of Mucosal DR(int) Macrophages and Increased Numbers of CD103(+) Dendritic Cells During anti-TNF-alpha Treatment in Patients With Crohn\u2019s Disease","volume":"51","author":"Dige","year":"2016","journal-title":"Scand J Gastroenterol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1002\/ibd.21818","article-title":"Regulatory Macrophages Induced by Infliximab are Involved in Healing In Vivo and In Vitro","volume":"18","author":"Vos","year":"2012","journal-title":"Inflammation Bowel Dis"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.10.008","article-title":"Anti-Tumor Necrosis Factor-Alpha Antibodies Induce Regulatory Macrophages in an Fc Region-Dependent Manner","volume":"140","author":"Vos","year":"2011","journal-title":"Gastroenterology"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2000.03360.x","article-title":"Mesalazine Inhibits Activation of Transcription Factor NF-kappaB in Inflamed Mucosa of Patients With Ulcerative Colitis","volume":"95","author":"Bantel","year":"2000","journal-title":"Am J Gastroenterol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.110.002683","article-title":"Diet-Induced Weight Loss Reduces Colorectal Inflammation: Implications for Colorectal Carcinogenesis","volume":"93","author":"Pendyala","year":"2011","journal-title":"Am J Clin Nutr"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.668654\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T10:52:28Z","timestamp":1620903148000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.668654\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,12]]},"references-count":49,"alternative-id":["10.3389\/fimmu.2021.668654"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.668654","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,12]]},"article-number":"668654"}}