A lower duodenal immune response is associated with an increase of insulin resistance in patients with morbid obesity

ABSTRACT OBJECTIVE The intestinal immune response could play an important role in obesity-related comorbidities. We aim to study the profile of duodenal cytokines and chemokines in patients

with morbid obesity (MO), its relation with insulin resistance (IR) and the intake of metformin, and with the evolution of MO after sleeve gastrectomy (SG). RESEARCH DESIGN AND METHODS

Duodenal levels of 24 cytokines and 9 chemokines were analyzed in 14 nonobese and in 54 MO who underwent SG: with lower IR (MO-lower-IR), with higher IR (MO-higher-IR), and with type 2

diabetes treated with metformin (MO-metf-T2DM). RESULTS MO-lower-IR had higher levels of cytokines related to Th1, Th2, Th9, Th17, Th22, M1 macrophages, and chemokines involved in the

recruitment of macrophages and T-lymphocytes (_p_ < 0.05), and total (CD68 expression) and M1 macrophages (ITGAX expression) (_p_ < 0.05) when compared with nonobese patients, but with

a decrease in M2 macrophages (MRC1 expression) (_p_ < 0.05). In MO-higher-IR, these chemokines and cytokines decreased and were similar to those found in nonobese patients. In

MO-metf-T2DM, only IL-4 (Th2) and IL-22 (Th22) increased their levels with regard to MO-higher-IR (_p_ < 0.05). In MO-higher-IR and MO-metf-T2DM, there was a decrease of CD68 expression

(_p_ < 0.05) while ITGAX and MRC1 were similar with regard to MO-lower-IR. We found an association between CXCL8, TNFβ and IL-2 with the evolution of body mass index (BMI) after SG (_p_ 

< 0.05). CONCLUSIONS There is an association between a higher IR and a lower duodenal immune response in MO, with a slight increase in those patients with metformin treatment. Intestinal

immune response could be involved in the evolution of BMI after SG. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution

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DISEASES Article Open access 09 June 2020 IN SEVERE OBESITY, SUBCUTANEOUS ADIPOSE TISSUE CELL-DERIVED CYTOKINES ARE EARLY MARKERS OF IMPAIRED GLUCOSE TOLERANCE AND ARE MODULATED BY QUERCETIN

Article 15 May 2021 EMERGING CONCEPTS IN INTESTINAL IMMUNE CONTROL OF OBESITY-RELATED METABOLIC DISEASE Article Open access 10 May 2021 REFERENCES * Barbarroja N, López-Pedrera R, Mayas MD,

García-Fuentes E, Garrido-Sánchez L, Macías-González M, et al. The obese healthy paradox: is inflammation the answer? Biochem J. 2010;430:141–9. * Zeyda M, Stulnig TM. Obesity,

inflammation, and insulin resistance-a mini-review. Gerontology. 2009;55:379–86. Article  CAS  Google Scholar  * Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in

adipose tissue macrophage polarization. J Clin Investig. 2007;117:175–84. Article  CAS  Google Scholar  * Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, et al. B cells promote

insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med. 2011;17:610–7. * Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ, Cheng LE, Mohapatra

A, et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med. 2013;210:535–49. * Raphael I, Nalawade S, Eagar TN,

Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74:5–17. Article  CAS  Google Scholar  * Martinez FO, Sica A, Mantovani A,

Locati M. Macrophage activation and polarization. Front Biosci. 2008;13:453–61. Article  CAS  Google Scholar  * Crane MJ, Daley JM, van Houtte O, Brancato SK, Henry WL Jr, Albina JE. The

monocyte to macrophage transition in the murine sterile wound. PLoS ONE. 2014;9:e86660. * Monteiro-Sepulveda M, Touch S, Mendes-Sá C, André S, Poitou C, Allatif O, et al. Jejunal T cell

inflammation in human obesity correlates with decreased enterocyte insulin signaling. Cell Metab. 2015;22:113–24. * Ding S, Lund PK. Role of intestinal inflammation as an early event in

obesity and insulin resistance. Curr Opin Clin Nutr Metab Care. 2011;14:328–33. Article  CAS  Google Scholar  * Winer DA, Luck H, Tsai S, Winer S. The intestinal immune system in obesity and

insulin resistance. Cell Metab. 2016;23:413–26. Article  CAS  Google Scholar  * Hard GC. Some biochemical aspects of the immune macrophage. Br J Exp Pathol. 1970;51:97–105. CAS  PubMed 

PubMed Central  Google Scholar  * Lopes EC, Heineck I, Athaydes G, Meinhardt NG, Souto KE, Stein AT. Is bariatric surgery effective in reducing comorbidities and drug costs? A systematic

review and meta-analysis. Obes Surg. 2015;25:1741–9. * Gutierrez-Repiso C, Garcia-Serrano S, Moreno-Ruiz FJ, Alcain-Martinez G, Rodriguez-Pacheco F, Garcia-Fuentes E. Jejunal gluconeogenesis

associated with insulin resistance level and its evolution after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2017;13:623–30. * García-Fuentes E, García-Almeida JM, García-Arnés J,

Rivas-Marín J, Gallego-Perales JL, González-Jiménez B, et al. Morbidly obese individuals with impaired fasting glucose have a specific pattern of insulin secretion and sensitivity: effect of

weight loss after bariatric surgery. Obes Surg. 2006;16:1179–88. * Rodriguez-Pacheco F, Garcia-Serrano S, Garcia-Escobar E, Gutierrez-Repiso C, Garcia-Arnes J, Valdes S, et al. Effects of

obesity/fatty acids on the expression of GPR120. Mol Nutr Food Res. 2014;58:1852–60. * Bisgaard LS, Mogensen CK, Rosendahl A, Cucak H, Nielsen LB, Rasmussen SE, et al. Bone marrow-derived

and peritoneal macrophages have different inflammatory response to oxLDL and M1/M2 marker expression - implications for atherosclerosis research. Sci Rep. 2016;6:35234. * Escamilla A,

Bautista MJ, Zafra R, Pacheco IL, Ruiz MT, Martínez-Cruz S, et al. Fasciola hepática induces eosinophil apoptosis in the migratory and biliary stages of infection in sheep. Vet Parasitol.

2016;216:84–88. * Wynn TA. Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol. 2015;15:271–82. Article  CAS  Google Scholar  * Mantovani A, Biswas SK, Galdiero MR, Sica

A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2013;229:176–85. Article  CAS  Google Scholar  * Hussaarts L, García-Tardón N, van Beek L,

Heemskerk MM, Haeberlein S, van der Zon GC, et al. Chronic helminth infection and helminth-derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese

mice. FASEB J. 2015;29:3027–39. * Ye J, McGuinness OP. Inflammation during obesity is not all bad: evidence from animal and human studies. Am J Physiol Endocrinol Metab. 2013;304:E466–E477.

Article  CAS  Google Scholar  * Kuhn KA, Manieri NA, Liu TC, Stappenbeck TS. IL-6 stimulates intestinal epithelial proliferation and repair after injury. PLoS ONE. 2014;9:e114195. Article 

Google Scholar  * Obermeier F, Hausmann M, Kellermeier S, Kiessling S, Strauch UG, Duitman E, et al. IL-15 protects intestinal epithelial cells. Eur J Immunol. 2006;36:2691–9. * Araújo JR,

Tomas J, Brenner C, Sansonetti PJ. Impact of high-fat diet on the intestinal microbiota and small intestinal physiology before and after the onset of obesity. Biochimie. 2017;141:97–106.

Article  Google Scholar  * Moreno-Navarrete JM, Sabater M, Ortega F, Ricart W, Fernández-Real JM. Circulating zonulin, a marker of intestinal permeability, is increased in association with

obesity-associated insulin resistance. PLoS ONE. 2012;7:e37160. Article  CAS  Google Scholar  * Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, et al. Changes in gut

microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008;57:1470–81. * Sallusto F, Lanzavecchia A, Mackay CR.

Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses. Immunol Today. 1998;19:568–74. Article  CAS  Google Scholar  * Dickensheets HL, Donnelly RP. IFN-gamma

and IL-10 inhibit induction of IL–1 receptor type I and type II gene expression by IL–4 and IL–13 in human monocytes. J Immunol. 1997;159:6226–33. CAS  PubMed  Google Scholar  * Licona-Limón

P, Henao-Mejia J, Temann AU, Gagliani N, Licona-Limón I, Ishigame H, et al. Th9 cells drive host immunity against gastrointestinal worm infection. Immunity. 2013;39:744–57. * Kaplan MH. Th9

cells: differentiation and disease. Immunol Rev. 2013;252:104–15. Article  Google Scholar  * Dalmas E, Venteclef N, Caer C, Poitou C, Cremer I, Aron-Wisnewsky J, et al. T cell-derived IL-22

amplifies IL-1β-driven inflammation in human adipose tissue: relevance to obesity and type 2 diabetes. Diabetes. 2014;63:1966–77. * Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, et

al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med. 2008;14:282–9. * Cani PD, Osto M, Geurts L, Everard A. Involvement of gut

microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes. 2012;3:279–88. Article  Google Scholar  * Wang LJ, Cao Y, Shi HN. Helminth

infections and intestinal inflammation. World J Gastroenterol. 2008;14:5125–32. Article  CAS  Google Scholar  * Smith JM, Johanesen PA, Wendt MK, Binion DG, Dwinell MB. CXCL12 activation of

CXCR4 regulates mucosal host defense through stimulation of epithelial cell migration and promotion of intestinal barrier integrity. Am J Physiol Gastrointest Liver Physiol.

2005;288:G316–G326. Article  CAS  Google Scholar  * Veilleux A, Mayeur S, Bérubé JC, Beaulieu JF, Tremblay E, Hould FS, et al. Altered intestinal functions and increased local inflammation

in insulin-resistant obese subjects: a gene-expression profile analysis. BMC Gastroenterol. 2015;15:119. * Richard C, Wadowski M, Goruk S, Cameron L, Sharma AM, Field CJ. Individuals with

obesity and type 2 diabetes have additional immune dysfunction compared with obese individuals who are metabolically healthy. BMJ Open Diabetes Res Care. 2017;5:e000379. * Cani PD, Amar J,

Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761–72. * Sieweke MH, Allen JE. Beyond stem cells:

self-renewal of differentiated macrophages. Science. 2013;342:1242974. Article  Google Scholar  * Bayer AL, Pugliese A, Malek TR. The IL–2/IL–2R system: from basic science to therapeutic

applications to enhance immune regulation. Immunol Res. 2013;57:197–209. Article  CAS  Google Scholar  * Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces insulin resistance in

3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem. 2003;278:45777–84. Article  CAS  Google

Scholar  * Lindegaard KK, Jorgensen NB, Just R, Heegaard PM, Madsbad S. Effects of Roux-en-Y gastric bypass on fasting and postprandial inflammation-related parameters in obese subjects with

normal glucose tolerance and in obese subjects with type 2 diabetes. Diabetol Metab Syndr. 2015;7:12. Article  Google Scholar  * Ruddle NH. Lymphotoxin and TNF: how it all began-a tribute

to the travelers. Cytokine Growth Factor Rev. 2014;25:83–89. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN) and

CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM) are initiatives of ISCIII (Spain). We gratefully acknowledge the Imaging platform of the Institute of Biomedical Research in Malaga

(IBIMA) (Spain). This work was supported in part by a grant from the Instituto de Salud Carlos III, Spain (PI12/00338) (“Una manera de hacer Europa”). This study has been co-funded by FEDER

funds. AHP is supported by a grant from the Ministerio de Educación y Formación Professional (Spain) (FPU14/01972). CSF is supported by a grant from the ISCIII (Spain) (FI16/00241). LGS is

supported by the Miguel Servet program from the ISCIII (Spain) (MS13/00188). CR is supported by a grant from BEIPD-COFUND-OPD, (Belgium) (R.EURO.0992-J-F-B-32). EGF is supported by the

Nicolas Monardes program from the Consejería de Salud de Andalucía (Spain) (C-0031-2016). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Instituto de Investigación Biomédica de Málaga-IBIMA,

Málaga, Spain Ailec Ho-Plagaro, Concepción Santiago-Fernandez, Sara García-Serrano, Cristina Rodriguez, Lourdes Garrido-Sanchez, Alejandro Escamilla, Guillermo Alcaín-Martínez & Eduardo

Garcia-Fuentes * Unidad de Gesti ón Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, Málaga, Spain Ailec Ho-Plagaro, Concepción Santiago-Fernandez, Cristina

Rodriguez, Guillermo Alcaín-Martínez, Beatriz Garcia-Muñoz, Natalia Ruiz-Santana & Eduardo Garcia-Fuentes * Universidad de Málaga, Málaga, Spain Ailec Ho-Plagaro * Unidad de Gestión

Clínica de Endocrinología y Nutrición, Hospital Regional Universitario de Málaga, Málaga, Spain Sara García-Serrano & Montserrat Gonzalo * CIBER de Diabetes y Enfermedades Metabólicas

Asociadas-CIBERDEM, Málaga, Spain Sara García-Serrano * Unidad de Gestión Clínica de Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Málaga, Spain Lourdes

Garrido-Sanchez * CIBER Fisiología de la Obesidad y Nutrición-CIBEROBN, Málaga, Spain Lourdes Garrido-Sanchez & Eduardo Garcia-Fuentes * Unidad de Gestión Clínica de Cirugía General,

Digestiva y Trasplantes, Hospital Regional Universitario de Málaga, Málaga, Spain Custodia Montiel-Casado * Unidad de Gestión Clínica de Aparato Digestivo, Hospital Regional Universitario de

Málaga, Málaga, Spain Luis Vázquez-Pedreño Authors * Ailec Ho-Plagaro View author publications You can also search for this author inPubMed Google Scholar * Concepción Santiago-Fernandez

View author publications You can also search for this author inPubMed Google Scholar * Sara García-Serrano View author publications You can also search for this author inPubMed Google

Scholar * Cristina Rodriguez View author publications You can also search for this author inPubMed Google Scholar * Lourdes Garrido-Sanchez View author publications You can also search for

this author inPubMed Google Scholar * Alejandro Escamilla View author publications You can also search for this author inPubMed Google Scholar * Montserrat Gonzalo View author publications

You can also search for this author inPubMed Google Scholar * Custodia Montiel-Casado View author publications You can also search for this author inPubMed Google Scholar * Guillermo

Alcaín-Martínez View author publications You can also search for this author inPubMed Google Scholar * Beatriz Garcia-Muñoz View author publications You can also search for this author

inPubMed Google Scholar * Natalia Ruiz-Santana View author publications You can also search for this author inPubMed Google Scholar * Luis Vázquez-Pedreño View author publications You can

also search for this author inPubMed Google Scholar * Eduardo Garcia-Fuentes View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS Conceived and

designed the study: EGF. Participated in the selection of patients and samples: EGF, AHP, SGS, MG , CMC, LGS, GAM, BGM, NRS, and LVP. Performed the experiments: AHP, SGS, CSF, AE, and CR.

Analyzed the data: AHP, CR, AE, and EGF. Wrote the paper: AHP and EGF. All authors helped to revise the paper and read and approved the final paper. EGF is the guarantor of this paper.

CORRESPONDING AUTHORS Correspondence to Lourdes Garrido-Sanchez or Eduardo Garcia-Fuentes. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no conflict of

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Ho-Plagaro, A., Santiago-Fernandez, C., García-Serrano, S. _et al._ A lower duodenal immune response is associated with an increase of insulin resistance in patients with morbid obesity.

_Int J Obes_ 44, 340–352 (2020). https://doi.org/10.1038/s41366-019-0458-1 Download citation * Received: 18 December 2018 * Revised: 19 July 2019 * Accepted: 28 July 2019 * Published: 25

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