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.

  • Article
  • Published:

Animal Models

Interplay between colonic inflammation and tachykininergic pathways in the onset of colonic dysmotility in a mouse model of diet-induced obesity

International Journal of Obesity volume 43, pages 331–343 (2019)Cite this article

Subjects

Abstract

Background

The murine model of high fat diet (HFD)-induced obesity is characterized by an increment of intestinal permeability, secondary to an impairment of mucosal epithelial barrier and enteric inflammation, followed by morphofunctional rearrangement of the enteric nervous system. The present study investigated the involvement of abdominal macrophages in the mechanisms underlying the development of enteric dysmotility associated with obesity.

Methods

Wild type C57BL/6J mice were fed with HFD (60% kcal from fat) or normocaloric diet (NCD, 18% kcal from fat) for 8 weeks. Groups of mice fed with NCD or HFD were treated with clodronate encapsulated into liposomes to deplete abdominal macrophages. Tachykininergic contractions, elicited by electrical stimulation or exogenous substance P (SP), were recorded in vitro from longitudinal muscle colonic preparations. Substance P distribution was examined by confocal immunohistochemistry. The density of macrophages in the colonic wall was examined by immunohistochemical analysis. Malondialdehyde (MDA, colorimetric assay) and IL-1β (ELISA assay) levels were also evaluated.

Results

MDA and IL-1β levels were increased in colonic tissues from HFD-treated animals. In colonic preparations, electrically evoked tachykininergic contractions were enhanced in HFD mice. Immunohistochemistry displayed an increase in substance P immunoreactivity in myenteric ganglia, as well as in the muscular layers of colonic cryosections from obese mice. Macrophage depletion in HFD mice was associated with a significant reduction of colonic inflammation. In addition, the decrease in macrophage density attenuated the morphofunctional alterations of tachykininergic pathways observed in obese mice.

Conclusion

Obesity elicited by HFD determines a condition of colonic inflammation, followed by a marked rearrangement of motor excitatory tachykininergic enteric nerves. Macrophage depletion counteracted the morphofunctional changes of colonic neuromuscular compartment, suggesting a critical role for these immune cells in the onset of enteric dysmotility associated with obesity.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest. 2011;121:2111–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Carolan E, Tobin LM, Mangan BA, Corrigan M, Gaoatswe G, Byrne G, et al. Altered distribution and increased IL-17 production by mucosal-associated invariant T cells in adult and childhood obesity. J Immunol. 2015;194:5775–80.

    Article  CAS  PubMed  Google Scholar 

  3. Sun S, Ji Y, Kersten S, Qi L. Mechanisms of inflammatory responses in obese adipose tissue. Annu Rev Nutr. 2012;32:261–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lam YY, Ha CW, Campbell CR, Mitchell AJ, Dinudom A, Oscarsson J, et al. Increased gut permeability and microbiota change associate with mesenteric fat inflammation and metabolic dysfunction in diet-induced obese mice. PLoS ONE. 2012;7:e34233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Raybould HE. Gut microbiota, epithelial function and derangements in obesity. J Physiol. 2012;590:441–6.

    Article  CAS  PubMed  Google Scholar 

  6. Stenman LK, Holma R, Korpela R. High-fat-induced intestinal permeability dysfunction associated with altered fecal bile acids. World J Gastroenterol. 2012;18:923–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bertrand RL, Senadheera S, Markus I, Liu L, Howitt L, Chen H, et al. A Western diet increases serotonin availability in rat small intestine. Endocrinology. 2011;152:36–47.

    Article  CAS  PubMed  Google Scholar 

  8. Nezami BG, Mwangi SM, Lee JE, Jeppsson S, Anitha M, Yarandi SS, et al. MicroRNA 375 mediates palmitate-induced enteric neuronal damage and high-fat diet-induced delayed intestinal transit in mice. Gastroenterology. 2014;146:473–83.

    Article  CAS  PubMed  Google Scholar 

  9. Fysekidis M, Bouchoucha M, Bihan H, Reach G, Benamouzig R, Catheline JM. Prevalence and co-occurrence of upper and lower functional gastrointestinal symptoms in patients eligible for bariatric surgery. Obes Surg. 2012;22:403–10.

    Article  PubMed  Google Scholar 

  10. Le Pluart D, Sabate JM, Bouchoucha M, Hercberg S, Benamouzig R, Julia C. Functional gastrointestinal disorders in 35,447 adults and their association with body mass index. Aliment Pharmacol Ther. 2015;41:758–67.

    Article  PubMed  Google Scholar 

  11. Ridha M, Nourse SE, Selamet Tierney ES. Pediatric interventions using noninvasive vascular health indices. Hypertension. 2015;65:949–55.

    Article  CAS  PubMed  Google Scholar 

  12. Di Giovangiulio M, Verheijden S, Bosmans G, Stakenborg N, Boeckxstaens GE, Matteoli G. The neuromodulation of the intestinal immune system and its relevance in inflammatory bowel disease. Front Immunol. 2015;6:590.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Muller PA, Koscso B, Rajani GM, Stevanovic K, Berres ML, Hashimoto D, et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell. 2014;158:300–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lomax AE, Fernandez E, Sharkey KA. Plasticity of the enteric nervous system during intestinal inflammation. Neurogastroenterol Motil. 2005;17:4–15.

    Article  CAS  PubMed  Google Scholar 

  15. Vasina V, Barbara G, Talamonti L, Stanghellini V, Corinaldesi R, Tonini M, et al. Enteric neuroplasticity evoked by inflammation. Auton Neurosci: Basic Clin. 2006;126-7:264–72.

    Article  Google Scholar 

  16. Neunlist M, Aubert P, Toquet C, Oreshkova T, Barouk J, Lehur PA, et al. Changes in chemical coding of myenteric neurones in ulcerative colitis. Gut. 2003;52:84–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. ter Beek WP, Biemond I, Muller ES, van den Berg M, Lamers CB. Substance P receptor expression in patients with inflammatory bowel disease. Determination by three different techniques, i.e., storage phosphor autoradiography, RT-PCR and immunohistochemistry. Neuropeptides. 2007;41:301–6.

    Article  PubMed  Google Scholar 

  18. Van Rooijen N, Sanders A. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods. 1994;174:83–93.

    Article  PubMed  Google Scholar 

  19. Siegmund B, Lehr HA, Fantuzzi G, Dinarello CA. IL-1 beta -converting enzyme (caspase-1) in intestinal inflammation. Proc Natl Acad Sci USA. 2001;98:13249–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Antonioli L, Fornai M, Colucci R, Awwad O, Ghisu N, Tuccori M, et al. The blockade of adenosine deaminase ameliorates chronic experimental colitis through the recruitment of adenosine A2A and A3 receptors. J Pharmacol Exp Ther. 2010;335:434–42.

    Article  CAS  PubMed  Google Scholar 

  21. Antonioli L, Pellegrini C, Fornai M, Tirotta E, Gentile D, Benvenuti L et al. Colonic motor dysfunctions in a mouse model of high-fat diet-induced obesity: an involvement of A2B adenosine receptors. Purinergic Signal. 2017;13:497–510.

  22. Mowat AM, Bain CC. Mucosal macrophages in intestinal homeostasis and inflammation. J Innate Immun. 2011;3:550–64.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Caputi V, Marsilio I, Filpa V, Cerantola S, Orso G, Bistoletti M, et al. Antibiotic-induced dysbiosis of the microbiota impairs gut neuromuscular function in juvenile mice. Br J Pharmacol. 2017;174:3623–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Orso G, Martinuzzi A, Rossetto MG, Sartori E, Feany M, Daga A. Disease-related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine. J Clin Invest. 2005;115:3026–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Engel MA, Leffler A, Niedermirtl F, Babes A, Zimmermann K, Filipovic MR, et al. TRPA1 and substance P mediate colitis in mice. Gastroenterology. 2011;141:1346–58.

    Article  CAS  PubMed  Google Scholar 

  26. Kim KA, Gu W, Lee IA, Joh EH, Kim DH. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS ONE. 2012;7:e47713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Laurila A, Cole SP, Merat S, Obonyo M, Palinski W, Fierer J, et al. High-fat, high-cholesterol diet increases the incidence of gastritis in LDL receptor-negative mice. Arterioscler Thromb Vasc Biol. 2001;21:991–6.

    Article  CAS  PubMed  Google Scholar 

  28. Kolbus D, Ramos OH, Berg KE, Persson J, Wigren M, Bjorkbacka H, et al. CD8+T cell activation predominate early immune responses to hypercholesterolemia in Apoe(-)(/)(-) mice. BMC Immunol. 2010;11:58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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  PubMed  PubMed Central  Google Scholar 

  30. Gulhane M, Murray L, Lourie R, Tong H, Sheng YH, Wang R, et al. High fat diets induce colonic epithelial cell stress and inflammation that is reversed by IL-22. Sci Rep. 2016;6:28990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lam YY, Ha CW, Hoffmann JM, Oscarsson J, Dinudom A, Mather TJ, et al. Effects of dietary fat profile on gut permeability and microbiota and their relationships with metabolic changes in mice. Obesity. 2015;23:1429–39.

    Article  CAS  PubMed  Google Scholar 

  32. Lim SM, Jeong JJ, Woo KH, Han MJ, Kim DH. Lactobacillus sakei OK67 ameliorates high-fat diet-induced blood glucose intolerance and obesity in mice by inhibiting gut microbiota lipopolysaccharide production and inducing colon tight junction protein expression. Nutr Res. 2016;36:337–48.

    Article  CAS  PubMed  Google Scholar 

  33. Anitha M, Reichardt F, Tabatabavakili S, Nezami BG, Chassaing B, Mwangi S, et al. Intestinal dysbiosis contributes to the delayed gastrointestinal transit in high-fat diet fed mice. Cell Mol Gastroenterol Hepatol. 2016;2:328–39.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Mushref MA, Srinivasan S. Effect of high fat-diet and obesity on gastrointestinal motility. Ann Transl Med. 2013;1:14.

    PubMed  PubMed Central  Google Scholar 

  35. Antonioli MF L, Pellegrini C, Tirotta E, Gentile D, Benvenuti L, Caputi V, et al. Colonic dysmotility associated with high fat diet-induced obesity: role of the enteric glia. Gastroenterology. 2017;152:S180

    Article  Google Scholar 

  36. Fu XY, Li Z, Zhang N, Yu HT, Wang SR, Liu JR. Effects of gastrointestinal motility on obesity. Nutr Metab. 2014;11:3.

    Article  Google Scholar 

  37. Johnson AR, Milner JJ, Makowski L. The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunol Rev. 2012;249:218–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ghigliotti G, Barisione C, Garibaldi S, Fabbi P, Brunelli C, Spallarossa P, et al. Adipose tissue immune response: novel triggers and consequences for chronic inflammatory conditions. Inflammation. 2014;37:1337–53.

    Article  CAS  PubMed  Google Scholar 

  39. Bing C. Is interleukin-1beta a culprit in macrophage-adipocyte crosstalk in obesity? Adipocyte. 2015;4:149–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Khan WI, Collins SM. Gut motor function: immunological control in enteric infection and inflammation. Clin Exp Immunol. 2006;143:389–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Margolis KG, Gershon MD. Neuropeptides and inflammatory bowel disease. Curr Opin Gastroenterol. 2009;25:503–11.

    Article  CAS  PubMed  Google Scholar 

  42. Mikkelsen HB. Interstitial cells of Cajal, macrophages and mast cells in the gut musculature: morphology, distribution, spatial and possible functional interactions. J Cell Mol Med. 2010;14:818–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Luck H, Tsai S, Chung J, Clemente-Casares X, Ghazarian M, Revelo XS, et al. Regulation of obesity-related insulin resistance with gut anti-inflammatory agents. Cell Metab. 2015;21:527–42.

    Article  CAS  PubMed  Google Scholar 

  44. Bu L, Gao M, Qu S, Liu D. Intraperitoneal injection of clodronate liposomes eliminates visceral adipose macrophages and blocks high-fat diet-induced weight gain and development of insulin resistance. AAPS J. 2013;15:1001–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Stienstra R, Saudale F, Duval C, Keshtkar S, Groener JE, van Rooijen N, et al. Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology. 2010;51:511–22.

    Article  CAS  PubMed  Google Scholar 

  46. Negrin KA, Roth Flach RJ, DiStefano MT, Matevossian A, Friedline RH, Jung D, et al. IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis. PLoS ONE. 2014;9:e107265.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author contributions

LA, RC, MF, CP, GH and CB designed the study, DG, MCG, VC, GO, NB, CSe, CI, BC, and ZHN collected and analyzed data, LA, RC, MF, CSc, CP, GH, and CB wrote the manuscript. All authors discussed the results and commented on the manuscript.

Funding

This work was supported by PRA_2016_20 granted by the University of Pisa and by the supported by U.S. National Institutes of Health (NIH) NIH 1R01DK113790 grant. The present work was funded by University of Padova (Italy) PRID 2016 to R.C, by University of Padova (Italy) Assegno di Ricerca 2016 and by San Camillo Hospital, Treviso (Italy) Grant 2015 to M.C.G.

Author information

Author notes

  1. These authors contributed equally: L. Antonioli, V. Caputi.

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Luca Antonioli, Matteo Fornai, Carolina Pellegrini, Daniela Gentile, Nunzia Bernardini, Cristina Segnani, Chiara Ippolito & Corrado Blandizzi

  2. Department of Anesthesiology, Columbia University, New York, NY, 10032, USA

    Luca Antonioli, Balázs Csóka, György Haskó & Zoltán H. Németh

  3. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy

    Valentina Caputi, Maria Cecilia Giron & Rocchina Colucci

  4. San Camillo Hospital, Treviso, Italy

    Valentina Caputi

  5. APC Microbiome Ireland, University College Cork, T12YT20 Cork, Ireland

    Valentina Caputi

  6. Scientific Institute IRCCS Eugenio Medea, Bosisio Parini-, Lecco, Italy

    Genny Orso

  7. Department of Surgery, Morristown Medical Center, Morristown, NJ, 07960, USA

    Zoltán H. Németh

  8. Laboratory of Clinical Pharmacology, University of Parma, Parma, Italy

    Carmelo Scarpignato

Authors
  1. Luca Antonioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valentina Caputi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matteo Fornai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carolina Pellegrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniela Gentile
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Cecilia Giron
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Genny Orso
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nunzia Bernardini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cristina Segnani
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chiara Ippolito
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Balázs Csóka
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. György Haskó
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Zoltán H. Németh
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Carmelo Scarpignato
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Corrado Blandizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Rocchina Colucci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matteo Fornai.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Antonioli, L., Caputi, V., Fornai, M. et al. Interplay between colonic inflammation and tachykininergic pathways in the onset of colonic dysmotility in a mouse model of diet-induced obesity. Int J Obes 43, 331–343 (2019). https://doi.org/10.1038/s41366-018-0166-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-018-0166-2

This article is cited by

Search

Advanced search

Quick links