Abstract

Galanin, a neuropeptide, regulates immune and inflammatory responses via GALR1-3. GALRs have emerged as potential therapeutic targets for inflammatory bowel disease (IBD), yet their mechanistic roles remain unclear. Based on evolutionary analysis, we identified a long galanin isoform (GAL53), generated by alternative splicing in non-mammalian vertebrates. Here we show that the chicken ortholog cGAL53 is robustly expressed in colonic tissue but downregulated upon dextran sulfate sodium (DSS)-induced colitis. Administration of cGAL53 alleviates colitis-associated weight loss, colon shortening, bleeding, and inflammation in both chickens and mice. These effects are abolished in Galr2-deficient mice, highlighting receptor dependency. Moreover, epithelial cell-specific Arrb2 and Gnaq knockout models demonstrate that cGAL53 protects the gut barrier and reduces inflammation by activating β-arrestin2-biased GALR2 signaling. Our findings reveal a naturally occurring long galanin peptide with potent anti-inflammatory activity and propose evolutionary medicine-guided biased GALR2 agonism as a therapeutic strategy for IBD.

Data availability

Publicly available datasets and databases used were following: colon biopsies from IBD patients and healthy controls (GSE11223, GSE235236). The RNA-sequencing generated in this study have been deposited in the NCBI database under accession code ID [PRJNA1334145]. All other data are available within the paper and its supplementary information. This manuscript does not report original code. Source data are provided with this paper.

References

Karwowski, C. A., Keljo, D. & Szigethy, E. Strategies to improve quality of life in adolescents with inflammatory bowel disease. Inflamm. Bowel Dis. 15, 1755–1764 (2009).

Google Scholar 1.

Sands, B. E. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology 126, 1518–1532 (2004).

Google Scholar 1.

Guan, Q. A comprehensive review and update on the pathogenesis of inflammatory bowel disease. J. Immunol. Res. 2019, 7247238 (2019).

Google Scholar 1.

Monteleone, G., Fina, D., Caruso, R. & Pallone, F. New mediators of immunity and inflammation in inflammatory bowel disease. Curr. Opin. Gastroenterol. 22, 361–364 (2006).

Google Scholar 1.

Kaser, A., Zeissig, S. & Blumberg, R. S. Inflammatory bowel disease. Annu. Rev. Immunol. 28, 573–621 (2010).

Google Scholar 1.

Kaplan, G. G. The global burden of IBD: from 2015 to 2025. Nat. Rev. Gastroenterol. Hepatol. 12, 720–727 (2015).

Google Scholar 1.

Mitsukawa, K., Lu, X. & Bartfai, T. Galanin, galanin receptors, and drug targets. *Exp.*Suppl. 102, 7–23 (2010).

Google Scholar 1.

Kofler, B., Liu, M. L., Jacoby, A. S., Shine, J. & Iismaa, T. P. Molecular cloning and characterisation of the mouse preprogalanin gene. Gene 182, 71–75 (1996).

Google Scholar 1.

Vrontakis, M. E. Galanin: a biologically active peptide. Curr. Drug Targets CNS Neurol. Disord. 1, 531–541 (2002).

Google Scholar 1.

Parthiban, M. & Shanmughavel, P. Three dimensional modeling of N-terminal region of galanin and its interaction with the galanin receptor. Bioinformation 2, 119–125 (2007).

Google Scholar 1.

Webling, K. E., Runesson, J., Bartfai, T. & Langel, U. Galanin receptors and ligands. Front. Endocrinol. 3, 146 (2012).

Google Scholar 1.

Wang, B. et al. Differential activation of six galanin receptors by the spexin peptide in yellowtail kingfish (Seriola lalandi). Gen. Comp. Endocrinol. 359, 114629 (2024).

Google Scholar 1.

Wang, S., He, C., Hashemi, T. & Bayne, M. Cloning and expressional characterization of a novel galanin receptor. Identification of different pharmacophores within galanin for the three galanin receptor subtypes. J. Biol. Chem. 272, 31949–31952 (1997).

Google Scholar 1.

Kuteeva, E., Hokfelt, T., Wardi, T. & Ogren, S. O. Galanin, galanin receptor subtypes and depression-like behaviour. Cell Mol. Life Sci. 65, 1854–1863 (2008).

Google Scholar 1.

Depczynski, B. et al. Distribution and characterization of the cell types expressing GALR2 mRNA in brain and pituitary gland. Ann. N. Y. Acad. Sci. 863, 120–128 (1998).

Google Scholar 1.

Fathi, Z. et al. Cloning, pharmacological characterization and distribution of a novel galanin receptor. Brain Res. Mol. Brain Res. 51, 49–59 (1997).

Google Scholar 1.

Waters, S. M. & Krause, J. E. Distribution of galanin-1, −2 and −3 receptor messenger RNAs in central and peripheral rat tissues. Neuroscience 95, 265–271 (2000).

Google Scholar 1.

Smith, K. E. et al. Cloned human and rat galanin GALR3 receptors. Pharmacology and activation of G-protein inwardly rectifying K+ channels. J. Biol. Chem. 273, 23321–23326 (1998).

Google Scholar 1.

Lang, R. et al. Physiology, signaling, and pharmacology of galanin peptides and receptors: three decades of emerging diversity. Pharm. Rev. 67, 118–175 (2015).

Google Scholar 1.

Reyes-Alcaraz, A., Lee, Y. N., Yun, S., Hwang, J. I. & Seong, J. Y. Conformational signatures in beta-arrestin2 reveal natural biased agonism at a G-protein-coupled receptor. Commun. Biol. 1, 128 (2018).

Google Scholar 1.

Kim, D. K. et al. Coevolution of the spexin/galanin/kisspeptin family: spexin activates galanin receptor type II and III. Endocrinology 155, 1864–1873 (2014).

Google Scholar 1.

He, L. et al. Galanin ameliorates liver inflammation and fibrosis in mice by activating AMPK/ACC signaling and modifying macrophage inflammatory phenotype. Front. Immunol. 14, 1161676 (2023).

Google Scholar 1.

Gross, K. J. & Pothoulakis, C. Role of neuropeptides in inflammatory bowel disease. Inflamm. Bowel Dis. 13, 918–932 (2007).

Google Scholar 1.

El-Salhy, M. & Hausken, T. The role of the neuropeptide Y (NPY) family in the pathophysiology of inflammatory bowel disease (IBD). Neuropeptides 55, 137–144 (2016).

Google Scholar 1.

Tatemoto, K., Rokaeus, A., Jornvall, H., McDonald, T. J. & Mutt, V. Galanin-a novel biologically active peptide from porcine intestine. FEBS Lett. 164, 124–128 (1983).

Google Scholar 1.

Melander, T. et al. Distribution of galanin-like immunoreactivity in the gastro-intestinal tract of several mammalian species. Cell Tissue Res. 239, 253–270 (1985).

Google Scholar 1.

Ekblad, E., Rokaeus, A., Hakanson, R. & Sundler, F. Galanin nerve fibers in the rat gut: distribution, origin and projections. Neuroscience 16, 355–363 (1985).

Google Scholar 1.

Bauer, F. E. et al. Distribution and molecular heterogeneity of galanin in human, pig, guinea pig, and rat gastrointestinal tracts. Gastroenterology 91, 877–883 (1986).

Google Scholar 1.

Bauer, F. E. [Galanin: a new biologically active gastrointestinal neuropeptide]. Z. Gastroenterol. 28, 160–169 (1990).

Google Scholar 1.

Rychlik, et al. Galanin-immunoreactive nerve fibers in the mucosal layer of the canine gastrointestinal tract during inflammatory bowel disease. J. Vet. Res. 59, 143–148 (2015). 1.

Talero, E., Sanchez-Fidalgo, S., Ramon Calvo, J. & Motilva, V. Galanin in the trinitrobenzene sulfonic acid rat model of experimental colitis. Int. Immunopharmacol. 6, 1404–1412 (2006).

Google Scholar 1.

Talero, E., Sanchez-Fidalgo, S., Calvo, J. R. & Motilva, V. Chronic administration of galanin attenuates the TNBS-induced colitis in rats. Regul. Pept. 141, 96–104 (2007).

Google Scholar 1.

Marrero, J. A., Matkowskyj, K. A., Yung, K., Hecht, G. & Benya, R. V. Dextran sulfate sodium-induced murine colitis activates NF-kappaB and increases galanin-1 receptor expression. Am. J. Physiol. Gastrointest. Liver Physiol. 278, G797–G804 (2000).

Google Scholar 1.

Matkowskyj, K. A. et al. Galanin contributes to the excess colonic fluid secretion observed in dextran sulfate sodium murine colitis. Inflamm. Bowel Dis. 10, 408–416 (2004).

Google Scholar 1.

Brunner, S. M. et al. Galanin receptor 3 attenuates inflammation and influences the gut microbiota in an experimental murine colitis model. Sci. Rep. 11, 564 (2021).

Google Scholar 1.

Dal Pont, G. C. et al. Novel models for chronic intestinal inflammation in chickens: intestinal inflammation pattern and biomarkers. Front. Immunol. 12, 676628 (2021).

Google Scholar 1.

Chen, Y., Zha, P., Xu, H. & Zhou, Y. An evaluation of the protective effects of chlorogenic acid on broiler chickens in a dextran sodium sulfate model: a preliminary investigation. Poult. Sci. 102, 102257 (2023).

Google Scholar 1.

Liu, L. et al. Establishment of an enteric inflammation model in broiler chickens by oral administration with dextran sulfate sodium. Animals 12, 3552 (2022). 1.

Dogra, S., Sona, C., Kumar, A. & Yadav, P. N. Tango assay for ligand-induced GPCR-beta-arrestin2 interaction: application in drug discovery. Methods Cell Biol. 132, 233–254 (2016).

Google Scholar 1.

Kocan, M., Dalrymple, M. B., Seeber, R. M., Feldman, B. J. & Pfleger, K. D. Enhanced BRET technology for the monitoring of agonist-induced and agonist-independent interactions between GPCRs and beta-arrestins. Front. Endocrinol. 1, 12 (2010).

Google Scholar 1.

Barreto, S. G. et al. Galanin receptor 3-a potential target for acute pancreatitis therapy. Neurogastroenterol. Motil. 23, e141–e151 (2011).

Google Scholar 1.

Williams, G. C. & Nesse, R. M. The dawn of Darwinian medicine. Q. Rev. Biol. 66, 1–22 (1991).

Google Scholar 1.

Stearns, S. C. & Ebert, D. Evolution in health and disease: work in progress. Q. Rev. Biol. 76, 417–432 (2001).

Google Scholar 1.

Natterson-Horowitz, B. et al. The future of evolutionary medicine: sparking innovation in biomedicine and public health. Front. Sci. 1, 997136 (2023). 1.

Deane, A. M., Chapman, M. J. & Horowitz, M. The therapeutic potential of a venomous lizard: the use of glucagon-like peptide-1 analogues in the critically ill. Crit. Care 14, 1004 (2010).

Google Scholar 1.

Holst, J. J. GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management. Nat. Metab. 6, 1866–1885 (2024).

Google Scholar 1.

Le Berre, C., Roda, G., Nedeljkovic Protic, M., Danese, S. & Peyrin-Biroulet, L. Modern use of 5-aminosalicylic acid compounds for ulcerative colitis. Expert Opin. Biol. Ther. 20, 363–378 (2020).

Google Scholar 1.

Bruscoli, S., Febo, M., Riccardi, C. & Migliorati, G. Glucocorticoid therapy in inflammatory bowel disease: mechanisms and clinical practice. Front. Immunol. 12, 691480 (2021).

Google Scholar 1.

Pithadia, A. B. & Jain, S. Treatment of inflammatory bowel disease (IBD). Pharm. Rep. 63, 629–642 (2011).

Google Scholar 1.

Deepak, P. & Loftus Jr, E. V. Ustekinumab in treatment of Crohn’s disease: design, development, and potential place in therapy. Drug Des. Dev. Ther. 10, 3685–3698 (2016).

Google Scholar 1.

Salas, A. et al. JAK-STAT pathway targeting for the treatment of inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 17, 323–337 (2020).

Google Scholar 1.

Saban, M. R., Nguyen, N. B., Hammond, T. G. & Saban, R. Gene expression profiling of mouse bladder inflammatory responses to LPS, substance P, and antigen-stimulation. Am. J. Pathol. 160, 2095–2110 (2002).

Google Scholar 1.

Lang, R. & Kofler, B. The galanin peptide family in inflammation. Neuropeptides 45, 1–8 (2011).

Google Scholar 1.

Nowik, N., Przyborowska, A., Sienkiewicz, W. & Podlasz, P. Protective role of galanin during chemically induced inflammation in zebrafish larvae. Biology 10, 99 (2021). 1.

Zhang, M. L., Fu, F. H. & Yu, L. C. Antinociception induced by galanin in anterior cingulate cortex in rats with acute inflammation. Neurosci. Lett. 638, 156–161 (2017).

Google Scholar 1.

Lee, M. J. et al. Galanin contributes to ultraviolet irradiation-induced inflammation in human skin. Exp. Dermatol. 26, 744–747 (2017).

Google Scholar 1.

Kriz, J. Inflammation in ischemic brain injury: timing is important. Crit. Rev. Neurobiol. 18, 145–157 (2006).

Google Scholar 1.

Yang, Y. et al. Characterization of the rat GAL2R promoter: positive role of ETS-1 in regulation of the rat GAL2R gene in PC12 cells. Mol. Neurobiol. 54, 4421–4431 (2017).

Google Scholar 1.

Unniappan, S., Lin, X. & Peter, R. E. Characterization of complementary deoxyribonucleic acids encoding preprogalanin and its alternative splice variants in the goldfish. Mol. Cell Endocrinol. 200, 177–187 (2003).

Google Scholar 1.

Martins, R. S. T. et al. Galanin isoforms by alternative splicing: structure, expression, and immunohistochemical location in the gonads of European sea bass. Gen. Comp. Endocrinol. 305, 113730 (2021).

Google Scholar 1.

Kohchi, C. & Tsutsui, K. Avian galanin: cloning of complementary DNAs and characterization of transcripts in different tissues. J. Exp. Zool. 287, 183–190 (2000).

Google Scholar 1.

Wu, S. et al. beta-arrestin1 protects intestinal tight junction through promoting mitofusin 2 transcription to drive parkin-dependent mitophagy in colitis. *Gastroenterol. Rep.*12, goae084 (2024).

Google Scholar 1.

Gao, H. et al. Identification of beta-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-kappaB pathways. Mol. Cell 14, 303–317 (2004).

Google Scholar 1.

Zeng, L. X. et al. Beta-arrestin2 encourages inflammation-induced epithelial apoptosis through ER stress/PUMA in colitis. Mucosal Immunol. 8, 683–695 (2015).

Google Scholar 1.

Lee, T. et al. Beta-arrestin-1 deficiency protects mice from experimental colitis. Am. J. Pathol. 182, 1114–1123 (2013).

Google Scholar 1.

Lee, T., Lee, E., Arrollo, D., Lucas, P. C. & Parameswaran, N. Non-hematopoietic beta-arrestin1 confers protection against experimental colitis. J. Cell Physiol. 231, 992–1000 (2016).

Google Scholar 1.

Peng, X. et al. COX-1/PGE(2)/EP4 alleviates mucosal injury by upregulating beta-arr1-mediated Akt signaling in colitis. Sci. Rep. 7, 1055 (2017).

Google Scholar 1.

Ye, X. et al. CCR5 expression in inflammatory bowel disease and its correlation with inflammatory cells and beta-arrestin2 expression. Scand. J. Gastroenterol. 52, 551–557 (2017).

Google Scholar 1.

Zhou, W. et al. Disulfiram with Cu(2+) alleviates dextran sulfate sodium-induced ulcerative colitis in mice. Theranostics 13, 2879–2895 (2023).

Google Scholar

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China (32170498 to S.S.L, 32270438 to C.D); National Science and Technology Major Project for Prevention and Treatment of Cancers, Cardio-cerebrovascular Diseases, Respiratory Diseases, and Metabolic Diseases (2025ZD0551800 to C.D); National Science and Technology Major Project (2023ZD0506800 to C.D); National Key R&D Program of China (2021YFF0702000 to C.D); 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYYC21011 to C.D); 1.3.5 Project of Center for High Altitude Medicine, West China Hospital, Sichuan University (GYYX24018 to C.D); National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z2023JC003 to C.D); Science and Technology Department of Sichuan Province (2022YFH0116 and TJZ2025EM08 to C.D); the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD to C.D); the “Kun lun Talents” of Qinghai-Top-Notch and Pioneering talent of Innovation and Entrepreneurship to C.D.

Author information

Author notes

These authors contributed equally: Shanshan Lai, Xianglin Kong, Jingwen Xue, Kaili Ma, Amanullah Amanullah.

Authors and Affiliations

Jiangsu Key Laboratory for Biodiversity and Biotechnology, State Key Laboratory of Microbial Technology, College of Life Sciences, Nanjing Normal University, Nanjing, PR China

Shanshan Lai, Xianglin Kong, Kaili Ma, Amanullah Amanullah, Yuwei Chen, Na Yang, Ting Zhang, Xiaofei Yan, Shah Kamal & Najeeb Ullah 1.

Department of High Altitude Medicine, Center for High Altitude Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China

Jingwen Xue, Kun Zheng, Tao Zeng, Chang Zhang, Juergen Brosius & Cheng Deng 1.

Institute of High Altitude Medicine, High Altitude Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China

Jingwen Xue, Kun Zheng, Tao Zeng, Chang Zhang & Cheng Deng 1.

Department of Life Sciences, Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan

Chingwei Luo 1.

Center for High Altitude Medicine, Xining, Qinghai, P. R. China

Cheng Deng

Authors

1. Shanshan Lai
2. Xianglin Kong
3. Jingwen Xue
4. Kaili Ma
5. Amanullah Amanullah
6. Yuwei Chen
7. Na Yang
8. Ting Zhang
9. Kun Zheng
10. Tao Zeng
11. Xiaofei Yan
12. Chang Zhang
13. Shah Kamal
14. Najeeb Ullah
15. Chingwei Luo
16. Juergen Brosius
17. Cheng Deng

Contributions

C.D. and S.L. conceived and supervised the whole project; X.K., J.X., K.M., Y.C., X.Y., S.L., S.K., N.Y., T.Z., N.J., A.A., C.Z., N.U., and T.Z. conducted experiments; J.X., X.Y., and K.Z. performed the GEO data and RNA sequencing analysis; X.K., J.X., S.L., C.L., A.A., K.M., and C.D. performed data analysis and interpretation; S.L. and X.K. wrote the paper; J.B., S.L., and C.D. revised the paper.

Corresponding author

Correspondence to Cheng Deng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Additional information

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

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Cite this article

Lai, S., Kong, X., Xue, J. et al. A novel long-galanin peptide from non-mammalian vertebrates mitigates the inflammatory response in IBD models via the biased GALR2/β-arrestin2 pathway. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66335-1

Download citation

Received: 01 January 2025

Accepted: 03 November 2025

Published: 13 December 2025

DOI: https://doi.org/10.1038/s41467-025-66335-1