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References

  1. Gupta K, Walton R, Kataria SP. 2021. Chemotherapy-induced nausea and vomiting: pathogenesis, recommendations, and new trends. Cancer Treat Res. Commun. 26: 100278.
  2. Zhang J, Ye ZW, Tew KD, Townsend DM. 2021. Cisplatin chemotherapy and renal function. Adv. Cancer Res. 152: 305-327.
  3. Lugones Y, Loren P, Salazar LA. 2022. Cisplatin resistance: genetic and epigenetic factors involved. Biomolecules 24: 12.
  4. Hata A, Okamoto I, Inui N, Okada M, Morise M, Akiyoshi K, et al. 2022. Randomized, double-blind, phase III study of fosnetupitant versus fosaprepitant for prevention of highly emetogenic chemotherapy-induced nausea and vomiting: CONSOLE. J. Clin. Oncol. 40: 180-188.
  5. Heckroth M, Luckett RT, Moser C, Parajuli D, Abell TL. 2021. Nausea and vomiting in 2021: a comprehensive update. J. Clin. Gastroenterol. 55: 279-299.
  6. Zhong W, Shahbaz O, Teskey G, Beever A, Kachour N, Venketaraman V, et al. 2021. Mechanisms of nausea and vomiting: current knowledge and recent advances in intracellular emetic signaling systems. Int. J. Mol. Sci. 28: 22.
  7. Zhao X, Wu H, Zhu R, Shang G, Wei J, Shang H, et al. 2023. Combination of thalidomide and Clostridium butyricum relieves chemotherapy-induced nausea and vomiting via gut microbiota and vagus nerve activity modulation. Front. Immunol. 14:1220165.
  8. Tsuge K, Inazumi T, Shimamoto A, Sugimoto Y. 2019. Molecular mechanisms underlying prostaglandin E2-exacerbated inflammation and immune diseases. Int. Immunol. 31: 597-606.
  9. Darmani NA. 2010. Mechanisms of broad-spectrum antiemetic efficacy of cannabinoids against chemotherapy-induced acute and delayed vomiting. Pharmaceuticals (Basel) 3: 2930-2955.
  10. Xu C, Gu L, Hu L, Jiang C, Li Q, Sun L, et al. 2023. FADS1-arachidonic acid axis enhances arachidonic acid metabolism by altering intestinal microecology in colorectal cancer. Nat. Commun. 14: 2042.
  11. Hennebelle M, Otoki Y, Yang J, Hammock BD, Levitt AJ, Taha AY, et al. 2017. Altered soluble epoxide hydrolase-derived oxylipins in patients with seasonal major depression: an exploratory study. Psychiatry Res. 2252: 94-101.
  12. Wang C, Liu W, Yao L, Zhang X, Zhang X, Ye C, et al. 2017. Hydroxyeicosapentaenoic acids and epoxyeicosatetraenoic acids attenuate early occurrence of nonalcoholic fatty liver disease. Br. J. Pharmacol. 174: 2358-2372.
  13. Propper DJ, Saunders MP, Salisbury AJ, Long L, O'Byrne KJ, Braybrooke JP, et al. 1999. Phase I study of the novel cyclic AMP (cAMP) analogue 8-chloro-cAMP in patients with cancer: toxicity, hormonal, and immunological effects. Clin. Cancer Res. 5: 1682-1689.
  14. Wu H, Guan C, Qin X, Xiang Y, Qi M, Luo Z, et al. 2007. Upregulation of substance P receptor expression by calcitonin gene-related peptide, a possible cooperative action of two neuropeptides involved in airway inflammation. Pulm. Pharmacol. Ther. 20: 513-524.
  15. Chen W, McRoberts JA, Ennes HS, Marvizon JC. 2021. cAMP signaling through protein kinase A and Epac2 induces substance P release in the rat spinal cord. Neuropharmacology 189: 108533.
  16. Cai T, Zheng SP, Shi X, Yuan LZ, Hu H, Zhou B, et al. 2022. Therapeutic effect of fecal microbiota transplantation on chronic unpredictable mild stress-induced depression. Front. Cell. Infect. Microbiol. 12: 900652.
  17. Chen D, Guo Y, Yang Y. 2022. Liujunanwei decoction attenuates cisplatin-induced nausea and vomiting in a rat-pica model partially mediated by modulating the gut micsrobiome. Front. Cell. Infect. Microbiol. 12: 876781.
  18. Huang N, Liu X, Pei X, Peng J, Wei H. 2022. The quantitative profiling of oxylipins from arachidonic acid by LC-MS/MS in feces at birth 3 days and 21 days of piglets. Metabolites 28: 12.
  19. Blackwood BP, Wood DR, Yuan C, Nicolas J, De Plaen IG, Farrow KN, et al. 2017. A role for cAMP and protein kinase A in experimental necrotizing enterocolitis. Am. J. Pathol. 187: 401-417.
  20. Horn CC, De Jonghe BC, Matyas K, Norgren R. 2009. Chemotherapy-induced kaolin intake is increased by lesion of the lateral parabrachial nucleus of the rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297: R1375-1382.
  21. Schoeler M, Caesar R. 2019. Dietary lipids, gut microbiota and lipid metabolism. Rev. Endocr. Metab. Disord. 20: 461-472.
  22. He Y, Zheng J, Ye B, Dai Y, Nie K. 2023. Chemotherapy-induced gastrointestinal toxicity: pathogenesis and current management. Biochem. Pharmacol. 216: 115787.
  23. Shojima Y, Ueno Y, Tanaka R, Yamashiro K, Miyamoto N, Hira K, et al. 2020. Eicosapentaenoic-to-arachidonic acid ratio predicts mortality and recurrent vascular events in ischemic stroke patients. J. Atheroscler. Thromb. 27: 969-977.
  24. Wu T, Wang G, Xiong Z, Xia Y, Song X, Zhang H, et al. 2022. Probiotics interact with lipids metabolism and affect gut health. Front. Nutr. 9: 917043.
  25. Wang T, Fu X, Chen Q, Patra JK, Wang D, Wang Z, et al. 2019. Arachidonic acid metabolism and kidney inflammation. Int. J. Mol. Sci. 27: 20.
  26. Calder PC. 2010. Omega-3 fatty acids and inflammatory processes. Nutrients 2: 355-374.
  27. Zeigerer A, Sekar R, Kleinert M, Nason S, Habegger KM, Müller TD. 2021. Glucagon's metabolic action in health and disease. Compr. Physiol. 11: 1759-1783.
  28. Ramakrishnan SK, Zhang H, Takahashi S, Centofanti B, Periyasamy S, Weisz K, et al. 2016. HIF2α is an essential molecular brake for postprandial hepatic glucagon response independent of insulin signaling. Cell Metab. 23: 505-516.
  29. Carpenter DO, Briggs DB, Knox AP, Strominger N. 1998. Excitation of area postrema neurons by transmitters, peptides, and cyclic nucleotides. J. Neurophysiol. 59: 358-369.
  30. Mori F, Pérez-Torres S, De Caro R, Porzionato A, Macchi V, Beleta J, et al. 2010. The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D. J. Chem. Neuroanat. 40: 36-42.
  31. Singh K, Cao H, Miaskowski C, Conley YP, Hammer M, Wright F, et al. 2021. Perturbations in endocytotic and apoptotic pathways are associated with chemotherapy-induced nausea. Biol. Res. Nurs. 223: 238-247.
  32. Fu Y, Wang Y, Gao H, Li D, Jiang R, Ge L, et al. 2021. Associations among dietary omega-3 polyunsaturated fatty acids, the gut microbiota, and intestinal immunity. Mediators Inflamm. 2021: 8879227.

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Article

Research article

J. Microbiol. Biotechnol. 2024; 34(9): 1769-1777

Published online September 28, 2024 https://doi.org/10.4014/jmb.2403.03044

Copyright © The Korean Society for Microbiology and Biotechnology.

The Gut Microbial Lipid Metabolite 14(15)-EpETE Inhibits Substance P Release by Targeting GCG/PKA Signaling to Relieve Cisplatin-Induced Nausea and Vomiting in Rats

Man Lu1, Liwei Xie2, Sijie Yin1, Jing Zhou1, Lingmei Yi1, and Ling Ye1*

1Department of Anesthesiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), No. 54 Youdian Rd., Shangcheng District, Hangzhou, Zhejiang 310006, P.R. China
2Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Rd., Hangzhou, Zhejiang 310006, P.R. China

Correspondence to:Ling Ye,      jiena2024@163.com

Received: March 24, 2024; Revised: June 12, 2024; Accepted: June 25, 2024

Abstract

Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect related to activation of substance P (SP). SP activation can result from dysregulation of the gut-brain axis, and also from activation of protein kinase A signaling (PKA) signaling. In this study, we connected these factors in an attempt to unveil the mechanisms underlying CINV and develop new therapeutic strategies. Female rats were injected with cisplatin (Cis) to induce pica. Fecal samples were collected before/after injection, and subjected to lipid metabolomics analysis. In another portion of pica rats, the PKA inhibitor KT5720 was applied to investigate the involvement of PKA signaling in CINV, while fecal microbiota transplantation (FMT) was implemented to verify the therapeutic effect of the lipid metabolite 14(15)-EpETE. Pica symptoms were recorded, followed by ileal histological examination. The targeting relationship between 14(15)-EpETE and glucagon was determined by bioinformatics. SP and glucagon/PKA signaling in rat ileum, serum, and/or brain substantia nigra were detected by immunohistochemistry, enzyme-linked immunosorbent assay, and/or western blot. The results showed a significantly lower level of 14(15)-EpETE in rat feces after Cis injection. KT5720 treatment alleviated Cis-induced pica symptoms, ileal injury, SP content increase in the ileum, serum, and brain substantia nigra, and ileal PKA activation in rats. The ileal level of glucagon was elevated by Cis in rats. FMT exerted an effect similar to that of KT5720 treatment, relieving the Cis-induced changes, including ileal glucagon/PKA activation in rats. Our findings demonstrate that FMT restores 14(15)-EpETE production, which inhibits SP release by targeting GCG/PKA signaling, ultimately mitigating CINV.

Keywords: Chemotherapy-induced nausea and vomiting, gut microbial lipid metabolites, 14(15)-epoxyeicosatetraenoic acids, substance P, glucagon/protein kinase A signaling

References

  1. Gupta K, Walton R, Kataria SP. 2021. Chemotherapy-induced nausea and vomiting: pathogenesis, recommendations, and new trends. Cancer Treat Res. Commun. 26: 100278.
  2. Zhang J, Ye ZW, Tew KD, Townsend DM. 2021. Cisplatin chemotherapy and renal function. Adv. Cancer Res. 152: 305-327.
  3. Lugones Y, Loren P, Salazar LA. 2022. Cisplatin resistance: genetic and epigenetic factors involved. Biomolecules 24: 12.
  4. Hata A, Okamoto I, Inui N, Okada M, Morise M, Akiyoshi K, et al. 2022. Randomized, double-blind, phase III study of fosnetupitant versus fosaprepitant for prevention of highly emetogenic chemotherapy-induced nausea and vomiting: CONSOLE. J. Clin. Oncol. 40: 180-188.
  5. Heckroth M, Luckett RT, Moser C, Parajuli D, Abell TL. 2021. Nausea and vomiting in 2021: a comprehensive update. J. Clin. Gastroenterol. 55: 279-299.
  6. Zhong W, Shahbaz O, Teskey G, Beever A, Kachour N, Venketaraman V, et al. 2021. Mechanisms of nausea and vomiting: current knowledge and recent advances in intracellular emetic signaling systems. Int. J. Mol. Sci. 28: 22.
  7. Zhao X, Wu H, Zhu R, Shang G, Wei J, Shang H, et al. 2023. Combination of thalidomide and Clostridium butyricum relieves chemotherapy-induced nausea and vomiting via gut microbiota and vagus nerve activity modulation. Front. Immunol. 14:1220165.
  8. Tsuge K, Inazumi T, Shimamoto A, Sugimoto Y. 2019. Molecular mechanisms underlying prostaglandin E2-exacerbated inflammation and immune diseases. Int. Immunol. 31: 597-606.
  9. Darmani NA. 2010. Mechanisms of broad-spectrum antiemetic efficacy of cannabinoids against chemotherapy-induced acute and delayed vomiting. Pharmaceuticals (Basel) 3: 2930-2955.
  10. Xu C, Gu L, Hu L, Jiang C, Li Q, Sun L, et al. 2023. FADS1-arachidonic acid axis enhances arachidonic acid metabolism by altering intestinal microecology in colorectal cancer. Nat. Commun. 14: 2042.
  11. Hennebelle M, Otoki Y, Yang J, Hammock BD, Levitt AJ, Taha AY, et al. 2017. Altered soluble epoxide hydrolase-derived oxylipins in patients with seasonal major depression: an exploratory study. Psychiatry Res. 2252: 94-101.
  12. Wang C, Liu W, Yao L, Zhang X, Zhang X, Ye C, et al. 2017. Hydroxyeicosapentaenoic acids and epoxyeicosatetraenoic acids attenuate early occurrence of nonalcoholic fatty liver disease. Br. J. Pharmacol. 174: 2358-2372.
  13. Propper DJ, Saunders MP, Salisbury AJ, Long L, O'Byrne KJ, Braybrooke JP, et al. 1999. Phase I study of the novel cyclic AMP (cAMP) analogue 8-chloro-cAMP in patients with cancer: toxicity, hormonal, and immunological effects. Clin. Cancer Res. 5: 1682-1689.
  14. Wu H, Guan C, Qin X, Xiang Y, Qi M, Luo Z, et al. 2007. Upregulation of substance P receptor expression by calcitonin gene-related peptide, a possible cooperative action of two neuropeptides involved in airway inflammation. Pulm. Pharmacol. Ther. 20: 513-524.
  15. Chen W, McRoberts JA, Ennes HS, Marvizon JC. 2021. cAMP signaling through protein kinase A and Epac2 induces substance P release in the rat spinal cord. Neuropharmacology 189: 108533.
  16. Cai T, Zheng SP, Shi X, Yuan LZ, Hu H, Zhou B, et al. 2022. Therapeutic effect of fecal microbiota transplantation on chronic unpredictable mild stress-induced depression. Front. Cell. Infect. Microbiol. 12: 900652.
  17. Chen D, Guo Y, Yang Y. 2022. Liujunanwei decoction attenuates cisplatin-induced nausea and vomiting in a rat-pica model partially mediated by modulating the gut micsrobiome. Front. Cell. Infect. Microbiol. 12: 876781.
  18. Huang N, Liu X, Pei X, Peng J, Wei H. 2022. The quantitative profiling of oxylipins from arachidonic acid by LC-MS/MS in feces at birth 3 days and 21 days of piglets. Metabolites 28: 12.
  19. Blackwood BP, Wood DR, Yuan C, Nicolas J, De Plaen IG, Farrow KN, et al. 2017. A role for cAMP and protein kinase A in experimental necrotizing enterocolitis. Am. J. Pathol. 187: 401-417.
  20. Horn CC, De Jonghe BC, Matyas K, Norgren R. 2009. Chemotherapy-induced kaolin intake is increased by lesion of the lateral parabrachial nucleus of the rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297: R1375-1382.
  21. Schoeler M, Caesar R. 2019. Dietary lipids, gut microbiota and lipid metabolism. Rev. Endocr. Metab. Disord. 20: 461-472.
  22. He Y, Zheng J, Ye B, Dai Y, Nie K. 2023. Chemotherapy-induced gastrointestinal toxicity: pathogenesis and current management. Biochem. Pharmacol. 216: 115787.
  23. Shojima Y, Ueno Y, Tanaka R, Yamashiro K, Miyamoto N, Hira K, et al. 2020. Eicosapentaenoic-to-arachidonic acid ratio predicts mortality and recurrent vascular events in ischemic stroke patients. J. Atheroscler. Thromb. 27: 969-977.
  24. Wu T, Wang G, Xiong Z, Xia Y, Song X, Zhang H, et al. 2022. Probiotics interact with lipids metabolism and affect gut health. Front. Nutr. 9: 917043.
  25. Wang T, Fu X, Chen Q, Patra JK, Wang D, Wang Z, et al. 2019. Arachidonic acid metabolism and kidney inflammation. Int. J. Mol. Sci. 27: 20.
  26. Calder PC. 2010. Omega-3 fatty acids and inflammatory processes. Nutrients 2: 355-374.
  27. Zeigerer A, Sekar R, Kleinert M, Nason S, Habegger KM, Müller TD. 2021. Glucagon's metabolic action in health and disease. Compr. Physiol. 11: 1759-1783.
  28. Ramakrishnan SK, Zhang H, Takahashi S, Centofanti B, Periyasamy S, Weisz K, et al. 2016. HIF2α is an essential molecular brake for postprandial hepatic glucagon response independent of insulin signaling. Cell Metab. 23: 505-516.
  29. Carpenter DO, Briggs DB, Knox AP, Strominger N. 1998. Excitation of area postrema neurons by transmitters, peptides, and cyclic nucleotides. J. Neurophysiol. 59: 358-369.
  30. Mori F, Pérez-Torres S, De Caro R, Porzionato A, Macchi V, Beleta J, et al. 2010. The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D. J. Chem. Neuroanat. 40: 36-42.
  31. Singh K, Cao H, Miaskowski C, Conley YP, Hammer M, Wright F, et al. 2021. Perturbations in endocytotic and apoptotic pathways are associated with chemotherapy-induced nausea. Biol. Res. Nurs. 223: 238-247.
  32. Fu Y, Wang Y, Gao H, Li D, Jiang R, Ge L, et al. 2021. Associations among dietary omega-3 polyunsaturated fatty acids, the gut microbiota, and intestinal immunity. Mediators Inflamm. 2021: 8879227.