Citrus aurantium L. extract alleviate depression by inhibiting gut microbiota-mediated inflammation in mice
Abstract
Gut microbiota plays a crucial role in the pathophysiology of depression. This study aimed to explore the antidepressant effect of mature whole Citrus aurantium fruit extract (FEMC) in the chronic unpredictable mild stress (CUMS) model. The behavioral tests were applied to assess antidepressant effect and 16S rRNA sequencing was used to analyze the changes of gut microbiota. The results showed that the major components of FEMC were naringin and neohesperidin and significantly increased the sucrose preference index of the mice. FEMC also could reduce the feeding latency in an open field test and the rest time in a novelty suppressed feeding test. In addition, FEMC could increase CUMS-induced reduction in the levels of BDNF, PSD95, and SYN in the hippocampus. Moreover, FEMC intervention slightly decreased the ratio of Firmicutes to Bacteroidota. Meanwhile, FEMC reduced the abundance of the Prevotellaceae_Ga6A1_group, [Ruminococcus]_torques_group, which have been reported to be closely related to inflammation. Bioinformatics analysis revealed that mitogen-activated protein kinase (MAPK) signaling pathway and lipopolysaccharide biosynthesis were involved in the anti-inflammatory effect of FEMC in the CUMS animal model. Finally, the ELISA results showed that FEMC could significantly reduce the expression of pro-inflammatory cytokines IL-6 and TNF-α in the serum of depressive mice. Our results suggest FEMC can ameliorate depressive behavior by inhibiting gut microbiota-mediated inflammation in mice.
References
I. Suntar, H. Khan, S. Patel, et al., An overview on Citrus aurantium L.: its functions as food ingredient and therapeutic agent, Oxid. Med. Cell Longev. 2018 (2018) 7864269. https://doi.org/10.1155/2018/7864269.
Y. Yi, H.X. Wang, J.R. He, Advances in bioactive components and functions of Citrus aurantium L., Hubei Agricultural Sciences 53 (2014) 3721-3725. https://doi.org/10.14088/j.cnki.issn0439-8114.2014.16.073.
S.Z. Yang, C.F. Zhou, B.Y. Gong, et al., Quality analysis and evaluation of Citrus aurantium L. wild strains from Hunan province, Sci. Technol. Food Industry 16 (2017) 43-49. https://doi.org/10.13386/j.issn1002-0306.2017.16.009.
D. Barreca, G. Gattuso, E. Bellocco, et al., Flavanones: citrus phytochemical with health-promoting properties, Biofactors. 43 (2017) 495-506. https://doi.org/10.1002/biof.1363.
S. Maksoud, R.M. Abdel-Massih, H.N. Rajha, et al., Citrus aurantium L. active constituents, biological effects and extraction methods. An updated review, Molecules 26 (2021) 5832. https://doi.org/10.3390/molecules26195832.
C.Y. Shen, J.J. Lin, J.G. Jiang, et al., Potential roles of dietary flavonoids from Citrus aurantium L. var. amara Engl. in atherosclerosis development, Food Funct. 11 (2020) 561-571. https://doi.org/10.1039/c9fo02336d.
C. Spagnuolo, S. Moccia, G.L. Russo, Anti-inflammatory effects of flavonoids in neurodegenerative disorders, Eur. J. Med. Chem. 153 (2018) 105-115. https://doi.org/10.1016/j.ejmech.2017.09.001.
N. Braidy, S. Behzad, S. Habtemariam, et al., Neuroprotective effects of citrus fruit-derived flavonoids, nobiletin and tangeretin in Alzheimer’s and Parkinson’s disease, CNS Neurol. Disord. Drug Targets. 16 (2017) 387-397. https://doi.org/10.2174/1871527316666170328113309.
J.J. Sun, F.H. Fu, Q.L. Li, Optimization the technology of preparation of whole sweet orange cloudy juice by complex enzymatic, Food Machinery 33 (2017) 189-193. https://doi.org/10.13652/j.issn.1003-5788.2017.08.041.
Q.L. Li, J.J. Sun, Y. Shan, et al., Whole juice-processing quality evaluation of different citrus varieties, Food Sci. 40 (2019) 36-44. https://doi.org/10.7506/spkx1002-6630-20180624-453.
Y. Yang, Y. Shan, S.H. Ding, et al., Effect of high-energy ball milling on particle size and rheological properties of whole pulp of Gannan navel orange, Food Sci. 40 (2019) 109-115. https://doi.org/10.7506/spkx1002-6630-20180521-291.
X. Chen, J.L.H. Ting, Y. Peng, et al., Comparing three types of Mandarin powders prepared via microfluidic-jet spray drying: physical properties, phenolic retention and volatile profiling, Foods 10 (2021) 123. https://doi.org/10.3390/foods10010123.
R.M. McCarron, B. Shapiro, J. Rawles, et al., Depression, Ann. Intern. Med. 174 (2021) ITC65-80. https://doi.org/10.7326/AITC202105180.
G.S. Alexopoulos, Depression in the elderly, Lancet. 365 (2005) 1961-1970. https://doi.org/10.1016/S0140-6736(05)66665-2.
K. Smith, Mental health: a world of depression, Nature 515 (2014) 181. https://doi.org/10.1038/515180a.
GBD 2019 Mental disorders collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the global burden of disease study 2019, Lancet Psychiatry 9 (2022) 137-150. https://doi.org/10.1016/S2215-0366(21)00395-3.
K. Hawton, I. Casañas, C. Comabella, et al., Risk factors for suicide in individuals with depression: a systematic review, J. Affect. Disord. 147 (2013) 17-28. https://doi.org/10.1016/j.jad.2013.01.004.
J.M. Bolton, D. Gunnell, G. Turecki, Suicide risk assessment and intervention in people with mental illness, BMJ 351 (2015) h4978. https://doi.org/10.1136/bmj.h4978.
Y. Lu, C. Tang, C.S. Liow, et al., A regressional analysis of maladaptive rumination, illness perception and negative emotional outcomes in Asian patients suffering from depressive disorder, Asian J. Psychiatr. 12 (2014) 69-76. https://doi.org/10.1016/j.ajp.2014.06.014.
C.A. Depp, S. Dev, L.T. Eyler, Bipolar depression and cognitive impairment shared mechanisms and new treatment avenues, Psychiatr. Clin. North Am. 39 (2016) 95-109. https://doi.org/10.1016/j.psc.2015.09.004.
L. Zaninotto, M. Solmi, N. Veronese, et al., A meta-analysis of cognitive performance in melancholic versus non-melancholic unipolar depression, J. Affect Disord. 201 (2016) 15-24. https://doi.org/10.1016/j.jad.2016.04.039.
C. Pittenger, R.S. Duman, Stress, depression, and neuroplasticity: a convergence of mechanisms, Neuropsychopharmacology 33 (2008) 88-109. https://doi.org/10.1038/sj.npp.1301574.
A. Sawamoto, S. Okuyama, K. Yamamoto, et al., 3,5,6,7,8,3’,4’-Heptamethoxy-flavone, a citrus flavonoid, ameliorates corticosterone-induced depression-like behavior and restores brain-derived neurotrophic factor expression, neurogenesis, and neuroplasticity in the hippocampus, Molecules 21 (2016) 541-553. https://doi.org/10.3390/molecules21040541.
Q. Li, F.L. Qu, Y. Gao, et al., Piper sarmentosum Roxb. produces antidepressant-like effects in rodents, associated with activation of the CREB-BDNF-ERK signaling pathway and reversal of HPA axis hyperactivity, J. Ethnopharmacol. 199 (2017) 9-19. https://doi.org/10.1016/j.jep.2017.01.037.
D.J. Lyons, R. Ammari, A. Hellysaz, et al., Serotonin and antidepressant SSRIs inhibit rat neuroendocrine dopamine neurons: parallel actions in the lactotrophic axis, J. Neurosci. 36 (2016) 7392-7406. https://doi.org/10.1523/JNEUROSCI.4061-15.2016.
K. Kamińska, A. Górska, K. Noworyta-Sokołowska, et al., The effect of chronic co-treatment with risperidone and novel antidepressant drugs on the dopamine and serotonin levels in the rats frontal cortex, Pharmacol. Rep. 70 (2018) 1023-1031. https://doi.org/10.1016/j.pharep.2018.04.009.
Y. Xu, J. Feng, J.Y. Guo, Mechanism underlying the antidepressant effect of Fructus aurantii, Chinese Journal of Clinical Pharmacology and Therapeutics. 18 (2013) 1086-1092.
M. Wu, H. Zhang, C. Zhou, et al. Identification of the chemical constituents in aqueous extract of Zhi-Qiao and evaluation of its antidepressant effect, Molecules 20 (2015) 6925-6940. https://doi.org/10.3390/molecules20046925.
T.L.K. Bear, J.E. Dalziel, J. Coad, et al., The role of the gut microbiota in dietary interventions for depression and anxiety, Adv. Nutr. 11 (2020) 890-907. https://doi.org/10.1093/advances/nmaa016.
X. Zhang, S. Chen, M. Zhang, et al., Effects of fermented milk containing Lacticaseibacillus paracasei strain Shirota on constipation in patients with depression: a randomized, double-blind, placebo-controlled trial, Nutrients 13 (2021) 2238. https://doi.org/10.3390/nu13072238.
Y. Fan, O. Pedersen, Gut microbiota in human metabolic health and disease, Nat. Rev. Microbiol. 19 (2021) 55-71. https://doi.org/10.1038/s41579-020-0433-9.
Y. Nie, F.J. Luo, Q.L. Lin, Dietary nutrition and gut microflora: a promising target for treating diseases, Trends Food Sci. Technol. 75 (2018) 72-80. https://doi.org/10.1016/j.tifs.2018.03.002
X. Hu, T. Wang, F. Jin, Alzheimer’s disease and gut microbiota, Sci. China Life Sci. 59 (2016) 1006-1023. https://doi.org/10.1007/s11427-016-5083-9.
S. Liang, X. Wu, X. Hu, et al., Recognizing depression from the microbiota-gut-brain axis, Int. J. Mol. Sci. 19 (2018) 1592. https://doi.org/10.3390/ijms19061592.
K. Zhao, M. Yao, X. Zhang, et al., Flavonoids and intestinal microbes interact to alleviate depression, J. Sci. Food Agric. 102 (2022) 1311-1318. https://doi.org/10.1002/jsfa.11578.
I. Jabri Karoui, B. Marzouk, Characterization of bioactive compounds in Tunisian bitter orange (Citrus aurantium L.) peel and juice and determination of their antioxidant activities, Biomed. Res. Int. 2013 (2013) 345415. https://doi.org/10.1155/2013/345415.
Y. Nogata, K. Sakamoto, H. Shiratsuchi, et al. Flavonoid composition of fruit tissues of citrus species, Biosci. Biotechnol. Biochem. 70 (2006) 178-192. https://doi.org/10.1271/bbb.70.178.
J. Bai, J.A. Manthey, B.L. Ford, et al., Effect of extraction, pasteurization and cold storage on flavonoids and other secondary metabolites in fresh orange juice, J. Sci. Food Agric. 93 (2013) 2771-2781. https://doi.org/10.1002/jsfa.6097.
M. Nollet, Models of depression: unpredictable chronic mild stress in mice, Curr. Protoc. 8 (2021) e208. https://doi.org/10.1002/cpz1.208.
P. Willner, The chronic mild stress (CMS) model of depression: history, evaluation and usage, Neurobiol. Stress. 6 (2016) 78-93. https://doi.org/10.1016/j.ynstr.2016.08.002.
S. Antoniuk, M. Bijata, E. Ponimaskin, et al., Chronic unpredictable mild stress for modeling depression in rodents: meta-analysis of model reliability, Neurosci. Biobehav. Rev. 99 (2019) 101-116. https://doi.org/10.1016/j.neubiorev.2018.12.002.
C. Hu, Y. Luo, H. Wang, et al., Re-evaluation of the interrelationships among the behavioral tests in rats exposed to chronic unpredictable mild stress, PLoS One 12 (2017) e0185129. https://doi.org/10.1371/journal.pone.0185129.
A.K. Kraeuter, P.C. Guest, Z. Sarnyai, The open field test for measuring locomotor activity and anxiety-like behavior, Methods Mol. Biol. 1916 (2019) 99-103. https://doi.org/10.1007/978-1-4939-8994-29.
H. Kuniishi, S. Ichisaka, M. Yamamoto, et al., Early deprivation increases high-leaning behavior, a novel anxiety-like behavior, in the open field test in rats, Neurosci. Res. 123 (2017) 27-35. https://doi.org/10.1016/j.neures.2017.04.012.
J.C. Zhang, W. Yao, K. Hashimoto, Brain-derived neurotrophic factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets, Curr. Neuropharmacol. 14 (2016) 721-731. https://doi.org/10.2174/1570159x14666160119094646.
S.E. Hyman, How mice cope with stressful social situations, Cell 131 (2007) 232-234. https://doi.org/10.1016/j.cell.2007.10.008.
O. Berton, C.A. McClung, R.J. Dileone, et al., Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress, Science 311 (2006) 864-868. https://doi.org/10.1126/science.1120972.
C. Björkholm, L.M. Monteggia, BDNF - a key transducer of antidepressant effects, Neuropharmacology 102 (2016) 72-79. https://doi.org/10.1016/j.neuropharm.2015.10.034.
M.D. Mardones, P.V. Jorquera, A. Herrera-Soto, et al. PSD95 regulates morphological development of adult-born granule neurons in the mouse hippocampus, J. Chem. Neuroanat. 98 (2019) 117-123. https://doi.org/10.1016/j.jchemneu.2019.04.009.
W. Qu, N.K. Liu, X. Wu, et al., Disrupting nNOS-PSD95 interaction improves neurological and cognitive recoveries after traumatic brain injury, Cereb. Cortex. 30 (2020) 3859-3871. https://doi.org/10.1093/cercor/bhaa002.
Y.A. Kolos, I.P. Grigoriyev, D.E. Korzhevskyi, A synaptic marker synaptophysin, Morfologiia. 147 (2015) 78-82.
J.L. Wu, Z. Yuan, Y.L. Wang, et al., Effects of electro-nape-acupuncture on synaptic plasticity related proteins of hippocampal in mild cognitive dysfunction rats induced by chronic sleep deprivation, Journal of Hunan University of Chinese Medicine 41 (2021) 370-375.
A.R. Brunoni, R. Machado-Vieira, C.A. Jr. Zarate, et al., Assessment of non-BDNF neurotrophins and GDNF levels after depression treatment with sertraline and transcranial direct current stimulation in a factorial, randomized, sham-controlled trial (SELECT-TDCS): an exploratory analysis, Prog. Neuropsychopharmacol. Biol. Psychiatry 56 (2015) 91-96. https://doi.org/10.1016/j.pnpbp.2014.08.009.
D.A. Tata, E. Dandi, E. Spandou, Expression of synaptophysin and BDNF in the medial prefrontal cortex following early life stress and neonatal hypoxia-ischemia, Dev. Psychobiol. 63 (2021) 173-182. https://doi.org/10.1002/dev.22011.
P. Kundu, E. Blacher, E. Elinav, et al., Our gut microbiome: the evolving inner self, Cell 171 (2017) 1481-1493. https://doi.org/10.1016/j.cell.2017.11.024.
M. Valles-Colomer, G. Falony, Y. Darzi, et al., The neuroactive potential of the human gut microbiota in quality of life and depression, Nat. Microbiol. 4 (2019) 623-632. https://doi.org/10.1038/s41564-018-0337-x.
C.A. Simpson, C. Diaz-Arteche, D. Eliby, et al. The gut microbiota in anxiety and depression - a systematic review, Clin. Psychol. Rev. 83 (2021) 101943. https://doi.org/10.1016/j.cpr.2020.101943.
O.V. Averina, Y.A. Zorkina, R.A. Yunes, et al., Bacterial metabolites of human gut microbiota correlating with depression, Int. J. Mol. Sci. 21 (2020) 9234. https://doi.org/10.3390/ijms21239234.
Y.E. Chung, H.C. Chen, H.L. Chou, et al. Exploration of microbiota targets for major depressive disorder and mood related traits, J. Psychiatr. Res. 111 (2019) 74-82. https://doi.org/10.1016/j.jpsychires.2019.01.016.
W.T. Lai, W.F. Deng, S.X. Xu, et al., Shotgun metagenomics reveals both taxonomic and tryptophan pathway differences of gut microbiota in major depressive disorder patients, Psychol. Med. 51 (2021) 90-101. https://doi.org/10.1017/S0033291719003027.
O. Kohler, J. Krogh, O. Mors, et al., Inflammation in depression and the potential for anti-Inflammatory treatment, Curr. Neuropharmacol. 14 (2016) 732-742. https://doi.org/10.2174/1570159x14666151208113700.
X. Liu, C. Liu, Baicalin ameliorates chronic unpredictable mild stress-induced depressive behavior: involving the inhibition of NLRP3 inflammasome activation in rat prefrontal cortex, Int. Immunopharmacol. 48 (2017) 30-34. https://doi.org/10.1016/j.intimp.2017.04.019.
E. Beurel, M. Toups, C.B. Nemeroff, The bidirectional relationship of depression and inflammation: double trouble, Neuron. 107 (2020) 234-256. https://doi.org/10.1016/j.neuron.2020.06.002.
H.Z. Zhu, Y.D. Liang, Q.Y. Ma, et al., Xiaoyaosan improves depressive-like behavior in rats with chronic immobilization stress through modulation of the gut microbiota, Biomed. Pharmacother. 112 (2019) 108621. https://doi.org/10.1016/j.biopha.2019.108621.
Z. Zeng, X. Guo, J. Zhang, et al., Lactobacillus paracasei modulates the gut microbiota and improves inflammation in type 2 diabetic rats, Food Funct. 12 (2021) 6809-6820. https://doi.org/10.1039/d1fo00515d.
Z. Zhang, X. Lin, Y. Huang, et al. An integrated gut microbiota and network pharmacology study on Fuzi-Lizhong pill for treating diarrhea-predominant irritable bowel syndrome, Front. Pharmacol. 12 (2021) 746923. https://doi.org/10.3389/fphar.2021.746923.
B.R. Stevens, R. Goel, K. Seungbum, et al., Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression, Gut 67 (2018) 1555-1557. https://doi.org/10.1136/gutjnl-2017-314759.
京公网安备11010802044758号