{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:32:21Z","timestamp":1792524741301,"version":"4.5.0"},"reference-count":93,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004001","name":"Guizhou Provincial Science and Technology Department","doi-asserted-by":"publisher","award":["[2024]01503-3"],"award-info":[{"award-number":["[2024]01503-3"]}],"id":[{"id":"10.13039\/501100004001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004001","name":"Guizhou Provincial Science and Technology Department","doi-asserted-by":"publisher","award":["MS [2025]560"],"award-info":[{"award-number":["MS [2025]560"]}],"id":[{"id":"10.13039\/501100004001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004001","name":"Guizhou Provincial Science and Technology Department","doi-asserted-by":"publisher","award":["CXPTXM [2025]010"],"award-info":[{"award-number":["CXPTXM [2025]010"]}],"id":[{"id":"10.13039\/501100004001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004001","name":"Guizhou Provincial Science and Technology Department","doi-asserted-by":"publisher","award":["KXJZ [2025]014"],"award-info":[{"award-number":["KXJZ [2025]014"]}],"id":[{"id":"10.13039\/501100004001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004001","name":"Guizhou Provincial Science and Technology Department","doi-asserted-by":"publisher","award":["[2025]021"],"award-info":[{"award-number":["[2025]021"]}],"id":[{"id":"10.13039\/501100004001","id-type":"DOI","asserted-by":"publisher"}]},{"award":["[2024]01503-3"],"award-info":[{"award-number":["[2024]01503-3"]}],"id":[{"id":"https:\/\/ror.org\/00kwnh405","id-type":"ROR","asserted-by":"publisher"}]},{"award":["MS [2025]560"],"award-info":[{"award-number":["MS [2025]560"]}],"id":[{"id":"https:\/\/ror.org\/00kwnh405","id-type":"ROR","asserted-by":"publisher"}]},{"award":["CXPTXM [2025]010"],"award-info":[{"award-number":["CXPTXM [2025]010"]}],"id":[{"id":"https:\/\/ror.org\/00kwnh405","id-type":"ROR","asserted-by":"publisher"}]},{"award":["KXJZ [2025]014"],"award-info":[{"award-number":["KXJZ [2025]014"]}],"id":[{"id":"https:\/\/ror.org\/00kwnh405","id-type":"ROR","asserted-by":"publisher"}]},{"award":["[2025]021"],"award-info":[{"award-number":["[2025]021"]}],"id":[{"id":"https:\/\/ror.org\/00kwnh405","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010265","name":"Guizhou Medical University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100010265","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/035y7a716","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Foods"],"abstract":"<jats:p>Depression is a common mental disorder that substantially impairs patients\u2019 daily life and work. To identify natural and safe preventive options, we investigated the preventive effect and underlying mechanism of the Ganoderma lucidum and Rosa roxburghii Tratt formula (GLRRTF) on depression. A total of 72 chemical components in GLRRTF were identified by UHPLC-ESI-Q-Exactive Plus Orbitrap-MS Analysis. GLRRTF (containing 400 mg\/kg of G. lucidum extract and 800 mg\/kg of R. roxburghii extract per day), administered as a 1-week preventive intervention followed by 4 weeks of co-administration with chronic unpredictable mild stress, prevented the development of depression-like behaviors in male C57BL\/6J mice and reduced neuronal damage in the hippocampus. Airflow-assisted desorption electrospray ionization mass spectrometry imaging and enzyme-linked immunosorbent assays showed that GLRRTF corrected abnormalities in neurotransmitter levels. The 16S rRNA sequencing indicated that GLRRTF restored dysbiosis of the gut microbiota. Metabolomic profiling revealed that GLRRTF increased the level of tryptophan and promoted tryptophan metabolism towards the 5-HT and indole pathways in feces and the brain. Western blot demonstrated that GLRRTF increased 5-HT production from tryptophan in the brain by regulating tryptophan hydroxylase 2 and DOPA decarboxylase. GLRRTF activated the PI3K\/AKT pathway by regulating brain-derived neurotrophic factor and its receptor tropomyosin receptor kinase B. This research provides a comprehensive mechanistic understanding of GLRRTF\u2019s preventive effect against depression, highlighting its potential as a novel, safe, and preventive functional food formulation.<\/jats:p>","DOI":"10.3390\/foods15091535","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T15:09:33Z","timestamp":1777388973000},"page":"1535","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Ganoderma lucidum and Rosa roxburghii Tratt Formulation Prevents Depressive-like Behaviors in Mice by Modulating Tryptophan Metabolism via the Gut\u2013Brain Axis and Upregulating the BDNF\/TrkB\/PI3K\/AKT Pathway"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5918-625X","authenticated-orcid":false,"given":"Fangling","family":"Feng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China"},{"name":"Engineering Research Center of Microbiology and Biochemical Pharmaceutical, Guizhou Provincial Department of Education, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China"},{"name":"Engineering Research Center of Microbiology and Biochemical Pharmaceutical, Guizhou Provincial Department of Education, Guiyang 561113, China"},{"name":"Experimental Animal Center, Guizhou Medical University, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chencen","family":"Lai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China"},{"name":"Engineering Research Center of Microbiology and Biochemical Pharmaceutical, Guizhou Provincial Department of Education, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyu","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China"},{"name":"Engineering Research Center of Microbiology and Biochemical Pharmaceutical, Guizhou Provincial Department of Education, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China"},{"name":"Engineering Research Center of Microbiology and Biochemical Pharmaceutical, Guizhou Provincial Department of Education, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6545-472X","authenticated-orcid":false,"given":"Jiuming","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China"},{"name":"Engineering Research Center of Microbiology and Biochemical Pharmaceutical, Guizhou Provincial Department of Education, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengjiao","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China"},{"name":"Engineering Research Center of Microbiology and Biochemical Pharmaceutical, Guizhou Provincial Department of Education, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuli","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China"},{"name":"Engineering Research Center of Microbiology and Biochemical Pharmaceutical, Guizhou Provincial Department of Education, Guiyang 561113, China"},{"name":"Guizhou Provincial Engineering Research Center of Food Nutrition and Health, Guizhou Medical University, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lazur, J., Hnatyk, K., Ka\u0142a, K., Su\u0142kowska-Ziaja, K., and Muszy\u0144ska, B. (2023). Discovering the Potential Mechanisms of Medicinal Mushrooms Antidepressant Activity: A Review. Antioxidants, 12.","DOI":"10.3390\/antiox12030623"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7797","DOI":"10.1007\/s11033-023-08650-8","article-title":"Modulating cyclic nucleotides pathways by bioactive compounds in combatting anxiety and depression disorders","volume":"50","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Gonda, X., Tarazi, F.I., and Dome, P. (2024). The emergence of antidepressant drugs targeting GABAA receptors: A concise review. Biochem. Pharmacol., 228.","DOI":"10.1016\/j.bcp.2024.116481"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Dobrek, L., and G\u0142owacka, K. (2023). Depression and Its Phytopharmacotherapy\u2014A Narrative Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054772"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.tifs.2022.10.019","article-title":"Plant-derived bioactive components regulate gut microbiota to prevent depression and depressive-related neurodegenerative diseases: Focus on neurotransmitters","volume":"129","author":"Song","year":"2022","journal-title":"Trends Food Sci. Technol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Yoon, S., Iqbal, H., Kim, S.M., and Jin, M. (2023). Phytochemicals that act on synaptic plasticity as potential prophylaxis against stress-induced depressive disorder. Biomol. Ther., 31.","DOI":"10.4062\/biomolther.2022.116"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Trigo, M. (2021). The role of the gut-brain axis in depression and anxiety disorders. Eur. Psychiatry, 64.","DOI":"10.1192\/j.eurpsy.2021.1840"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Gong, P., Wang, J., Long, H., Yang, W., Chen, X., Li, N., Chen, F., Zhang, J., and Guo, Y. (2025). Edible and Medicinal Fungi as Candidate Natural Antidepressants: Mechanisms and Nutritional Implications. Mol. Nutr. Food Res., 69.","DOI":"10.1002\/mnfr.70080"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Naoi, M., Wu, Y., Maruyama, W., and Shamoto-Nagai, M. (2025). Phytochemicals modulate biosynthesis and function of serotonin, dopamine, and norepinephrine for treatment of monoamine neurotransmission-related psychiatric diseases. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26072916"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.chom.2018.05.003","article-title":"Gut microbiota regulation of tryptophan metabolism in health and disease","volume":"23","author":"Agus","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Pardossi, S., Fagiolini, A., and Cuomo, A. (2024). Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252313098"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Molska, M., Mruczyk, K., Cisek-Wo\u017aniak, A., Prokopowicz, W., Szyde\u0142ko, P., Jakuszewska, Z., Marzec, K., and Trocholepsza, M. (2024). The Influence of Intestinal Microbiota on BDNF Levels. Nutrients, 16.","DOI":"10.3390\/nu16172891"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Tu, F., Pang, Q., Huang, T., Zhao, Y., Liu, M., and Chen, X. (2017). Apigenin ameliorates post-stroke cognitive deficits in rats through histone acetylation-mediated neurochemical alterations. Med. Sci. Monit. Int. Med. J. Exp. Clin. Res., 23.","DOI":"10.12659\/MSM.902770"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.jad.2022.08.059","article-title":"Antibiotics-induced depression in mice via the microbiota-gut-brain axis","volume":"318","author":"Fan","year":"2022","journal-title":"J. Affect. Disord."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Correia, A.S., Cardoso, A., and Vale, N. (2023). BDNF unveiled: Exploring its role in major depression disorder serotonergic imbalance and associated stress conditions. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15082081"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Fan, Y., Luan, X., Wang, X., Li, H., Zhao, H., Li, S., Li, X., and Qiu, Z. (2025). Exploring the association between BDNF related signaling pathways and depression: A literature review. Brain Res. Bull., 220.","DOI":"10.1016\/j.brainresbull.2024.111143"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Swallah, M.S., Bondzie-Quaye, P., Wang, H., Shao, C.-S., Hua, P., Bashir, M.A., Holman, J.B., Sossah, F.L., and Huang, Q. (2023). Potentialities of Ganoderma lucidum extracts as functional ingredients in food formulation. Food Res. Int., 172.","DOI":"10.1016\/j.foodres.2023.113161"},{"key":"ref_18","unstructured":"Wachtel-Galor, S., Yuen, J., Buswell, J.A., and Benzie, I.F. (2012). Ganoderma lucidum (Lingzhi or Reishi): A medicinal mushroom. Herbal Medicine: Biomolecular and Clinical Aspects, CRC Press."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1615\/IntJMedMushrooms.v17.i3.10","article-title":"Evaluation of anticonvulsant, antidepressant-, and anxiolytic-like effects of an aqueous extract from cultured mycelia of the Lingzhi or Reishi medicinal mushroom Ganoderma lucidum (Higher Basidiomycetes) in mice","volume":"17","author":"Socala","year":"2015","journal-title":"Int. J. Med. Mushrooms"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Qin, Y., Hu, X., Chen, X., Jiang, Y.-P., Jin, X.-J., Li, G., Li, Z.-H., Yang, J.-H., and Cui, S.-Y. (2024). Sporoderm-removed Ganoderma lucidum spores ameliorated early depression-like behavior in a rat model of sporadic Alzheimer\u2019s disease. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1406127"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.brainresbull.2021.03.002","article-title":"Ganoderma lucidum polysaccharides ameliorated depression-like behaviors in the chronic social defeat stress depression model via modulation of Dectin-1 and the innate immune system","volume":"171","author":"Li","year":"2021","journal-title":"Brain Res. Bull."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mi, X., Zeng, G.-R., Liu, J.-Q., Luo, Z.-S., Zhang, L., Dai, X.-M., Fang, W.-T., Zhang, J., and Chen, X.-C. (2022). Ganoderma lucidum triterpenoids improve maternal separation-induced anxiety- and depression-like behaviors in mice by mitigating inflammation in the periphery and brain. Nutrients, 14.","DOI":"10.3390\/nu14112268"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Wang, L., Wei, T., Zheng, L., Jiang, F., Ma, W., Lu, M., Wu, X., and An, H. (2023). Recent Advances on Main Active Ingredients, Pharmacological Activities of Rosa roxbughii and Its Development and Utilization. Foods, 12.","DOI":"10.3390\/foods12051051"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Jain, A., Sarsaiya, S., Gong, Q., Wu, Q., and Shi, J. (2024). Chemical diversity, traditional uses, and bioactivities of Rosa roxburghii Tratt: A comprehensive review. Pharmacol. Ther., 259.","DOI":"10.1016\/j.pharmthera.2024.108657"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1021\/acs.jafc.5c13128","article-title":"Decoding the Protective Mechanisms of Rosa roxburghii Fermented Juice against CUMS-Induced Depression-like Behaviors: Insights from Gut Microbiota and Neuroinflammation","volume":"74","author":"Lai","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chen, F., Wang, L., Jin, F., Li, L., Wang, T., Gao, M., Li, L., Wang, Y., Lou, Z., and Yang, J. (2022). Neuroprotection of Kaji-Ichigoside F1 via the BDNF\/Akt\/mTOR Signaling Pathways against NMDA-Induced Neurotoxicity. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232416150"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chen, F., Li, L., Huang, M., Wang, Y., Wang, L., Jin, F., Yang, L., Gao, M., Li, L., and Wang, Y. (2024). Natural product Kaji-ichigoside F1 exhibits rapid antidepression via activating the AMPA\u2013BDNF\u2013mTOR pathway and inhibiting the NMDAR\u2013CaMKII\u03b1 pathway. Phytomedicine, 126.","DOI":"10.1016\/j.phymed.2024.155452"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Yin, C., Zhang, Y., Zhang, L., Tian, Y., Zhong, X., Fang, X., Yang, Y., and Tao, A. (2024). Exploring Rosa roxburghii Tratt polysaccharides: From extraction to application potential in functional products-An in-depth review. Int. J. Biol. Macromol., 280.","DOI":"10.1016\/j.ijbiomac.2024.135543"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Shoji, H., and Miyakawa, T. (2019). Increased depression-related behavior during the postpartum period in inbred BALB\/c and C57BL\/6 strains. Mol. Brain, 12.","DOI":"10.1186\/s13041-019-0490-z"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Sharma, S., Chawla, S., Kumar, P., Ahmad, R., and Verma, P.K. (2024). The chronic unpredictable mild stress (CUMS) Paradigm: Bridging the gap in depression research from bench to bedside. Brain Res., 1843.","DOI":"10.1016\/j.brainres.2024.149123"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Liaqat, H., Parveen, A., and Kim, S.Y. (2022). Neuroprotective natural products\u2019 regulatory effects on depression via gut\u2013brain axis targeting tryptophan. Nutrients, 14.","DOI":"10.3390\/nu14163270"},{"key":"ref_32","unstructured":"Xu, S.Y., Bian, R.L., and Chen, X. (2002). Pharmacological Experimental Methodology, People\u2019s Medical Publishing House. [3rd ed.]."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.bbrc.2022.05.041","article-title":"Effects of repeated drug administration on behaviors in normal mice and fluoxetine efficacy in chronic unpredictable mild stress mice","volume":"615","author":"Li","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.neubiorev.2018.12.002","article-title":"Chronic unpredictable mild stress for modeling depression in rodents: Meta-analysis of model reliability","volume":"99","author":"Antoniuk","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Schalla, M.A., K\u00fchne, S.G., Friedrich, T., Hanel, V., Kobelt, P., Goebel-Stengel, M., Rose, M., and Stengel, A. (2020). Sucrose preference and novelty-induced hypophagia tests in rats using an automated food intake monitoring system. J. Vis. Exp., 159.","DOI":"10.3791\/60953-v"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Kraeuter, A.-K., Guest, P.C., and Sarnyai, Z. (2018). The open field test for measuring locomotor activity and anxiety-like behavior. Pre-Clinical Models: Techniques and Protocols, Springer.","DOI":"10.1007\/978-1-4939-8994-2_9"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"De Kloet, E., and Molendijk, M. (2016). Coping with the forced swim stressor: Towards understanding an adaptive mechanism. Neural Plast., 2016.","DOI":"10.1155\/2016\/6503162"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Can, A., Dao, D.T., Terrillion, C.E., Piantadosi, S.C., Bhat, S., and Gould, T.D. (2012). The tail suspension test. J. Vis. Exp., 59.","DOI":"10.3791\/3769-v"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Leo, L.M., and Pamplona, F.A. (2014). Elevated plus maze test to assess anxiety-like behavior in the mouse. Bio-Protocol, 4.","DOI":"10.21769\/BioProtoc.1211"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1101\/pdb.prot073411","article-title":"Manual hematoxylin and eosin staining of mouse tissue sections","volume":"2014","author":"Cardiff","year":"2014","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_41","unstructured":"Kiernan, J. (2015). Histological and Histochemical Methods, Scion Publishing Ltd."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1177\/01926233251384928","article-title":"Red Deads, Ghosts, and the Afterlife: A Guide to Neuronal Cell Death","volume":"53","author":"Tokarz","year":"2025","journal-title":"Toxicol. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1177\/0192623315625859","article-title":"Recommendations from the INHAND apoptosis\/necrosis working group","volume":"44","author":"Elmore","year":"2016","journal-title":"Toxicol. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Li, C., Zhang, M., Zhao, Y., Yang, D., Zhao, M., Shang, L., Sun, X., Zhang, S., Wang, P., and Gao, X. (2025). Exploring the Impact of Pharmaceutical Excipient PEG400 on the Pharmacokinetics of Mycophenolic Acid Through In Vitro and In Vivo Experiments. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26010072"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Klindworth, A., Pruesse, E., Schweer, T., Peplies, J., Quast, C., Horn, M., and Gl\u00f6ckner, F.O. (2013). Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next-generation sequencing-based diversity studies. Nucleic Acids Res., 41.","DOI":"10.1093\/nar\/gks808"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Pichler, M., Coskun, \u00d6.K., Ortega-Arbul\u00fa, A.-S., Conci, N., W\u00f6rheide, G., Vargas, S., and Orsi, W.D. (2018). A 16S rRNA gene sequencing and analysis protocol for the Illumina MiniSeq platform. MicrobiologyOpen, 7.","DOI":"10.1002\/mbo3.611"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Chen, Z., Zhang, S., Sun, X., Meng, D., Lai, C., Zhang, M., Wang, P., Huang, X., and Gao, X. (2024). Rosa roxburghii fermented juice mitigates LPS-induced acute lung injury by modulation of intestinal flora and metabolites. Front. Microbiol., 15.","DOI":"10.3389\/fmicb.2024.1447735"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"99","DOI":"10.2144\/btn-2022-0034","article-title":"Western blotting (immunoblotting): History, theory, uses, protocol and problems","volume":"75","author":"Sule","year":"2023","journal-title":"Biotechniques"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Peng, L., Zhang, X., Tian, J., Wen, J., Qiu, R., Zheng, Y., Chen, C., and Ma, H. (2026). Desulfovibrio vulgaris trigger depression-like behavior in mice through dual disruption of colonic homeostasis and fatty acid metabolism. Physiol. Behav., 307.","DOI":"10.1016\/j.physbeh.2026.115232"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Ge, C., Wang, S., Wu, X., and Lei, L. (2024). Quercetin attenuates brain apoptosis in mice with chronic unpredictable mild stress-induced depression. Behav. Brain Res., 465.","DOI":"10.1016\/j.bbr.2024.114934"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Su, P., Liu, L., Gong, Y., Peng, S., Yan, X., Bai, M., Xu, E., and Li, Y. (2024). Kaempferol improves depression-like behaviors through shifting microglia polarization and suppressing NLRP3 via tilting the balance of PPAR\u03b3 and STAT1 signaling. Int. Immunopharmacol., 143.","DOI":"10.1016\/j.intimp.2024.113538"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Zhang, L., Lu, R.-R., Xu, R.-H., Wang, H.-H., Feng, W.-S., and Zheng, X.-K. (2023). Naringenin and apigenin ameliorates corticosterone-induced depressive behaviors. Heliyon, 9.","DOI":"10.1016\/j.heliyon.2023.e15618"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"292","DOI":"10.2174\/0115665232261045231215054305","article-title":"Catechin Protects against Lipopolysaccharide-induced Depressive-like Behaviour in Mice by Regulating Neuronal and Inflammatory Genes","volume":"24","author":"Yanfang","year":"2024","journal-title":"Curr. Gene Ther."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Damas, M.G., Genis-Mendoza, A.D., Cruz, V.P.-D.L., Canela-Tellez, G.D., Jim\u00e9nez-Estrada, I., Sanchez, J.H.N., Ramos-Ch\u00e1vez, L.A., Garc\u00eda, S., Ram\u00edrez-Ram\u00edrez, M., and Coral-V\u00e1zquez, R.M. (2021). Epicatechin treatment generates resilience to chronic mild stress-induced depression in a murine model through a modulatory effect on KAT. Physiol. Behav., 238.","DOI":"10.1016\/j.physbeh.2021.113466"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.ejphar.2012.02.034","article-title":"Evidence for the involvement of the monoaminergic system, but not the opioid system in the antidepressant-like activity of ellagic acid in mice","volume":"682","author":"Girish","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.intimp.2017.02.007","article-title":"Ferulic acid inhibits neuro-inflammation in mice exposed to chronic unpredictable mild stress","volume":"45","author":"Liu","year":"2017","journal-title":"Int. Immunopharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Song, Y., Xiao, F., Aa, J., and Wang, G. (2024). Desorption Electrospray Ionization Mass Spectrometry Imaging Techniques Depict a Reprogramming of Energy and Purine Metabolism in the Core Brain Regions of Chronic Social Defeat Stress Mice. Metabolites, 14.","DOI":"10.3390\/metabo14050284"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Liu, G.-X., Li, Z.-L., Lin, S.-Y., Wang, Q., Luo, Z.-Y., Wu, K., Zhou, Y.-L., and Ning, Y.-P. (2023). Mapping metabolite change in the mouse brain after esketamine injection by ambient mass spectrometry imaging and metabolomics. Front. Psychiatry, 14.","DOI":"10.3389\/fpsyt.2023.1109344"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.neuroimage.2009.12.043","article-title":"Cerebral asymmetries in 12-week-old C57Bl\/6J mice measured by magnetic resonance imaging","volume":"50","author":"Spring","year":"2010","journal-title":"Neuroimage"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1007\/s00702-023-02610-z","article-title":"Hemispheric asymmetries in mental disorders: Evidence from rodent studies","volume":"130","author":"Mundorf","year":"2023","journal-title":"J. Neural Transm."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Ocklenburg, S., Peterburs, J., and Mundorf, A. (2022). Hemispheric asymmetries in the amygdala: A comparative primer. Prog. Neurobiol., 214.","DOI":"10.1016\/j.pneurobio.2022.102283"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"15238","DOI":"10.1073\/pnas.1405648111","article-title":"Left\u2013right dissociation of hippocampal memory processes in mice","volume":"111","author":"Shipton","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Luscher, B., and Fuchs, T. (2015). GABAergic control of depression-related brain states. Advances in Pharmacology, Elsevier.","DOI":"10.1016\/bs.apha.2014.11.003"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"75","DOI":"10.2174\/1570159X22666240815120244","article-title":"Depression and the glutamate\/GABA-glutamine cycle","volume":"23","author":"Mamelak","year":"2025","journal-title":"Curr. Neuropharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/s41380-018-0219-x","article-title":"Cholinergic regulation of mood: From basic and clinical studies to emerging therapeutics","volume":"24","author":"Dulawa","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Maffei, M.E. (2020). 5-Hydroxytryptophan (5-HTP): Natural occurrence, analysis, biosynthesis, biotechnology, physiology and toxicology. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010181"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4409","DOI":"10.1038\/s41380-025-03044-7","article-title":"Implications of neurogenesis in depression through BDNF: Rodent models, regulatory pathways, gut microbiota, and potential therapy","volume":"30","author":"Han","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Liu, L., Wang, H., Zhang, H., Chen, X., Zhang, Y., Wu, J., Zhao, L., Wang, D., Pu, J., and Ji, P. (2022). Toward a deeper understanding of gut microbiome in depression: The promise of clinical applicability. Adv. Sci., 9.","DOI":"10.1002\/advs.202203707"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Dacaya, P., Sarapis, K., and Moschonis, G. (2025). The role and mechanisms of probiotic supplementation on depressive symptoms: A narrative review. Curr. Nutr. Rep., 14.","DOI":"10.1007\/s13668-025-00644-1"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Lv, J.-L., Bai, Y., Lv, Y.-E., Chen, C.-C., Qin, X.-M., Du, G.-H., and Zhou, Y.-Z. (2024). Integrated colon Microbiome and metabolomics to elucidate the antidepressant mechanisms of the Radix Bupleuri-Radix paeoniae Alba herb pair. Metab. Brain Dis., 40.","DOI":"10.1007\/s11011-024-01450-4"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Rao, Z., Li, J., Shi, B., Zeng, Y., Liu, Y., Sun, Z., Wu, L., Sun, W., and Tang, Z. (2021). Dietary tryptophan levels impact growth performance and intestinal microbial ecology in weaned piglets via tryptophan metabolites and intestinal antimicrobial peptides. Animals, 11.","DOI":"10.3390\/ani11030817"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Xie, J., Wu, W.-T., Chen, J.-J., Zhong, Q., Wu, D., Niu, L., Wang, S., Zeng, Y., and Wang, Y. (2023). Tryptophan metabolism as bridge between gut microbiota and brain in chronic social defeat stress-induced depression mice. Front. Cell. Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1121445"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.aninu.2022.07.005","article-title":"Characterizing the influence of gut microbiota on host tryptophan metabolism with germ-free pigs","volume":"11","author":"Liu","year":"2022","journal-title":"Anim. Nutr."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Guo, X., Lin, F., Yang, F., Chen, J., Cai, W., and Zou, T. (2022). Gut microbiome characteristics of comorbid generalized anxiety disorder and functional gastrointestinal disease: Correlation with alexithymia and personality traits. Front. Psychiatry, 13.","DOI":"10.3389\/fpsyt.2022.946808"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Borisova, M.A., Snytnikova, O.A., Litvinova, E.A., Achasova, K.M., Babochkina, T.I., Pindyurin, A.V., Tsentalovich, Y.P., and Kozhevnikova, E.N. (2020). Fucose Ameliorates Tryptophan Metabolism and Behavioral Abnormalities in a Mouse Model of Chronic Colitis. Nutrients, 12.","DOI":"10.3390\/nu12020445"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41573-019-0016-5","article-title":"Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond","volume":"18","author":"Platten","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.jpba.2019.06.043","article-title":"Development of an underivatized LC-MS\/MS method for quantitation of 14 neurotransmitters in rat hippocampus, plasma and urine: Application to CUMS induced depression rats","volume":"174","author":"Han","year":"2019","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Wang, D., Wu, J., Zhu, P., Xie, H., Lu, L., Bai, W., Pan, W., Shi, R., Ye, J., and Xia, B. (2022). Tryptophan-rich diet ameliorates chronic unpredictable mild stress induced depression-and anxiety-like behavior in mice: The potential involvement of gut-brain axis. Food Res. Int., 157.","DOI":"10.1016\/j.foodres.2022.111289"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Rust, C., Malan-Muller, S., van den Heuvel, L.L., Tonge, D., Seedat, S., Pretorius, E., and Hemmings, S.M.J. (2023). Platelets bridging the gap between gut dysbiosis and neuroinflammation in stress-linked disorders: A narrative review. J. Neuroimmunol., 382.","DOI":"10.1016\/j.jneuroim.2023.578155"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Philippe, C., de Edelenyi, F.S., Naudon, L., Druesne-Pecollo, N., Hercberg, S., Kesse-Guyot, E., Latino-Martel, P., Galan, P., and Rabot, S. (2021). Relation between Mood and the Host-Microbiome Co-Metabolite 3-Indoxylsulfate: Results from the Observational Prospective NutriNet-Sant\u00e9 Study. Microorganisms, 9.","DOI":"10.3390\/microorganisms9040716"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Roager, H.M., and Licht, T.R. (2018). Microbial tryptophan catabolites in health and disease. Nat. Commun., 9.","DOI":"10.1038\/s41467-018-05470-4"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.brainresbull.2015.09.010","article-title":"Changes in serotonin (5-HT) and brain-derived neurotrophic factor (BDFN) expression in frontal cortex and hippocampus of aged rat treated with high tryptophan diet","volume":"119","author":"Musumeci","year":"2015","journal-title":"Brain Res. Bull."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2882","DOI":"10.1038\/npp.2016.100","article-title":"ProBDNF Signaling Regulates Depression-Like Behaviors in Rodents under Chronic Stress","volume":"41","author":"Bai","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Liaqat, H., Parveen, A., and Kim, S.-Y. (2022). Antidepressive effect of natural products and their derivatives targeting BDNF-TrkB in gut\u2013brain axis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232314968"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3682","DOI":"10.1016\/j.celrep.2020.02.099","article-title":"Changes in gut microbiota by chronic stress impair the efficacy of fluoxetine","volume":"30","author":"Siopi","year":"2020","journal-title":"Cell Rep."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Shi, H.-J., Wu, D.-L., Chen, R., Li, N., and Zhu, L.-J. (2022). Requirement of hippocampal DG nNOS-CAPON dissociation for the anxiolytic and antidepressant effects of fluoxetine. Theranostics, 12.","DOI":"10.7150\/thno.70370"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Dong, H., Tang, X., Ye, J., and Xiao, W. (2023). 16S rRNA gene sequencing reveals the effect of fluoxetine on gut microbiota in chronic unpredictable stress-induced depressive-like rats. Ann. Gen. Psychiatry, 22.","DOI":"10.1186\/s12991-023-00458-x"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Zhao, L., Xiong, Z., Lu, X., Zheng, S., Wang, F., Ge, L., Su, G., Yang, J., and Wu, C. (2015). Metabonomic evaluation of chronic unpredictable mild stress-induced changes in rats by intervention of fluoxetine by HILIC-UHPLC\/MS. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129146"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.pneurobio.2019.01.006","article-title":"Sex differences in depression: Insights from clinical and preclinical studies","volume":"176","author":"Eid","year":"2019","journal-title":"Prog. Neurobiol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Ghaffar, T., Valeriani, F., and Spica, V.R. (2025). The sex related differences in health and Disease: A systematic review of sex-specific gut microbiota and Possible implications for microbial pathogenesis. Microb. Pathog., 209.","DOI":"10.1016\/j.micpath.2025.108094"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Pais, M.L., Martins, J., Castelo-Branco, M., and Goncalves, J. (2023). Sex differences in tryptophan metabolism: A systematic review focused on neuropsychiatric disorders. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24066010"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Eltokhi, A., Kurpiers, B., and Pitzer, C. (2021). Baseline Depression-Like Behaviors in Wild-Type Adolescent Mice Are Strain and Age but Not Sex Dependent. Front. Behav. Neurosci., 15.","DOI":"10.3389\/fnbeh.2021.759574"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1111\/j.1742-7843.2009.00516.x","article-title":"Sex differences in animal models of depression and antidepressant response","volume":"106","author":"Dalla","year":"2010","journal-title":"Basic Clin. Pharmacol. Toxicol."}],"container-title":["Foods"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2304-8158\/15\/9\/1535\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T04:17:56Z","timestamp":1777522676000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2304-8158\/15\/9\/1535"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,28]]},"references-count":93,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["foods15091535"],"URL":"https:\/\/doi.org\/10.3390\/foods15091535","relation":{},"ISSN":["2304-8158"],"issn-type":[{"value":"2304-8158","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,28]]}}}