A preliminary study of fecal microbiota transplantation alleviating inhibition of radiation-induced hippocampal neurogenesis in mice
Li Junyan, Zhang Junjun, Tian Ye
Department of Radiotherapy Oncology, the Second Affiliated Hospital of Soochow University, Institute of Radiotherapy Oncology, Soochow University, Suzhou Key Laboratory for Radiation Oncology, Suzhou 215004, China
Abstract：Objective To evaluate the effects of whole brain irradiation (WBI) and fecal microbiota transplantation (FMT) on hippocampal neurogenesis and the composition of gut microbiota in mice. Methods Forty specific pathogen free ICR male mice (8-week-old, weighed 30 g) were divided into four groups by simple random sample method: control group (group C), radiation group (group R), group C+FMT and group R+FMT, 10 in each group. Animal models were established by WBI at a dose of 10 Gy by 4 MeV electron beam. In group C+FMT and group R+FMT, mice were gavaged with normal fecal bacteria suspension on day 2 post-irradiation, while those in group C and group R were gavaged with phosphate buffered saline as alternative. Hippocampal tissues and feces in four groups were collected on day 15 post-irradiation. 16S rRNA sequencing was used to detect the species and abundance of fecal flora. BrdU+/NeuN+ immunofluorescence staining was performed to observe the neurogenesis in hippocampus of mice. Results WBI and FMT had no effect on survival rate and body weight of mice. WBI induced the inhibition of hippocampal neurogenesis and flora disorder. The quantity of Bacteroideae and Rumen bacteria was increased by 28.6% and 102.9%, whereas that of Lactobacillus was significantly decreased by 70.6% (P<0.05). FMT regulated the abundance of bacteria. The abundance of Enterobacteriaceae was significantly declined by 65.1% (P=0.028), while that of Lactobacillus was increased by 58.2% (P=0.015). FMT also promoted hippocampal neurogenesis to some extent after WBI. Conclusions This preliminary study demonstrates that FMT alleviates the inhibition of hippocampal neurogenesis and flora disorder induced by WBI in mice. Ionizing radiation directly acting on the whole brain of mice indirectly disturbs the composition of gut microbiota, which in turn affects the degree of hippocampal neurogenesis in the brain of mice. There is a bidirectional interaction between gut microbiota and brain.
Li Junyan,Zhang Junjun,Tian Ye. A preliminary study of fecal microbiota transplantation alleviating inhibition of radiation-induced hippocampal neurogenesis in mice[J]. Chinese Journal of Radiation Oncology, 2023, 32(2): 152-158.
[1] Haldbo-Classen L, Amidi A, Wu LM, et al.Long-term cognitive dysfunction after radiation therapy for primary brain tumors[J]. Acta Oncol, 2019,58(5):745-752. DOI: 10.1080/0284186X.2018.1557786. [2] Alam MJ, Kitamura T, Saitoh Y, et al.Adult neurogenesis conserves hippocampal memory capacity[J]. J Neurosci, 2018,38(31):6854-6863. DOI: 10.1523/JNEUROSCI. 2976-17.2018. [3] Jenrow KA, Brown SL, Lapanowski K, et al.Selective inhibition of microglia-mediated neuroinflammation mitigates radiation-induced cognitive impairment[J]. Radiat Res, 2013,179(5):549-556. DOI: 10.1667/RR3026.1. [4] Makale MT, McDonald CR, Hattangadi-Gluth JA, et al. Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours[J]. Nat Rev Neurol, 2017,13(1):52-64. DOI: 10.1038/nrneurol. 2016.185. [5] Sun Y, Baptista LC, Roberts LM, et al.The gut microbiome as a therapeutic target for cognitive impairment[J]. J Gerontol A Biol Sci Med Sci, 2020,75(7):1242-1250. DOI: 10.1093/gerona/glz281. [6] Schmidt T, Raes J, Bork P.The human gut microbiome: from association to modulation[J]. Cell, 2018,172(6):1198-1215. DOI: 10.1016/j.cell.2018.02.044. [7] Sokol H, Adolph TE.The microbiota: an underestimated actor in radiation-induced lesions?[J]. Gut, 2018,67(1):1-2. DOI: 10.1136/gutjnl-2017-314279. [8] Mao A, Sun C, Katsube T, et al.A minireview on gastrointestinal microbiota and radiosusceptibility[J]. Dose Response, 2020,18(4):1559325820963859. DOI: 10.1177/1559325820963859. [9] Martinez-Guryn K, Leone V, Chang EB.Regional diversity of the gastrointestinal microbiome[J]. Cell Host Microbe, 2019,26(3):314-324. DOI: 10.1016/j.chom.2019.08.011. [10] Zierer J, Jackson MA, Kastenmüller G, et al.The fecal metabolome as a functional readout of the gut microbiome[J]. Nat Genet, 2018,50(6):790-795. DOI: 10.1038/s41588-018-0135-7. [11] Cui M, Xiao H, Li Y, et al.Faecal microbiota transplantation protects against radiation-induced toxicity[J]. EMBO Mol Med, 2017,9(4):448-461. DOI: 10.15252/emmm. 201606932. [12] Vendrik K, Ooijevaar RE, de Jong P, et al. Fecal microbiota transplantation in neurological disorders[J]. Front Cell Infect Microbiol, 2020,10:98. DOI: 10.3389/fcimb. 2020.00098. [13] Möhle L, Mattei D, Heimesaat MM, et al.Ly6C(hi) monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis[J]. Cell Rep, 2016,15(9):1945-1956. DOI: 10.1016/j.celrep.2016.04.074. [14] Zhang LY, Chen LS, Sun R, et al.Effects of expression level of DNA repair-related genes involved in the NHEJ pathway on radiation-induced cognitive impairment[J]. J Radiat Res, 2013,54(2):235-242. DOI: 10.1093/jrr/rrs095. [15] Burz SD, Abraham AL, Fonseca F, et al.A guide for ex vivo handling and storage of stool samples intended for fecal microbiota transplantation[J]. Sci Rep, 2019,9(1):8897. DOI: 10.1038/s41598-019-45173-4. [16] Smirnova DV, Zalomova LV, Zagainova AV, et al.Cryopreservation of the human gut microbiota: current state and perspectives[J]. Int J Med Microbiol, 2019,309(5):259-269. DOI: 10.1016/j.ijmm.2019.06.001. [17] Burrello C, Garavaglia F, Cribiù FM, et al.Therapeutic faecal microbiota transplantation controls intestinal inflammation through IL10 secretion by immune cells[J]. Nat Commun, 2018,9(1):5184. DOI: 10.1038/s41467- 018-07359-8. [18] Weingarden AR, Vaughn BP.Intestinal microbiota, fecal microbiota transplantation, and inflammatory bowel disease[J]. Gut Microbes, 2017,8(3):238-252. DOI: 10.1080/19490976.2017.1290757. [19] Hvas CL, Dahl Jørgensen SM, Jørgensen SP, et al. Fecal microbiota transplantation is superior to fidaxomicin for treatment of recurrent clostridium difficile infection[J]. Gastroenterology, 2019,156(5):1324-1332.e3. DOI: 10.1053/j.gastro.2018.12.019. [20] He Z, Cui BT, Zhang T, et al.Fecal microbiota transplantation cured epilepsy in a case with Crohn's disease: the first report[J]. World J Gastroenterol, 2017,23(19):3565-3568. DOI: 10.3748/wjg.v23.i19.3565. [21] Kim MS, Kim Y, Choi H, et al.Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer's disease animal model[J]. Gut, 2020,69(2):283-294. DOI: 10.1136/gutjnl-2018-317431. [22] Sampson TR, Debelius JW, Thron T, et al.Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease[J]. Cell, 2016,167(6):1469-1480. DOI: 10.1016/j.cell.2016.11.018. [23] Kang DW, Adams JB, Gregory AC, et al.Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study[J]. Microbiome, 2017,5(1):10. DOI: 10.1186/s40168-016-0225-7. [24] Kundu P, Lee HU, Garcia-Perez I, et al. Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice[J]. Sci Transl Med, 2019,11(518):eaau4760. DOI: 10.1126/scitranslmed.aau4760. [25] Bárcena C, Valdés-Mas R, Mayoral P, et al.Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice[J]. Nat Med, 2019,25(8):1234-1242. DOI: 10.1038/s41591-019-0504-5. [26] Fitzgibbon G, Mills K.The microbiota and immune-mediated diseases: opportunities for therapeutic intervention[J]. Eur J Immunol, 2020,50(3):326-337. DOI: 10.1002/eji.201948322. [27] Nie X, Li L, Yi M, et al.The intestinal microbiota plays as a protective regulator against radiation pneumonitis[J]. Radiat Res, 2020,194(1):52-60. DOI: 10.1667/RR15579.1. [28] Chen Z, Wang B, Dong J, et al.Gut microbiota-derived l-histidine/imidazole propionate axis fights against the radiation-induced cardiopulmonary injury[J]. Int J Mol Sci, 2021,22(21):11436. DOI: 10.3390/ijms222111436. [29] Baxter M, Colville A.Adverse events in faecal microbiota transplant: a review of the literature[J]. J Hosp Infect, 2016,92(2):117-127. DOI: 10.1016/j.jhin.2015.10.024. [30] Dailey FE, Turse EP, Daglilar E, et al.The dirty aspects of fecal microbiota transplantation: a review of its adverse effects and complications[J]. Curr Opin Pharmacol, 2019,49:29-33. DOI: 10.1016/j.coph.2019.04.008.
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