Appropriate exercise level attenuates gut dysbiosis and valeric acid increase to improve neuroplasticity and cognitive function after surgery in mice
Zhongmeng Lai, Weiran Shan, Jun Li, Jia Min, Xianzhang Zeng, Zhiyi Zuo, Zhongmeng Lai, Weiran Shan, Jun Li, Jia Min, Xianzhang Zeng, Zhiyi Zuo
Abstract
Postoperative cognitive dysfunction (POCD) affects the outcome of millions of patients each year. Aging is a risk factor for POCD. Here, we showed that surgery induced learning and memory dysfunction in adult mice. Transplantation of feces from surgery mice but not from control mice led to learning and memory impairment in non-surgery mice. Low intensity exercise improved learning and memory in surgery mice. Exercise attenuated surgery-induced neuroinflammation and decrease of gut microbiota diversity. These exercise effects were present in non-exercise mice receiving feces from exercise mice. Exercise reduced valeric acid, a gut microbiota product, in the blood. Valeric acid worsened neuroinflammation, learning and memory in exercise mice with surgery. The downstream effects of exercise included attenuating growth factor decrease, maintaining astrocytes in the A2 phenotypical form possibly via decreasing C3 signaling and improving neuroplasticity. Similar to these results from adult mice, exercise attenuated learning and memory impairment in old mice with surgery. Old mice receiving feces from old exercise mice had better learning and memory than those receiving control old mouse feces. Surgery increased blood valeric acid. Valeric acid blocked exercise effects on learning and memory in old surgery mice. Exercise stabilized gut microbiota, reduced neuroinflammation, attenuated growth factor decrease and preserved neuroplasticity in old mice with surgery. These results provide direct evidence that gut microbiota alteration contributes to POCD development. Valeric acid is a mediator for this effect and a potential target for brain health. Low intensity exercise stabilizes gut microbiota in the presence of insult, such as surgery.
Conflict of interest statement
The authors declare no competing interests.
© 2021. The Author(s).
Figures
References
- Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International study of post-operative cognitive dysfunction. Lancet. 1998;351:857–61.
- Monk TG, Weldon BC, Garvan CW, Dede DE, van der Aa MT, Heilman KM, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology. 2008;108:18–30.
- Newman MF, Kirchner JL, Phillips-Bute B, Gaver V, Grocott H, Jones RH, et al. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N. Engl J Med. 2001;344:395–402.
- Hall M, Schwartzman A, Zhang J, Liu X. Ambulatory surgery data from hospitals and ambulatory surgery centers: 2010. National Health Statistics Report 2017.
- Li Y, Chen D, Wang H, Wang Z, Song F, Li H, et al. Intravenous versus volatile anesthetic effects on postoperative cognition in elderly patients undergoing laparoscopic abdominal surgery. Anesthesiology. 2021;134:381–94.
- Zhang J, Tan H, Jiang W, Zuo Z. Amantadine alleviates postoperative cognitive dysfunction possibly by increasing glial cell line-derived neurotrophic factor in rats. Anesthesiology. 2014;121:773–85.
- Lai Z, Min J, Li J, Shan W, Yu W, Zuo Z. Surgery trauma severity but not anesthesia length contributes to postoperative cognitive dysfunction in mice. J Alzheimers Dis. 2021;80:245–57.
- Zhang J, Tan H, Jiang W, Zuo Z. The choice of general anesthetics may not affect neuroinflammation and impairment of learning and memory after surgery in elderly rats. J Neuroimmune Pharm. 2015;10:179–89.
- Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M. Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci USA. 2010;107:20518–22.
- Blander JM, Longman RS, Iliev ID, Sonnenberg GF, Artis D. Regulation of inflammation by microbiota interactions with the host. Nat Immunol. 2017;18:851–60.
- Liang P, Shan W, Zuo Z. Perioperative use of cefazolin ameliorates postoperative cognitive dysfunction but induces gut inflammation in mice. J Neuroinflammation. 2018;15:235.
- Zhan G, Hua D, Huang N, Wang Y, Li S, Zhou Z, et al. Anesthesia and surgery induce cognitive dysfunction in elderly male mice: the role of gut microbiota. Aging (Albany NY) 2019;11:1778–90.
- Jiang XL, Gu XY, Zhou XX, Chen XM, Zhang X, Yang YT, et al. Intestinal dysbacteriosis mediates the reference memory deficit induced by anaesthesia/surgery in aged mice. Brain Behav Immun. 2019;80:605–15.
- Fan D, Li J, Zheng B, Hua L, Zuo Z. Enriched environment attenuates surgery-induced impairment of learning, memory, and neurogenesis possibly by preserving BDNF expression. Mol Neurobiol. 2016;53:344–54.
- Kawano T, Eguchi S, Iwata H, Tamura T, Kumagai N, Yokoyama M. Impact of preoperative environmental enrichment on prevention of development of cognitive impairment following abdominal surgery in a rat model. Anesthesiology. 2015;123:160–70.
- Liu Y, Wang Y, Ni Y, Cheung CKY, Lam KSL, Wang Y, et al. Gut microbiome fermentation determines the efficacy of exercise for diabetes prevention. Cell Metab. 2020;31:77–91 e5.
- Pyke W, Ifram F, Coventry L, Sung Y, Champion I, Javadi AH. The effects of different protocols of physical exercise and rest on long-term memory. Neurobiol Learn Mem. 2020;167:107128.
- Hayashi K, Oshima H, Shimizu M, Kobayashi K, Matsui S, Nishida Y, et al. Preoperative 6-minute walk distance is associated with postoperative cognitive dysfunction. Ann Thorac Surg. 2018;106:505–12.
- Feng X, Uchida Y, Koch L, Britton S, Hu J, Lutrin D, et al. Exercise prevents enhanced postoperative neuroinflammation and cognitive decline and rectifies the gut microbiome in a rat model of metabolic syndrome. Front Immunol. 2017;8:1768.
- Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 2012;13:93–110.
- Pandit RJ, Hinsu AT, Patel NV, Koringa PG, Jakhesara SJ, Thakkar JR, et al. Microbial diversity and community composition of caecal microbiota in commercial and indigenous Indian chickens determined using 16s rDNA amplicon sequencing. Microbiome. 2018;6:115.
- Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature. 2009;459:55–60.
- Litvinchuk A, Wan YW, Swartzlander DB, Chen F, Cole A, Propson NE, et al. Complement C3aR inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and alzheimer’s disease. Neuron. 2018;100:1337–53 e5.
- Barnum SR. Inhibition of complement as a therapeutic approach in inflammatory central nervous system (CNS) disease. Mol Med. 1999;5:569–82.
- Hutamekalin P, Takeda K, Tani M, Tsuga Y, Ogawa N, Mizutani N, et al. Effect of the C3a-receptor antagonist SB 290157 on anti-OVA polyclonal antibody-induced arthritis. J Pharm Sci. 2010;112:56–63.
- Gui L, Lei X, Zuo Z. Decrease of glial cell-derived neurotrophic factor contributes to anesthesia- and surgery-induced learning and memory dysfunction in neonatal rats. J Mol Med (Berl) 2017;95:369–79.
- Silva YP, Bernardi A, Frozza RL. The role of short-chain fatty acids from gut microbiota in gut-brain communication. Front Endocrinol (Lausanne) 2020;11:25.
- Dalile B, Van Oudenhove L, Vervliet B, Verbeke K. The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol. 2019;16:461–78.
- Sadler R, Cramer JV, Heindl S, Kostidis S, Betz D, Zuurbier KR, et al. Short-chain fatty acids improve poststroke recovery via immunological mechanisms. J Neurosci. 2020;40:1162–73.
- Magrone T, Jirillo E. The interaction between gut microbiota and age-related changes in immune function and inflammation. Immun Ageing. 2013;10:31.
- Parada Venegas D, De la Fuente MK, Landskron G, Gonzalez MJ, Quera R, Dijkstra G, et al. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol. 2019;10:277.
- Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L, et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun. 2014;5:3611.
- Spychala MS, Venna VR, Jandzinski M, Doran SJ, Durgan DJ, Ganesh BP, et al. Age-related changes in the gut microbiota influence systemic inflammation and stroke outcome. Ann Neurol. 2018;84:23–36.
- Biagi E, Nylund L, Candela M, Ostan R, Bucci L, Pini E, et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS ONE. 2010;5:e10667.
- Ji MH, Qiu LL, Mao MJ, Zhang L, Yang JJ. Hippocampal complement C3 might contribute to cognitive impairment induced by anesthesia and surgery. Neuroreport. 2020;31:507–14.
- Benakis C, Brea D, Caballero S, Faraco G, Moore J, Murphy M, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal gammadelta T cells. Nat Med. 2016;22:516–23.
- Walter J, Armet AM, Finlay BB, Shanahan F. Establishing or exaggerating causality for the gut microbiome: lessons from human microbiota-associated rodents. Cell. 2020;180:221–32.
- Klein C, Jonas W, Iggena D, Empl L, Rivalan M, Wiedmer P, et al. Exercise prevents high-fat diet-induced impairment of flexible memory expression in the water maze and modulates adult hippocampal neurogenesis in mice. Neurobiol Learn Mem. 2016;131:26–35.
- Prado Lima MG, Schimidt HL, Garcia A, Dare LR, Carpes FP, Izquierdo I, et al. Environmental enrichment and exercise are better than social enrichment to reduce memory deficits in amyloid beta neurotoxicity. Proc Natl Acad Sci USA. 2018;115:E2403–E09.
- Butler CW, Keiser AA, Kwapis JL, Berchtold NC, Wall VL, Wood MA, et al. Exercise opens a temporal window for enhanced cognitive improvement from subsequent physical activity. Learn Mem. 2019;26:485–92.
- Kitahara M, Inoue T, Mani H, Takamatsu Y, Ikegami R, Tohyama H, et al. Exercise and pharmacological inhibition of histone deacetylase improves cognitive function accompanied by an increase of gene expressions crucial for neuronal plasticity in the hippocampus. Neurosci Lett. 2021;749:135749.
- Singhal G, Morgan J, Jawahar MC, Corrigan F, Jaehne EJ, Toben C, et al. Short-term environmental enrichment, and not physical exercise, alleviate cognitive decline and anxiety from middle age onwards without affecting hippocampal gene expression. Cogn Affect Behav Neurosci. 2019;19:1143–69.
- Ramires Lima K, de Souza da Rosa AC, Severo Picua S, Souza ESS, Marks Soares N, Billig Mello-Carpes P. One single physical exercise session improves memory persistence by hippocampal activation of D1 dopamine receptors and PKA signaling in rats. Brain Res. 2021;1762:147439.
- Rajizadeh MA, Esmaeilpour K, Haghparast E, Ebrahimi MN, Sheibani V. Voluntary exercise modulates learning & memory and synaptic plasticity impairments in sleep deprived female rats. Brain Res. 2020;1729:146598.
- Cechella JL, Leite MR, Rosario AR, Sampaio TB, Zeni G. Diphenyl diselenide-supplemented diet and swimming exercise enhance novel object recognition memory in old rats. Age (Dordr) 2014;36:9666.
- Amirazodi F, Mehrabi A, Amirazodi M, Parsania S, Rajizadeh MA, Esmaeilpour K. The combination effects of resveratrol and swimming HIIT exercise on novel object recognition and open-field tasks in aged rats. Exp Aging Res. 2020;46:336–58.
- Gibb AA, McNally LA, Riggs DW, Conklin DJ, Bhatnagar A, Hill BG. Corrigendum: FVB/NJ mice are a useful model for examining cardiac adaptations to treadmill exercise. Front Physiol. 2017;8:800.
- Koch LG, Britton SL. Divergent selection for aerobic capacity in rats as a model for complex disease. Integr Comp Biol. 2005;45:405–15.
- Shan W, Li J, Xu W, Li H, Zuo Z. Critical role of UQCRC1 in embryo survival, brain ischemic tolerance and normal cognition in mice. Cell Mol Life Sci. 2019;76:1381–96.
- Leger M, Quiedeville A, Bouet V, Haelewyn B, Boulouard M, Schumann-Bard P, et al. Object recognition test in mice. Nat Protoc. 2013;8:2531–7.
- Torii T, Kanemitsu K, Hagiwara A. Simultaneous assay of fecal short-chain fatty and bile acids and ratio of total bile acids to butyrate in colon cancer. Chromatography. 2019;40:49–57.
- Lee J, d’Aigle J, Atadja L, Quaicoe V, Honarpisheh P, Ganesh BP, et al. Gut microbiota-derived short-chain fatty acids promote poststroke recovery in aged mice. Circulation Res. 2020;127:453–65.
- Feng C, Zhang Y, Yin J, Li J, Abounader R, Zuo Z. Regulatory factor X1 is a new tumor suppressive transcription factor that acts via direct downregulation of CD44 in glioblastoma. Neuro-Oncol. 2014;16:1078–85.
- Zheng B, Lai R, Li J, Zuo Z. Critical role of P2X7 receptors in the neuroinflammation and cognitive dysfunction after surgery. Brain Behav Immun. 2017;61:365–74.
- Sholl DA. Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat. 1953;87:387–406.
- Ferreira TA, Blackman AV, Oyrer J, Jayabal S, Chung AJ, Watt AJ, et al. Neuronal morphometry directly from bitmap images. Nat Methods. 2014;11:982–4.
Source: PubMed