Alterations in gut microbiota and metabolites contribute to postoperative sleep disturbances

Abstract

Background: The composition of the intestinal flora and the resulting metabolites affect patients' sleep after surgery.

Methods: We intended to elucidate the mechanisms by which disordered intestinal flora modulate the pathophysiology of postoperative sleep disturbances in hosts. In this study, we explored the impacts of anesthesia, surgery, and postoperative sleep duration on the fecal microbiota and metabolites of individuals classified postprocedurally as poor sleepers (PS) and good sleepers (GS), as diagnosed by the bispectral index. We also performed fecal microbiota transplantation in pseudo-germ-free (PGF) rats and applied Western blotting, immunohistochemistry, and gut permeability analyses to identify the potential mechanism of its effect.

Results: Research finding shows the PS group had significantly higher postoperative stool levels of the metabolites tryptophan and kynurenine than the GS group. PGF rats that received gut microbiota from PSs exhibited less rapid eye movement (REM) sleep than those that received GS microbiota (GS-PGF: 11.4% ± 1.6%, PS-PGF: 4.8% ± 2.0%, p < 0.001). Measurement of 5-hydroxytryptophan (5-HTP) levels in the stool, serum, and prefrontal cortex (PFC) indicated that altered 5-HTP levels, including reduced levels in the PFC, caused sleep loss in PGF rats transplanted with PS gut flora. Through the brain–gut axis, the inactivity of tryptophan hydroxylase 1 (TPH1) and TPH2 in the colon and PFC, respectively, caused a loss of REM sleep in PGF rats and decreased the 5-HTP level in the PFC.

Conclusions: These findings indicate that postoperative gut dysbiosis and defective 5-HTP metabolism may cause postoperative sleep disturbances. Clinicians and sleep researchers may gain new insights from this study.

Keywords

5-hydroxytryptophan / fecal microbiota transplantation / gut microbiota / metabolites / sleep

References

[1] Lin D, Huang X, Sun Y, Wei C, Wu A. Perioperative sleep disorder: a review. Front Med. 2021; 8: 640416.

[2] Wang X, Hua D, Tang X, et al. The role of perioperative sleep disturbance in postoperative neurocognitive disorders. Nat Sci Sleep. 2021; 13: 1395-1410.

[3] Hou J, Shen Q, Wan X, Zhao B, Wu Y, Xia Z. REM sleep deprivation-induced circadian clock gene abnormalities participate in hippocampal-dependent memory impairment by enhancing inflammation in rats undergoing sevoflurane inhalation. Behav Brain Res. 2019; 364: 167-176.

[4] Ni P, Dong H, Zhou Q, et al. Preoperative sleep disturbance exaggerates surgery-induced neuroinflammation and neuronal damage in aged mice. Mediat Inflamm. 2019; 2019: 8301725.

[5] Vacas S, Degos V, Maze M. Fragmented sleep enhances postoperative neuroinflammation but not cognitive dysfunction. Anesth Analg. 2017; 124: 270-276.

[6] Silva V, Palacios-Muñoz A, Okray Z, et al. The impact of the gut microbiome on memory and sleep in drosophila. J Exp Biol. 2021; 224. 224-234.

[7] Wang Z, Chen WH, Li SX, et al. Gut microbiota modulates the inflammatory response and cognitive impairment induced by sleep deprivation. Mol Psychiatry. 2021; 26: 6277-6292.

[8] Zhang Y, Xie B, Chen X, Zhang J, Yuan S. A key role of gut microbiota-vagus nerve/spleen axis in sleep deprivation-mediated aggravation of systemic inflammation after LPS administration. Life Sci. 2021; 265: 118736.

[9] El Aidy S, Bolsius YG, Raven F, Havekes R. A brief period of sleep deprivation leads to subtle changes in mouse gut microbiota. J Sleep Res. 2020; 29: e12920.

[10] Maki KA, Burke LA, Calik MW, et al. Sleep fragmentation increases blood pressure and is associated with alterations in the gut microbiome and fecal metabolome in rats. Physiol Genomics. 2020; 52: 280-292.

[11] Triplett J, Ellis D, Braddock A, et al. Temporal and region-specific effects of sleep fragmentation on gut microbiota and intestinal morphology in Sprague Dawley rats. Gut Microbes. 2020; 11: 706-720.

[12] Yang X, Wu Y, Xu X, et al. Impact of repeated infantile exposure to surgery and anesthesia on gut microbiota and anxiety behaviors at age 6-9. J Personal Med. 2023; 13: 823.

[13] Bi J, Xu Y, Li S, et al. Contribution of preoperative gut microbiota in postoperative neurocognitive dysfunction in elderly patients undergoing orthopedic surgery. Front Aging Neurosci. 2023; 17: 1108205.

[14] Sutanto C, Xia X, Heng C, et al. The impact of 5-hydroxytryptophan supplementation on sleep quality and gut microbiota composition in older adults: a randomized controlled trial. Clin Nutr. 2024; 43: 593-602.

[15] Yildizeli B, Ozyurtkan MO, Batirel HF, Kuşcu K, Bekiroğlu N, Yüksel M. Factors associated with postoperative delirium after thoracic surgery. Ann Thorac Surg. 2005; 79: 1004-1009.

[16] Halle IH, Westgaard TK, Wahba A, Oksholm T, Rustøen T, Gjeilo KH. Trajectory of sleep disturbances in patients undergoing lung cancer surgery: a prospective study. Interact Cardiovasc Thorac Surg. 2017; 25: 285-291.

[17] Lian X, Zhu Q, Sun L, Cheng Y. Effect of anesthesia/surgery on gut microbiota and fecal metabolites and their relationship with cognitive dysfunction. Front Syst Neurosci. 2021; 15: 655695.

[18] Liufu N, Liu L, Shen S, et al. Anesthesia and surgery induce age-dependent changes in behaviors and microbiota. Aging. 2020; 12: 1965-1986.

[19] Xu X, Wang K, Cao X, et al. Gut microbial metabolite Short-chain Fatt acids partially reverse surgery and anesthesia-induced behavior deficits in C57BL/6J mice. Front Neurosci. 2021; 15: 664641.

[20] Zhan G, Hua D, Huang N, et al. Anesthesia and surgery induce cognitive dysfunction in elderly male mice: the role of gut microbiota. Aging. 2019; 11: 1778-1790.

[21] Carozzi C, Rampil IJ. Bispectral index for sleep screening: it is time to move on. Minerva Anestesiol. 2011; 77: 485-487.

[22] Dahaba AA, Xue JX, Xu GX, Liu QH, Metzler H. Bilateral Bispectral Index (BIS)-Vista as a measure of physiologic sleep in sleep-deprived anesthesiologists. Minerva Anestesiol. 2011; 77: 388-393.

[23] Nieuwenhuijs D, Coleman EL, Douglas NJ, Drummond GB, Dahan A. Bispectral index values and spectral edge frequency at different stages of physiologic sleep. Anesth Analg. 2002; 94: 125-129. table of contents.

[24] Sleigh JW, Andrzejowski J, Steyn-Ross A, Steyn-Ross M. The bispectral index: a measure of depth of sleep? Anesth Analg. 1999; 88: 659-661.

[25] Benissa MR, Khirani S, Hartley S, et al. Utility of the bispectral index for assessing natural physiological sleep stages in children and young adults. J Clin Monit Comput. 2016; 30: 957-963.

[26] Giménez S, Romero S, Alonso JF, et al. Monitoring sleep depth: analysis of bispectral index (BIS) based on polysomnographic recordings and sleep deprivation. J Clin Monit Comput. 2017; 31: 103-110.

[27] Tan WF, Guo B, Ma H, Li XQ, Fang B, Lv HW. Changes in postoperative night bispectral index of patients undergoing thoracic surgery with different types of anesthesia management: a randomized controlled trial. Clin Exp Pharmacol Physiol. 2016a; 43: 304-311.

[28] Tan WF, Miao EY, Jin F, Ma H, Lu HW. Changes in first postoperative night Bispectral index after daytime sedation induced by Dexmedetomidine or midazolam under regional anesthesia: a randomized controlled trial. Reg Anesth Pain Med. 2016b; 41: 380-386.

[29] Gheorghe CE, Martin JA, Manriquez FV, Dinan TG, Cryan JF, Clarke G. Focus on the essentials: tryptophan metabolism and the microbiome-gut-brain axis. Curr Opin Pharmacol. 2019; 48: 137-145.

[30] Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology. 2017; 112: 399-412.

[31] Zhu F, Guo R, Wang W, et al. Transplantation of microbiota from drug-free patients with schizophrenia causes schizophrenia-like abnormal behaviors and dysregulated kynurenine metabolism in mice. Mol Psychiatry. 2020; 25: 2905-2918.

[32] Deng Y, Zhou M, Wang J, et al. Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain. Gut Microbes. 2021; 13: 1-16.

[33] Cho HJ, Savitz J, Dantzer R, Teague TK, Drevets WC, Irwin MR. Sleep disturbance and kynurenine metabolism in depression. J Psychosom Res. 2017; 99: 1-7.

[34] Pocivavsek A, Baratta AM, Mong JA, Viechweg SS. Acute kynurenine challenge disrupts sleep-wake architecture and impairs contextual memory in adult rats. Sleep. 2017; 40. zsx141-153.

[35] Rentschler KM, Baratta AM, Ditty AL, et al. Prenatal kynurenine elevation elicits sex-dependent changes in sleep and arousal during adulthood: implications for psychotic disorders. Schizophr Bull. 2021; 47: 1320-1330.

[36] Hery F, Pujol JF, Lopez M, Macon J, Glowinski J. Increased synthesis and utilization of serotonin in the central nervous system of the rat during paradoxical sleep deprivation. Brain Res. 1970; 21: 391-403.

[37] Jouvet M. Biogenic amines and the states of sleep. Science (New York, NY). 1969; 163: 32-41.

[38] Python A, Steimer T, de Saint HZ, Mikolajewski R, Nicolaidis S. Extracellular serotonin variations during vigilance states in the preoptic area of rats: a microdialysis study. Brain Res. 2001; 910: 49-54.

[39] Krone LB, Yamagata T, Blanco-Duque C, et al. A role for the cortex in sleep-wake regulation. Nat Neurosci. 2021; 24: 1210-1215.

[40] Chang CH, Chen MC, Qiu MH, Lu J. Ventromedial prefrontal cortex regulates depressive-like behavior and rapid eye movement sleep in the rat. Neuropharmacology. 2014; 86: 125-132.

[41] Amini M, Saboory E, Derafshpour L, et al. The impact of sleep deprivation on sexual behaviors and FAAH expression in the prefrontal cortex of male rats. Neurosci Lett. 2020; 735: 135254.

[42] Brunet JF, McNeil J, Doucet É, Forest G. The association between REM sleep and decision-making: supporting evidence. Physiol Behav. 2020; 225: 113109.

[43] Han Y, Wen X, Rong F, et al. Effects of chronic REM sleep restriction on D1 receptor and related signal pathways in rat prefrontal cortex. Biomed Res Int. 2015; 2015: 978236.

[44] Schredl M, Dyck S, Kühnel A. Lucid dreaming and the feeling of being refreshed in the morning: a diary study. Clocks Sleep. 2020; 2: 54-60.

[45] Cervo L, Canetta A, Calcagno E, et al. Genotype-dependent activity of tryptophan hydroxylase-2 determines the response to citalopram in a mouse model of depression. J Neurosci. 2005; 25: 8165-8172.

[46] Clark JA, Flick RB, Pai LY, et al. Glucocorticoid modulation of tryptophan hydroxylase-2 protein in raphe nuclei and 5-hydroxytryptophan concentrations in frontal cortex of C57/Bl6 mice. Mol Psychiatry. 2008; 13: 498-506.

[47] Campos-Rodriguez F, Cordero-Guevara J, Asensio-Cruz MI, et al. Interleukin 6 as a marker of depression in women with sleep apnea. J Sleep Res. 2021; 30: e13035.

[48] Xing C, Zhou Y, Xu H, et al. Sleep disturbance induces depressive behaviors and neuroinflammation by altering the circadian oscillations of clock genes in rats. Neurosci Res. 2021; 171: 124-132.

[49] McEown K, Takata Y, Cherasse Y, Nagata N, Aritake K, Lazarus M. Chemogenetic inhibition of the medial prefrontal cortex reverses the effects of REM sleep loss on sucrose consumption. elife. 2016; 5.e20269.

[50] Ogawa Y, Miyoshi C, Obana N, et al. Gut microbiota depletion by chronic antibiotic treatment alters the sleep/wake architecture and sleep EEG power spectra in mice. Sci Rep. 2020; 10: 19554.

[51] Bhowmik SK, An JH, Lee SH, Jung BH. Alteration of bile acid metabolism in pseudo germ-free rats [corrected]. Arch Pharm Res. 2012; 35: 1969-1977.

[52] Gong S, Lan T, Zeng L, et al. Gut microbiota mediates diurnal variation of acetaminophen induced acute liver injury in mice. J Hepatol. 2018; 69: 51-59.

[53] Li H, Xiao J, Li X, et al. Low cerebral exposure cannot hinder the neuroprotective effects of Panax Notoginsenosides. Drug Metab Dispos. 2018; 46: 53-65.

[54] Caron AM, Stephenson R. Energy expenditure is affected by rate of accumulation of sleep deficit in rats. Sleep. 2010; 33: 1226-1235.

[55] Feng H, Wen SY, Qiao QC, et al. Orexin signaling modulates synchronized excitation in the sublaterodorsal tegmental nucleus to stabilize REM sleep. Nat Commun. 2020; 11: 3661.

RIGHTS & PERMISSIONS

2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.