Differentiation of levels of consciousness in patients with prolonged disorders of consciousness (DOC) remains a major challenge, especially differentiation between vegetative state (VS) and minimally conscious state (MCS). This study was to investigate the alterations of gut microbiota in patients with DOC and to identify potential microbiome biomarkers that can differentiate levels of consciousness. In this study, we collected fecal samples from patients with prolonged DOC, including 19 patients in MCS and 14 patients in VS; 16S-rRNA sequencing was used to investigate the gut microbiome of patients. Gut microbiota diversity, composition, and discriminant bacterial taxa were analyzed to identify potential biomarkers for differentiating levels of consciousness. We found that diversity and composition of gut microbiome were significantly altered in patients with DOC, and decreased alpha diversity was associated with lower levels of consciousness. Specific bacterial taxa including Firmicutes, Escherichia_shigella, Raecalibacterium, Lachnospiraceae, and Ruminococcaceae_UCG_013 were more abundant in patients in MCS, whereas Clostridiales were more abundant in patients in VS. In conclusion, the study results demonstrated that patients with DOC exhibited distinct diversity and composition of gut microbiota. And there was a decreasing trend of alpha diversity of gut microbiota from patients in MCS to patients in VS, which indicates that lower alpha diversity was associated with more severe level of unconsciousness. Specific bacterial taxa may be potential biomarkers to differentiate MCS and VS.
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References
1.
FeiginVL, NicholsE, AlamT, et al.Global, regional, and national burden of neurological disorders, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. The Lancet Neurology, 2019; 18(5):459–480; doi: 10.1016/s1474-4422(18)30499-x
2.
GiacinoJT, FinsJJ, LaureysS, et al.Disorders of consciousness after acquired brain injury: The state of the science. Nat Rev Neurol, 2014; 10(2):99–114; doi: 10.1038/nrneurol.2013.279
3.
LaureysS, CelesiaGG, CohadonF, et al.; European Task Force on Disorders of Consciousness. Unresponsive wakefulness syndrome: A new name for the vegetative state or apallic syndrome. BMC Med, 2010; 8:68; doi: 10.1186/1741-7015-8-68
4.
GiacinoJT, AshwalS, ChildsN, et al.The minimally conscious state: Definition and diagnostic criteria. Neurology, 2002; 58(3):349–353; doi: 10.1212/wnl.58.3.349
5.
GiacinoJT, KalmarK, WhyteJ. The JFK Coma Recovery Scale-Revised: Measurement characteristics and diagnostic utility. Arch Phys Med Rehabil, 2004; 85(12):2020–2029; doi: 10.1016/j.apmr.2004.02.033
6.
GiacinoJT, SchnakersC, Rodriguez-MorenoD, et al.Behavioral assessment in patients with disorders of consciousness: Gold standard or fool’s gold? Prog Brain Res, 2009; 177:33–48.
7.
LuppiAI, CraigMM, PappasI, et al.Consciousness-specific dynamic interactions of brain integration and functional diversity. Nat Commun, 2019; 10(1):4616; doi: 10.1038/s41467-019-12658-9
8.
SniderSB, EdlowBL. MRI in disorders of consciousness. Curr Opin Neurol, 2020; 33(6):676–683; doi: 10.1097/WCO.0000000000000873
9.
ThibautA, PandaR, AnnenJ, et al.Preservation of brain activity in unresponsive patients identifies MCS star. Ann Neurol, 2021; 90(1):89–100; doi: 10.1002/ana.26095
10.
WuX, ZhangJ, CuiZ, et al.White matter deficits underlying the impaired consciousness level in patients with disorders of consciousness. Neurosci Bull, 2018; 34(4):668–678; doi: 10.1007/s12264-018-0253-3
11.
BodartO, AmicoE, GomezF, et al.Global structural integrity and effective connectivity in patients with disorders of consciousness. Brain Stimul, 2018; 11(2):358–365; doi: 10.1016/j.brs.2017.11.006
12.
JangSH, KwonYH. Neuroimaging characterization of recovery of impaired consciousness in patients with disorders of consciousness. Neural Regen Res, 2019; 14(7):1202–1207; doi: 10.4103/1673-5374.251299
13.
EngemannDA, RaimondoF, KingJR, et al.Robust EEG-based cross-site and cross-protocol classification of states of consciousness. Brain, 2018; 141(11):3179–3192; doi: 10.1093/brain/awy251
14.
LutkenhoffES, NigriA, Rossi SebastianoD, et al.EEG Power spectra and subcortical pathology in chronic disorders of consciousness. Psychol Med, 2022; 52(8):1491–1500; doi: 10.1017/S003329172000330X
15.
MaQ, XingC, LongW, et al.Impact of microbiota on central nervous system and neurological diseases: The gut-brain axis. J Neuroinflammation, 2019; 16(1):53; doi: 10.1186/s12974-019-1434-3
16.
CollinsSM, SuretteM, BercikP. The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol, 2012; 10(11):735–742; doi: 10.1038/nrmicro2876
17.
MoloneyRD, JohnsonAC, O’MahonySM, et al.Stress and the microbiota-gut-brain axis in visceral pain: Relevance to irritable bowel syndrome. CNS Neurosci Ther, 2016; 22(2):102–117; doi: 10.1111/cns.12490
18.
FungTC, OlsonCA, HsiaoEY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci, 2017; 20(2):145–155; doi: 10.1038/nn.4476
19.
SharonG, SampsonTR, GeschwindDH, et al.The central nervous system and the gut microbiome. Cell, 2016; 167(4):915–932; doi: 10.1016/j.cell.2016.10.027
20.
LinCH, ChenCC, ChiangHL, et al.Altered gut microbiota and inflammatory cytokine responses in patients with Parkinson’s disease. J Neuroinflammation, 2019; 16(1):129; doi: 10.1186/s12974-019-1528-y
21.
WangQ, DavisPB, QiX, et al.Gut-microbiota-microglia-brain interactions in Alzheimer’s disease: Knowledge-based, multi-dimensional characterization. Alzheimers Res Ther, 2021; 13(1):177; doi: 10.1186/s13195-021-00917-1
22.
OftHC, SimonDW, SunD. New insights into metabolism dysregulation after TBI. J Neuroinflammation, 2024; 21(1):184; doi: 10.1186/s12974-024-03177-6
23.
UrbanRJ, PylesRB, StewartCJ, et al.Altered fecal microbiome years after traumatic brain injury. J Neurotrauma, 2020; 37(8):1037–1051; doi: 10.1089/neu.2019.6688
24.
WinekK, DirnaglU, MeiselA. The gut microbiome as therapeutic target in central nervous system diseases: Implications for stroke. Neurotherapeutics, 2016; 13(4):762–774; doi: 10.1007/s13311-016-0475-x
25.
HouldenA, GoldrickM, BroughD, et al.Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production. Brain Behav Immun, 2016; 57:10–20; doi: 10.1016/j.bbi.2016.04.003
26.
YuX, ZhouG, ShaoB, et al.Gut microbiota dysbiosis induced by intracerebral hemorrhage aggravates neuroinflammation in mice. Front Microbiol, 2021; 12:647304; doi: 10.3389/fmicb.2021.647304
27.
YouW, ZhuY, WeiA, et al.Traumatic brain injury induces gastrointestinal dysfunction and dysbiosis of gut microbiota accompanied by alterations of bile acid profile. J Neurotrauma, 2022; 39(1–2):227–237; doi: 10.1089/neu.2020.7526
28.
YuJ, ChengQ, HeF, et al.Altered intestinal microbiomes and lipid metabolism in patients with prolonged disorders of consciousness. Front Immunol, 2022; 13:781148; doi: 10.3389/fimmu.2022.781148
29.
FingelkurtsAA, FingelkurtsAA, BagnatoS, et al.Long-term (six years) clinical outcome discrimination of patients in the vegetative state could be achieved based on the operational architectonics EEG analysis: A pilot feasibility study. Open Neuroimag J, 2016; 10:69–79; doi: 10.2174/1874440001610010069
30.
CavinatoM, FreoU, OriC, et al.Post-acute P300 predicts recovery of consciousness from traumatic vegetative state. Brain Inj, 2009; 23(12):973–980; doi: 10.3109/02699050903373493
31.
MartensG, DeltombeT, Foidart-DessalleM, et al.Clinical and electrophysiological investigation of spastic muscle over activity in patients with disorders of consciousness following severe brain injury. Clin Neurophysiol, 2019; 130(2):207–213; doi: 10.1016/j.clinph.2018.10.021
32.
OdamakiT, KatoK, SugaharaH, et al.Age-related changes in gut microbiota composition from newborn to centenarian: A cross-sectional study. BMC Microbiol, 2016; 16:90; doi: 10.1186/s12866-016-0708-5
33.
AndrewsK, MurphyL, MundayR, et al.Misdiagnosis of the vegetative state retrospective study in a rehabilitation unit. BMJ, 1996; 313(7048):13–16.
34.
SchnakersC, VanhaudenhuyseA, GiacinoJ, et al.Diagnostic accuracy of the vegetative and minimally conscious state: Clinical consensus versus standardized neurobehavioral assessment. BMC Neurol, 2009; 9:35; doi: 10.1186/1471-2377-9-35
35.
DemertziA, AntonopoulosG, HeineL, et al.Intrinsic functional connectivity differentiates minimally conscious from unresponsive patients. Brain, 2015; 138(Pt 9):2619–2631; doi: 10.1093/brain/awv169
36.
ChennuS, AnnenJ, WannezS, et al.Brain networks predict metabolism, diagnosis and prognosis at the bedside in disorders of consciousness. Brain, 2017; 140(8):2120–2132; doi: 10.1093/brain/awx163
37.
StenderJ, GosseriesO, BrunoM-A, et al.Diagnostic precision of PET imaging and functional MRI in disorders of consciousness: A clinical validation study. Lancet, 2014; 384(9942):514–522; doi: 10.1016/s0140-6736(14)60042-8
38.
CasarottoS, ComanducciA, RosanovaM, et al.Stratification of unresponsive patients by an independently validated index of brain complexity. Ann Neurol, 2016; 80(5):718–729; doi: 10.1002/ana.24779
39.
CasaliAG GO, RosanovaM, BolyM, et al.A theoretically based index of consciousness independent of sensory processing and behavior. Sci Transl Med, 2013; 5(198):198ra105.
40.
LucidiL, PettorrusoM, VellanteF, et al.Gut microbiota and bipolar disorder: An overview on a novel biomarker for diagnosis and treatment. Int J Mol Sci, 2021; 22(7):3723; doi: 10.3390/ijms22073723
41.
LiB, HeY, MaJ, et al.Mild cognitive impairment has similar alterations as Alzheimer’s disease in gut microbiota. Alzheimers Dement, 2019; 15(10):1357–1366; doi: 10.1016/j.jalz.2019.07.002
42.
NicholsonSE, WattsLT, BurmeisterDM, et al.Moderate traumatic brain injury alters the gastrointestinal microbiome in a time-dependent manner. Shock, 2019; 52(2):240–248; doi: 10.1097/SHK.0000000000001211
43.
DuD, TangW, ZhouC, et al.Fecal microbiota transplantation is a promising method to restore gut microbiota dysbiosis and relieve neurological deficits after traumatic brain injury. Oxid Med Cell Longev, 2021; 2021:5816837; doi: 10.1155/2021/5816837
44.
TanM, ZhuJ-C, DuJ, et al.Effects of probiotics on serum levels of Th1Th2 cytokine and clinical outcomes in severe traumatic brain-injured patients a prospective randomized pilot study. Crit Care, 2011; 15(6):R290.
45.
MaY, LiuT, FuJ, et al.Lactobacillus acidophilus exerts neuroprotective effects in mice with traumatic brain injury. J Nutr, 2019; 149(9):1543–1552; doi: 10.1093/jn/nxz105
46.
FuX, ZengH, ZhaoJ, et al.Inhibition of dectin-1 ameliorates neuroinflammation by regulating microglia/macrophage phenotype after intracerebral hemorrhage in mice. Transl Stroke Res, 2021; 12(6):1018–1034; doi: 10.1007/s12975-021-00889-2
47.
SchirmerM, GarnerA, VlamakisH, et al.Microbial genes and pathways in inflammatory bowel disease. Nat Rev Microbiol, 2019; 17(8):497–511; doi: 10.1038/s41579-019-0213-6
48.
NishioJ, HondaK. Immunoregulation by the gut microbiota. Cell Mol Life Sci, 2012; 69(21):3635–3650; doi: 10.1007/s00018-012-0993-6
49.
BenakisC, BreaD, CaballeroS, et al.Commensal microbiota affects ischemic stroke outcome by regulating intestinal gammadelta T cells. Nat Med, 2016; 22(5):516–523; doi: 10.1038/nm.4068
50.
ErnyD, Hrabě de AngelisAL, JaitinD, et al.Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci, 2015; 18(7):965–977; doi: 10.1038/nn.4030
51.
BranisteVA-AM, KowalC, AnuarF, et al.The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med, 2014; 6(263):263ra158.
52.
NhoK, Kueider-PaisleyA, MahmoudianDehkordiS, et al.; Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium. Altered bile acid profile in mild cognitive impairment and Alzheimer’s disease: Relationship to neuroimaging and CSF biomarkers. Alzheimers Dement, 2019; 15(2):232–244; doi: 10.1016/j.jalz.2018.08.012
53.
BhargavaP, SmithMD, MischeL, et al.Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation. J Clin Invest, 2020; 130(7):3467–3482; doi: 10.1172/JCI129401
54.
ZhuY, ChenZ, YouW, et al.A retrospective clinical analysis of the serum bile acid alteration caused by traumatic brain injury. Front Neurol, 2021; 12:624378; doi: 10.3389/fneur.2021.624378
55.
RidlonJM, KangDJ, HylemonPB, et al.Bile acids and the gut microbiome. Curr Opin Gastroenterol, 2014; 30(3):332–338; doi: 10.1097/MOG.0000000000000057
56.
WahlstromA, SayinSI, MarschallHU, et al.Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab, 2016; 24(1):41–50; doi: 10.1016/j.cmet.2016.05.005
