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1、Contents lists available at ScienceDirectPsychoneuroendocrinologyjournal homepage: prausnitzii(ATCC 27766)has preventive and therapeuticeffects on chronic unpredictable mild stress-induced depression-like andanxiety-like behavior in ratsZikai Haoa,b,Wei Wanga,b,Rong Guoa,b,Hong Liua,b,c,d,aInstitute

2、 of Environmental Biology and Life Support Technology,School of Biological Science and Medical Engineering,Beihang University,Room 516,YiFu Building,37#XueYuan,HaidianDistrict,Beijing,100083,ChinabBeijing Advanced Innovation Centre for Biomedical Engineering,Beihang University,Room 516,YiFu Building

3、,37#XueYuan,Haidian District,Beijing,102402,ChinacState Key Laboratory of Virtual Reality Technology and Systems,School of Computer Science and Engineering,Beihang University,Room 516,YiFu Building,37#XueYuan,HaidianDistrict,Beijing,100083,ChinadInternational Joint Research Center of Aerospace Biote

4、chnology&Medical Engineering,Beihang University,Room 516,YiFu Building,37#XueYuan,HaidianDistrict,Beijing,100083,ChinaA R T I C L E I N F OKeywords:PsychobioticMicrobiota-gut-brain axisFaecalibacterium prausnitziiCUMSAnxietyDepressionA B S T R A C TThe realization that the microbiota-gut-brain axis

5、plays a critical role in health and disease,including neu-ropsychiatric disorders,is rapidly advancingAn abundance of preclinical studies have shown that psycho-biotics acting via the brain-gut-axis can affect brain development,function and behavior.Here we testedwhether potential psychobiotics Faec

6、alibacterium prausnitzii(ATCC 27766)has anxiolytic and antidepressant-likeeffects and reverse the impact of chronic unpredictable mild stress(CUMS)in rats.The experiment was dividedinto two phases,the first stage was CUMS procedure period and the second stage was convalescence period.SDmale rats wer

7、e administered Faecalibacterium prausnitzii for 4 weeks prior to testing during each period.Behavior,growth status,SCFAs produced,plasma cytokine,endocrinology and bone mineral density(BMD)wereassessed.Our findings indicate that the administration of F.prausnitzii had preventive and therapeutic effe

8、cts onCUMS-induced depression-like and anxiety-like behavior.In addition,F.prausnitzii administration could sig-nificantly prevent the reduction of the whole-body,femur and tibia BMD during the recovery phase.Moreover,the growth status of rats fed the F.prausnitzii was better than the rats by CUMS.A

9、nd F.prausnitzii administrationled to higher levels of SCFAs in the cecum and higher levels of cytokines interleukin-10(IL-10)in the plasma,prevented the effects on corticosterone,C-reaction protein and cytokines interleukin-6(IL-6)release induced byCUMS,changes that were associated with the effects

10、 seen on behavior.These results provide further evidencethat gut microflora play a role in anxiety and depression.Subject to the confirmation of these results,probioticsmight offer a useful novel therapeutic approach to neuropathological disorders and/or as adjunct therapies inpsychiatric disorders

11、and support the recent broadening of the definition of psychobiotic.Finally,this studysupports F.prausnitzii has significant potential as a psychobiotic.1.IntroductionThe intestine and the brain are intimately connected via the brain-gut axis,which involves bidirectional communication via neural,en-

12、docrine and immune pathways(Mayer et al.,2014;Steenbergen et al.,2015).In recent years,increasing evidence suggests that the micro-biota-gut-brain axis plays a key role in regulating brain functions,particularly emotional processing and behavior(Bharwani et al.,2016;Dinan and Cryan,2012;Rackers et a

13、l.,2018).An abundance ofpreclinical studies has shown that probiotics acting via the brain-gut-axis can affect brain development,function and behavior(Bharwaniet al.,2016).It has previously been shown that the prebiotic sia-lyllactose is able to diminish stress-induced alterations in colonic mu-cosa

14、-associated microbiota community structure,anxiety-like behavior,and immature neuron cell numbers irrespective of immune or endo-crine functionality in mice/rats(Savignac et al.,2013;Tarr et al.,2015).This has prompted a growing interest in the possibility of targeting thegut microbiota to beneficia

15、lly impact human brain function andhttps:/doi.org/10.1016/j.psyneuen.2019.02.025Received 25 November 2018;Received in revised form 23 February 2019;Accepted 25 February 2019Corresponding author at:Institute of Environmental Biology and Life Support Technology,School of Biological Science and Medical

16、 Engineering,BeihangUniversity,Room 516,YiFu Building,37#XueYuan,HaidianDistrict,Beijing,100083,China.E-mail address:LH(H.Liu).Psychoneuroendocrinology 104(2019)1321420306-4530/2019 Elsevier Ltd.All rights reserved.Tbehavior.Drug therapy in addition to some psychotherapy models mayhelp relieve anxie

17、ty,these may be associated with consuming certainfoods,for this reason,improving the quality of the diet can be helpimprove mood and feel comfortable.So,recent scientific evidence in-dicates that a diet with low nutritional value is associated with an in-creased risk of anxiety disorder,so maybe lin

18、ked to an increased risk ofdeveloping an anxiety disorder(Begaa and Messaoudi,2018;Messaoudiand Begaa,2018).Psychobiotics have been defined as bacteria that ingested in ade-quate amounts to produce a positive mental health benefit(Dinan et al.,2013).Considering the potential impact of putative psych

19、obiotics uponcentral nervous system processes,especially stress,mood,anxiety andcognition(Dinan et al.,2015),the prospect of targeting the gut mi-crobiota as a potential modifiable risk factor for stress-related disordersis appealing.Preclinical research has indicated that chronic probioticadministr

20、ation can reduce anxiety-like and depressivelike behavior,and can normalise associated physiological outputs such as corticos-terone and noradrenaline in plasma,brain-derived neurotrophic factor(BDNF)in the brain and immune function(Janik et al.,2016;Kellyet al.,2017;Rudzki et al.,2019).There is a g

21、rowing appreciation of theneed to translate this promising preclinical work to the clinic while atthe same time recognising the challenges inherent in this process(Kellyet al.,2016).The intestinal microbial balance may alter the regulationof inflammatory responses and in so doing may be involved in

22、themodulation of mood and behavior(Forsythe et al.,2012;Foster andMcVey Neufeld,2013).More recently,Faecalibacterium prausnitzii,based on a case study in a closed experimental human life supportsystem(Hao et al.,2018),had the highest abundance and showed asignificant positive correlation with mood.T

23、he moreover,a negativecorrelation was observed between Faecalibacterium and the severity ofdepressive symptoms,and the relative abundance of Faecalibacteriumwas significantly increased after patients responded to antidepressanttherapy(Jiang et al.,2015)Faecalibacterium is a genus of bacteria.Itssole

24、 known species,Faecalibacterium prausnitzii represents around 5%from the total fecal microbiota in healthy adults(Hold et al.,2003).Furthermore,the levels of F.prausnitzii have been found to be decreasedin patients suffering from intestinal and metabolic disorders such asinflammatory bowel diseases(

25、IBD),irritable bowel syndrome(IBS),colorectal cancer(CRC),obesity,celiac disease(Balamurugan et al.,2010;Furet et al.,2010;Rajilistojanovi et al.,2011)and depressivedisorder(SP et al.,2005).F.prausnitzii exhibits anti-inflammatory ef-fects on cellular and TNBS colitis models,partly due to secreted m

26、e-tabolites able to block NF-kappaB activation and IL-8 production.(Sokolet al.,2008).F.prausnitzii produces butyrate and other short-chain fattyacids through the fermentation of dietary fiber(Louis and Flint,2010).Butyrate along with other fermentation-derived SCFAs(e.g.acetate,propionate)and the s

27、tructurally related ketone bodies(e.g.acet-oacetate and d-hydroxybutyrate)show the interesting effects in var-ious diseases,including obesity,diabetes,inflammatory(bowel)dis-eases,and colorectal cancer as well as neurological disorders(Stillinget al.,2016b).Depression is associated with the presence

28、 of biomarkersof inflammation such as elevated interleukin(IL)-6,tumor necrosisfactor alpha,and the acute phase protein,C reactive protein(OBrienet al.,2004).Similar elevated biomarkers of inflammation have beenseen in anxiety states and are known to occur as a result of stress.Decreased bone minera

29、l density(BMD)has been reported in patientssuffering from major depressive disorder.And excessive cortisol pro-duction results in decreased BMD,inflammatory mediators that mighthave a role in the biology of major depression and a host of otherfactors may also be involved in somatic consequences of d

30、epressionsuch as osteoporosis(Licinio and Wong,1999).The F.prausnitzii mayalter the regulation of inflammatory responses and in so doing may beinvolved in the modulation of mood,behavior and BMD(Forsythe et al.,2012;Foster and McVey Neufeld,2013).Regarding F.prausnitzii,al-though little is known abo

31、ut its safety,there is a clear potential of thisspecies as a next-generation probiotic(Martin et al.,2017).However,there is almost no research on F.prausnitzii and depres-sion.Therefore,this study used depression model rats to explore theeffect and mechanism of F.prausnitzii on depression.Models of

32、de-pression are conducted in order to put animals without depression asclosely as possible to the clinical situation.Many different models ofdepression are used in the research conducted at present,includinglearned helplessness,forced swim test,or social defeat stress(PORSOLTet al.,1977;Yan et al.,2

33、010).More recently,the chronic unpredictablemild stress(CUMS)model is the most frequently used and consideredone of the most perfect models of depression(Gambarana et al.,2001;Yan et al.,2010).In this model,rats or mice are exposed chronically toa constant bombardment of unpredictable micro-stressor

34、s(i.e.,restric-tion,inversion of the light-darkness cycle,deprivation of water or food,wet litter,etc.),resulting in the development of a plethora of beha-vioural changes,including a behavioural correlate of the clinical coresymptom of depression and anxiety.However,it can be restored tonormal level

35、s by chronic treatment with antidepressant drugs(Willner,2016).In the current study,the experiment was divided into two phases,the first stage was CUMS procedure period and the second stage wasconvalescence period.We took these two stages to investigate whetheradministration of F.prausnitzii has pre

36、ventive and therapeutic effects onCUMS-induced depression-like and anxiety-like behavior in parallelwith associated changes in growth status,SCFAs produced,cytokine,endocrinology and bone mineral density in rats.2.Material and methods2.1.AnimalsSixty male Sprague-Dawley(SD)rats obtained from Charles

37、 RiverLabs(Beijing)were chosen for this study.At the beginning of the study,the weight of each rat is 230250g.All rats received standard labora-tory diet(Vital River Laboratory Animal Technology Co.Ltd,Beijing,China)and tap water ad libitum under a 12h lightdark cycle(lights on07301930)and a constan

38、t temperature of 2122 and humidity of55 5%.All animals were group-housed in Macrolon cages(37 cmlong,26cm wide,17cm high)and were allowed to adapt to the en-vironment for 2 weeks prior to any experiment.The experimentalprocedures followed the National Institutes of Health Guide for the Careand Use o

39、f Laboratory Animals,and the experiments were approved bythe University Animal Use Committee.2.2.Experimental protocols2.2.1.Treatments and sacrificeThe experiment was divided into two phases,the first phase wasCUMS procedure period(further described in details,from the thirdweek to the sixth week)a

40、nd the second phase was a convalescenceperiod(from the eighth week to the eleventh week).After 2 weeks ofadaptive feeding,the rats were randomly divided into 3 groups duringthe CUMS procedure period.They are unhandled control group(Free-1,n=20);CUMS group(Cums,n=30)and CUMS+F.prausnitzii group(Cums+

41、Fp,n=10).After the end of the first phase,the rest rats weredivided into 3 groups during the convalescence period.The rest rats ofunhandled control group were named Free-2(n=10);the rest rats ofCums group were divided into two different treatment groups groups,they are non-treated group(Control,n=10

42、)and F.prausnitzii-treatedgroup(Fp,n=10).They were fed with standard laboratory diet adlibitum(Vital River Laboratory Animal Technology Co.Ltd,Beijing,China).Rats in each group were weighed every week.Food intake wasmeasured before each supplementary.One week of food intake wasdefined as the total w

43、eight of seven days of all supplementary foodminus the weight of the remnant food.Two or three rats of from thesame experimental group were housed per cage.And the rats from thesame group were re-distributed in per cage every week after the weightof the rats and the amount of food consumed were meas

44、ured.TheZ.Hao,et al.Psychoneuroendocrinology 104(2019)132142133amount of food consumed was averaged between the two or three rats.Food efficiency was defined as weight gain divided by food intake.Toward the end of the each phase,the animals underwent a series ofbehavioral testing including Open fiel

45、d test(OF),Elevated plus maze(EPM)and Forced swim test(FST).In addition,bone mineral density(BMD)was measured before the rats were killed.The details of theexperimental procedure are shown in Fig.1.Fig.1.Animal treatment and experimental procedure.Where:W0-W2,animal adaptation time;Animals were divi

46、ded intothree groups(Free group;Cums group;Cums+Fp group)onthe last day of the second week;W2-W6,CUMS procedureperiod of Cums group and Cums+Fp group;the rest rats ofunhandled control group was named Free-2,the rest animalsof Cums group were divided into two groups(Control group;Fp group)on the last

47、 day of the 7th week;W7-W11,Recoveryphase;CUMS,chronic unpredictable mild stress;OF,Openfield test;EPM,Elevated plus maze;FST,Forced swim test;BMD,Bone mineral density.Fig.2.Body weight,weight gain,food intake,intestinal transit time and food efficiency of rats in different group during the experime

48、nt.Temporal evolution of bodyweights weekly and total weight gain of each phase from 2nd-6thweeks,A,F(2,27)=63.1 and from 7th-11thweeks B,F(2,27)=49.2;Evolution of food intakeweekly and total food intake of each phase from 2nd-6thweeks C,F(2,27)=48.6 and from 7th-11thweeks D,F(2,27)=91.2;Intestinal

49、transit time of the differentgroup of rats E,first phase,F(2,27)=7.7;second phase,F(2,27)=2.9;Food efficiency(weight gain/food intake)of the different group of rats F,first phase,F(2,27)=0.9;second phase,F(2,27)=0.4).Data are shown as averages and error bars represent SD in Figs.2A and 2B;All values

50、 in all other figures were presented assingle data points superimposed to boxplots(n=10 in each group)。*p 0.05,*p 0.01,*p 0.001.One-way ANOVA with Duncans test during eachphase.Z.Hao,et al.Psychoneuroendocrinology 104(2019)1321421342.2.2.CUMS procedureThe CUMS protocol was performed as described pre