1
ABSTRACT 1
Con ex : A bidi ec ional ela ionship be ween gu mic obio a (GM) and ci cadian 2
hy hms has been p oposed. Objec i e: The aim o his s udy was o analyse he e icacy 3
o p obio ic o p ebio ic in e en ion on sleep quali y and quan i y. Da a sou ces, 4
selec ion and ex ac ion: A sys ema ic e iew and me a-analysis we e conduc ed using 5
he da abases PubMed-Medline, Embase, CINAHL and Web o Science. Only 6
andomised clinical ials w i en in English o Spanish we e conside ed. The ini ial 7
sea ch esul ed in 219 a icles. Following he emo al o duplica es and conside a ion o 8
he selec ion c i e ia, 25 a icles we e selec ed o he sys ema ic e iew and 18 a icles 9
o he me a-analysis. Resul s: The e ec o mic obio a modula ion showed no 10
signi ican imp o emen on sleep quali y in ou me a-analysis (p=0.31). In e ms o sleep 11
du a ion, he me a-analysis ound no imp o emen due o GM modula ion (p=0.43). 12
Conclusions: Ou me a-analysis esul s indica e ha he e is s ill insu icien e idence o 13
suppo he ela ionship be ween GM modula ion and imp o ed sleep quali y. While 14
se e al s udies assume ha including p obio ics in he die will undoub edly imp o e 15
sleep quali y, mo e esea ch is needed o ully unde s and his phenomenom. Sys ema ic 16
Re iew Regis a ion: PROSPERO egis a ion no. CRD42021245118. 17
18
2
INTRODUCTION 19
Gu mic obio a (GM) e e s o he se o mo e han 1000 species o li ing mic oo ganisms 20
such as i uses, bac e ia, a chaea, ungi and p o is s ha colonise he gas oin es inal 21
ac .1 The GM cons i u es a hos -speci ic ecosys em ha is gene ically inhe i ed and 22
ma u es du ing childhood, a ec ing indi iduals’ physiological homeos asis.2 The 23
unc ions o GM include con olling he p oli e a ion o pa hogenic bac e ia, egula ing 24
nu ien abso p ion and me abolism, modula ing he immune sys em and pa icipa ing in 25
he syn hesis o me aboli es such as sho -chain a y acids (SCFA) and i amins ha 26
p o ide bene i s o he hos .3–6 27
GM composi ion depends on se e al ac o s such as die , inges ion o ce ain d ugs, age 28
and gene ics, bu in gene al he dominan mic obial communi ies a e he phyla 29
Fi micu es, Bac e oide es, Ac inobac e ia and P o eobac e ia.7 Ce ain ac o s can a ec 30
he di e si y o GM leading o a p ocess known as in es inal dysbiosis.8,9 I has been 31
p oposed ha he phenomenon o dysbiosis could be ela ed o he de elopmen o 32
diso de s, such as obesi y and au ism, h ough wha is known as he gu -b ain axis 33
(GBA).10–12 The gu has an in insic inne a ion, he en e ic ne ous sys em (ENS), 34
composed o senso y neu ons ha de ec physicochemical changes, mo o neu ons and 35
in e neu ons loca ed in en e ic ganglia o ming a complex ne wo k o mo e han 500 36
million neu ons.13 In succession, he ne ous cells o he ENS can communica e wi h 37
b ain neu ons and GM ia GBA. This communica ion sys em is bidi ec ional and is 38
ca ied ou in h ee main pa hways: he agus ne e, he sys emic ci cula ion and he 39
immune sys em in ol ing neu o ansmi e s and neu omodula o s.13 40
3
Due o he bidi ec ional ela ionship be ween he cen al ne ous sys em (CNS) and GM, 41
se e al s udies ha e associa ed sleep dis u bances wi h changes in GM composi ion, as 42
hey obse ed ha pa ien s wi h insomnia had lowe mic obial ichness and di e si y 43
caused by a deple ion o anae obic bac e ia and SCFA-p oducing bac e ia ela ed o 44
con ol indi iduals.14,15 Lachnospi a and Bac e oides, in pa icula , a e common bac e ia 45
in pa ien s wi h acu e insomnia, whe eas Faecalibac e ium and Blau ia a e equen in 46
pa ien s wi h ch onic insomnia.14 47
Rega ding sleep, i is wo h no ing ha i plays a key ole in de elopmen , g ow h and 48
immune unc ion. Insu icien sleep has been associa ed wi h an inc eased isk o 49
mo ali y and he de elopmen o ca dio ascula and co ona y hea disease, hype ension 50
and diabe es.16 Addi ionally, i has been p oposed ha sleep quali y dis u bances may be 51
d i en by hypo halamic-pi ui a y-ad enal (HPA) axis o e ac i i y and co isol 52
hype sec e ion.17 The bene icial e ec s o GM on he CNS ia he GBA ha e led some 53
esea che s o sugges ha GM in e ac s wi h he ci cadian sys em, as he gu in luences 54
ene gy s a us by con olling physiological unc ions such as diges ion and nu ien 55
abso p ion, unc ions ha a e also egula ed by he gene ic clock. 56
The use o p obio ics and p ebio ics o manage in es inal dysbiosis ha e been es ed in 57
humans. Fo example, he adminis a ion o p obio ics con aining li e mic oo ganisms 58
showed bene icial e ec s on pa hologies such as dia hoea, coli is, and in lamma o y 59
bowel disease.18,19 P ebio ics p omo e he selec i e g ow h o bac e ia by p e en ing he 60
g ow h o pa hogens in he colonic lo a. The ood componen s ha seem o exe he bes 61
p ebio ic e ec a e uc ooligosaccha ides (FOS), inulin and lac ulose.20,21 In ecen 62
yea s, he adminis a ion o p ebio ics and p obio ics has been in es iga ed wi h he aim 63
o ea ing insomnia in bo h expe imen al animals and humans, al hough con adic o y 64
4
da a ha e been ound.22 Fo example, he adminis a ion o Lac obacillus b e is DL1-11, 65
L. b e is SBC8803 and L. e men um PS150TM was able o inc ease sleep du a ion and 66
dec ease sleep la ency in mice.23–25 Simila ly, ea men s wi h Lac obacillus gasse i 67
CP2305 and Lac obacillus casei s ain Shi o a (LcS) imp o ed sleep quali y in heal hy 68
adul s a ec ed by s ess.26,27 Howe e , ano he s udy ound no changes in sleep quali y 69
a e adminis a ion o Lac obacillus acidophilus Rosell-52 and Bi idobac e ium 70
longum Rosell-175 in s ess-a ec ed olun ee s.28 Rega ding p ebio ics such as inulin o 71
galac o-oligosaccha ides (GOS), i seems ha hey ha e no e ec on sleep dis u bances 72
ei he in adul s o in child en.29,30 73
The main hypo hesis p oposed in ela ion o he seda i e e ec o some p obio ic s ains 74
is associa ed o he immune sys em modula ion. The p oduc ion o p o-in lamma o y 75
cy okines such as in e leukin 1-be a (IL-1β) and umou nec osis ac o alpha (TNF-α) 76
has been ound o be inc eased in a s exposed o ch onic sleep es ic ion, indica ing he 77
p esence o in lamma o y p ocesses in sleep- es ic ed expe imen al animals.31 In his 78
ega d, he e is e idence o an i-in lamma o y e ec s o p obio ic s ains such as 79
Lac obacillus plan a um, which hinde s he exp ession o IL-1β and TNF-α while 80
inc easing he exp ession o IL-10, an an i-in lamma o y cy okine, in a s ea ed wi h 81
2,4,6- ini obenzenesul onic acid (TNBS)-induced coli is.32 82
To da e, e idence o he e ec o p obio ics on sleep quali y is e y limi ed,33,34 bu no 83
e idence has been ound o o he modula o s o GM, such as p ebio ics o FMT. Thus, 84
he o e all aim o his e iew was o analyse how GM in e en ion by p obio ics o 85
p ebio ics a ec s sleep quali y and quan i y, wi h o he ac o s such as sleep du a ion as 86
seconda y objec i es. 87
5
METHODS 88
A sys ema ic e iew was conduc ed wi h s udies un il Sep embe 2022 ollowing he 89
P e e ed Repo ing I ems o Sys ema ic e iews and Me a-Analyses (PRISMA) 90
guidelines35 (Table S1) and he Coch ane sys ema ic e iew manual.36 The p o ocol o 91
his s udy was egis e ed in PROSPERO (CRD42021245118). 92
Da abases 93
The esea ch ques ion used in he sea ch o in o ma ion wi hin his e iew ollowed he 94
Pa ien -In e en ion-Ou comes (PIO) s uc u e (Table 1): “How does GM modula ion 95
in luence sleep quali y?”, as a consequence o he unc ion o he in es inal mic obio a 96
like an an i-in lamma o y and neu op o ec i e agen o he cen al ne ous sys em ha 97
in e ac s wi h he ci cadian sys em. 98
[INSERT TABLE 1 AROUND HERE] 99
Fou da abases we e used o collec da a (PubMed-Medline, CINAHL, Embase and Web 100
o Science), and sea ch s a egies we e de eloped by combining s uc u ed language 101
(Medical Subjec Heading) and na u al language. The s a egies adap ed o each da abase 102
a e shown in Table S2. 103
S udy eligibili y c i e ia 104
The inclusion c i e ia used o his e iew we e as ollows: andomised clinical ials 105
(RCTs) pe o med in humans, published in Spanish o English, and ele an o he aim o 106
he s udy, including a measu e o sleep quali y and du a ion. Re iews, con e ence 107
abs ac s, quali a i e s udies, o desc ip i e o obse a ional s udies wi hou a con ol 108

6
g oup we e excluded. Simila ly, s udies conduc ed on he paedia ic popula ion we e 109
disca ded. No s udies we e excluded due o me hodological laws o age es ic ions. 110
Selec ion o s udies and me hodological quali y 111
Two au ho s (EGH and CRG) ca ied ou he a icle selec ion p ocess independen ly; in 112
case o disc epancy, a hi d esea che (PR) was consul ed. Likewise, he me hodological 113
quali y was e alua ed using he Jadad scale o andomised clinical ials. This scale is 114
composed o 5 i ems ha se e o e alua e he quali y o RCTs in a simple manne .37 A 115
sco e o mo e han 3 poin s is associa ed wi h a high-quali y s udy, while a sco e o less 116
han 3 poin s is associa ed wi h a low-quali y s udy; hese sco es a e based on he quali y 117
o double blinding, andomiza ion and ollow-up.38 I should be no ed ha his scale 118
co e s some o he elemen s ela ed o biases, hus acqui ing eliabili y and ex e nal 119
alidi y.39 120
Da a ex ac ion 121
Da a we e ex ac ed independen ly by wo in es iga o s (EGH and CRG) om each o 122
he s udies and abula ed as ollows: (1) e e ence; (2) numbe o pa icipan s; (3) 123
in e en ion used; (4) du a ion o in e en ion; (5) a iables analyzed; and (6) main 124
ou comes. 125
The WebPlo Digi ize p og am was used o ob ain he da a om hose a icles ha 126
p o ided only he ele an esul s in g aphs. This so wa e has al eady been used by o he 127
au ho s in me a-analyses, demons a ing i s e ec i eness in ex ac ing da a om 128
g aphs.40,41 129
S a is ical analysis 130
7
The me a-analysis o he included ials was pe o med using Re iew Manage (Re Man) 131
so wa e e sion 5.4. 132
E ec size 133
The e ec size was measu ed by he mean di e ence and s anda d de ia ion o s anda d 134
e o be ween he con ol and expe imen al g oups. 135
Fo he main a iable, sleep quali y, he ollowing ques ionnai es we e used: Pi sbu gh 136
Sleep Quali y Ques ionnai e (PSQI), Nume ic Ra ing Scale (NRS) and A hens Insomnia 137
Scale (AIS). 138
The s udies included in he me a-analysis had o p o ide da a on means, s anda d 139
de ia ion o s anda d e o ; o could be calcula ed om o he da a p o ided. O he wise, 140
he co esponding au ho was con ac ed and, i no esponse was ecei ed, hey we e 141
disca ded om he me a-analysis. 142
He e ogenei y and publica ion bias 143
Depending on he deg ee o he e ogenei y (I2) ob ained, a andom-e ec s model (I2≥50%) 144
o a ixed-e ec s model (I2 ≤50%) was used o pe o m he me a-analysis. A o es plo 145
ep esen ed he analysis. In addi ion, he p- alue was conside ed signi ican when i was 146
<0.05. 147
A sensi i i y analysis was also used o obse e whe he changes in he da a o in he 148
objec i e o he analysis a ec ed he esul s and conclusions o his e iew. I a e 149
sensi i i y analysis, he conclusions did no change, hey we e conside ed obus . Fo his 150
8
pu pose, each o he s udies was excluded independen ly o iden i y which o hem had a 151
signi ican in luence on he indings. 152
RESULTS 153
A e sea ching he di e en da abases, 219 a icles we e ini ially e ie ed. One hunded 154
i y-one a icles we e sc eened by eading hei i le and abs ac a e emo ing 155
duplica es (68 documen s). The numbe o publica ions conside ed in his sys ema ic 156
e iew was educed o 25 a e ull- ex analysis, wi h 18 ials included in he me a-157
analysis. The en i e p ocess is depic ed in Figu e 1. 158
[INSERT FIGURE 1 AROUND HERE] 159
Included s udies 160
The s udy popula ion included a highe p opo ion o heal hy people and s uden s (60%). 161
O e all, he s udies inco po a ed a o al o 2192 pa icipan s, wi h a mean o 91.33 162
indi iduals (max= 581, min= 10) and a mean in e en ion du a ion o 7.12 weeks (max= 163
24, min=1). 164
Mos s udies used p obio ics as modula o s o GM. The mos -used p obio ic species we e 165
Lac obacillus and Bi idobac e ium, hough Saccha omyces ce e isiae, S ep ococcus and 166
En e ococcus aecalis we e also used, as we e h ee ypes o p ebio ics (Inulin, GOS and 167
FOS). Di e en s ains o Lac obacillus (acidophilus, bulga is, hamnosus, casei, 168
plan a um, e men um, delb ueckii ssp. Bulga icus, eu e i, gasse i, casei Shi o a, 169
hel e icus) and o Bi idobac e ium (animalis ssp. lac is, longum, adolescen is, b e e, 170
bi idum, longum ssp. in an is) we e used in he assays. Only one s udy used p ebio ics, 171
p ima ily inulin and uc o-oligosaccha ides, as GM modi ie s. Fu he mo e, s udies ha 172
9
used synbio ics in he in e en ion g oup we e included. Lac obacillus and 173
Bi idobac e ium s ains we e used as p obio ics, and inulin and FOS we e used as 174
p ebio ics. 175
Sleep quali y was analysed in 88.46% o he selec ed s udies, while sleep du a ion was 176
analysed in 30.77%. The esul s ex ac ed om he RCTs, as well as hei cha ac e is ics, 177
a e shown in Table 2. 178
[INSERT TABLE 2 AROUND HERE] 179
Me hodological quali y: assessmen o bias 180
Figu e 2 shows he o e all sco e o each i em, wi h he lowes isk o bias in s udies ha 181
included andomisa ion and a desc ip ion o pa icipan blinding. Howe e , he ials did 182
no usually s a e how his andomisa ion and blinding we e pe o med, no whe he he 183
a e o he pa icipan s was known. On he o he hand, Figu e 3 shows he e alua ion o 184
he me hodological quali y and isk o bias using he Jadad scale o he s udies included 185
in he sys ema ic e iew. Wi h he excep ion o he s udies by Lee e al. (2021), Que o e 186
al. (2021), Rode e al. (2022), Sha ie e al. (2022), Valle e al. (2021), Wäli aa a e al. 187
(2019) and Wang e al. (2021), whose me hodological quali y is qui e high, his igu e 188
shows ha some s udies ha e i ems wi h some de iciencies.26–29,42–62,52,59,60 189
[INSERT FIGURE 2 AND 3 AROUND HERE] 190
Sleep quali y and du a ion 191
T ea ing heal hy s uden s, we ound se e al a icles.26,27,43,45,49,51,56,63 All o hem used 192
p obio ics as he in e en ion in hei expe imen al g oups, mos ly using Lac obacillus as 193
16
In e es ingly, ecen indings sugges ha immune sys em cells can in luence GBA since 327
an in lamma o y en i onmen in he in es inal mucosa can inc ease pe meabili y and hus 328
impac b ain ac i i y78, as some cy okines ha e been shown o c oss he blood b ain 329
ba ie (BBB) and p omo e neu oin lamma ion.79 In e ms o immune sys em s a us, 330
Wang e al. (2021) concluded ha a combina ion o p obio ic s ains including 331
Bi idobac e ium longum, Lac obacillus acidophilus, and En e ococcus aecalis we e able 332
o educe plasma IL-6 le els in olde adul s on he 5 h-7 h day pos -su ge y 44. This e ec 333
on IL-6 was also shown in imma u e en e ocy es u ilising p obio ic condi ioned media 334
(PCM) om Bi idobac e ium longum subsp in an is and Lac obacillus acidophilus, bu 335
no isola ed o ganisms, which a enua ed and dec eased IL-6 induced by IL-1.80,81 336
Con e sely, IL-1Ra, IL-10, IL-1b, IL-6, IL-8, and TNF-α concen a ions did no al e 337
a e adminis a ion o Lac obacillus acidophilus (DDS-1), Bi idobac e ium animalis spp. 338
lac is (UABla-12) and L. hamnosus (JB-1) o he in e en ion g oup.50,60 In his con ex , 339
L. hamnosus GG (LGG) has no been demons a ed o change IL-10 le els, bu has been 340
epo ed o inc ease IL-10R2 ecep o subuni exp ession and dec ease TNF- exp ession 341
in he mouse colon.82 Ano he s udy ound ha LGG-condi ioned medium educed TNF- 342
p oduc ion in LPS-ac i a ed mac ophages.83 343
Co isol is well known o in luence he sleep quali y and du a ion, as high le els inc ease 344
waking ime and lack o sleep inc eases co isol le els.84 The e ec o p obio ic 345
supplemen a ion on sali a y and plasma co isol le els has yielded con adic o y esul s. 346
In only h ee o he ials included in his s udy, blood and sali a y co isol le els we e 347
al e ed a e adminis a ion o Bi idobac e ium, Lac obacillus, and En e ococcus 348
s ains.44,49,60 In his manne , p obio ic supplemen a ion has been documen ed in ce ain 349
ials o signi ican ly educe plasma co isol le els in s essed-ou s uden s and adul s.85,86 350

17
In he o he ials e alua ed, p obio ics ailed o lowe co isol le els.27,43,50,63 This is 351
consis en wi h a cu en clinical ial in which Bi idobac e ium b e e CCFM1025 was 352
adminis e ed o pa ien s wi h majo dep ession, ye ailed o lowe se um co isol le els.87 353
Nume ous s udies on mic obio a-de i ed me aboli es ha e sugges ed ha low SCFA 354
concen a ions may con ibu e o he de elopmen o neu opsychia ic diseases, obesi y, 355
and au ism.88–90 Addi ionally, g ea e aecal p opionic acid le els in in an s a e associa ed 356
wi h longe pe iods o unin e up ed sleep.91 These indings show ha consuming 357
p obio ic s ains de i ed om SCFA-p oducing bac e ia could be an a ac i e s a egy. 358
Only Nishida e al. (2019) s udied he impac s o p obio ic consump ion on SCFAs, 359
concluding ha Lac obacillus gasse i p obio ic supplemen a ion inc eased n- ale ic 360
le els in heal hy olun ee s bu did no a ec o he SCFAs such as p opionic and ace ic 361
acids.27 Simila , esea ch using Bi idobac e ium animalis subsp. lac is BB-12 (BB-12) 362
ound ha i did no signi ican ly enhance aecal SCFA le els in heal hy adul s.92,93 363
Limi a ions 364
The numbe o s udies included in he me a-analysis is limi ed owing o lack o da a se s 365
equi ed o p ocess and comple e he analysis. While we a emp ed o con ac all 366
co esponding au ho s o s udies ha did no con ain his in o ma ion, we did no always 367
ecei e a esponse. As a esul , ou s udies mus be excluded om he me a-analysis and 368
he sys ema ic e iew.42,46,49,51 Ano he limi a ion o conside when in e p e ing he 369
esul s o his me a-analysis is he la ge a iabili y in in e en ion leng h, which anges 370
om 1 week in he s udy by Wang e al. (2021) o 24 weeks in he s udy by Nishida e al. 371
(2019), he e o e his he e ogenei y may ha e an impac on he analysis and he 372
magni ude o ou comes be ween in e en ions may no be accu a ely examined. 373
18
Rega ding he adminis a ion o p ebio ics, only one RCT was i ed in he inclusion 374
c i e ia, he e o e we canno d aw a p ecise conclusion abou he in luence o p ebio ics 375
on sleep. Ano he aspec o conside when in e p e ing and analysing he esul s is ha a 376
signi ican p opo ion o he included s udies used sel - epo scales o assess sleep 377
quali y. In addi ion o hese alida ed scales95-97, i would ha e been in e es ing o include 378
objec i e measu es o sleep quali y, wi h he PSQI being he mos commonly used in he 379
s udies selec ed. Finally, since i was ou side he scope o his manusc ip , he esponse 380
o he gu mic obiome o p obio ic o p ebio ic in e en ion was no assessed in his 381
sys ema ic e iew and me a-analysis, and hus he e ec o mic obiome modula ion om 382
he in e en ions could no be de e mined. Ra he han concluding he issue, ou indings 383
pa e way o u u e esea ch o de e mine which in e en ions a e associa ed wi h a 384
measu able gu mic obiome esponse and whe he his co ela es wi h changes in sleep 385
quali y. Likewise, u u e clinical ials should conside de ailing he blinding me hods and 386
pa icipan d opou a e in o de o imp o e igou and ep oducibili y, as hese i ems ank 387
lowes in ou quali y assessmen o included s udies. 388
CONCLUSIONS 389
Al hough se e al s udies ag ee ha modula ion o he mic obio a a ec s sleep quali y, 390
he esul s o ou me a-analysis do no show ha he implemen a ion o p obio ics in he 391
die leads o a signi ican imp o emen in sleep quali y. The as majo i y o he bac e ia 392
used in he s udies included in his s udy we e om he Lac obacillus and Bi idobac e ium 393
amilies, while En e ococcus aecalis, S ep ococcus he mophilus, and Saccha omyces 394
ce e isiae we e also used. 395
19
Few s udies p o ided su icien da a o be included in ou me a-analysis in e ms o sleep 396
du a ion, which did no include s a is ically signi ican da a. Because o his, i would be 397
in e es ing o expand esea ch in his a ea o ha e access o a la ge amoun o da a and 398
he e o e be able o ob ain a mo e exhaus i e and p ecise conclusion. Only one clinical 399
ial wi h p ebio ics was included in his s udy, which used Inulin and FOS in i s 400
expe imen al g oup. Due o limi ed a ailabili y o s udies ob ained du ing ou sea ch, we 401
a e unable o d aw any conclusions on he e ec s o including p ebio ics in he die ; 402
hence, i would also be wo h conduc ing addi ional esea ch in his a ea. 403
ACKNOWLEDGMENTS 404
The CTS-451 Resea ch G oup and he CEINSA Resea ch Cen e ha e suppo ed his 405
esea ch. 406
Funding. This esea ch ecei ed no speci ic g an om any unding agency in he public, 407
comme cial, o no - o -p o i sec o s. 408
Decla a ions o in e es . The au ho s ha e no ele an in e es s o decla e. 409
SUPPORTING INFORMATION 410
Table S1: PRISMA checklis . 411
Table S2: Sea ch s a egies in each da abase used. 412
REFERENCES 413
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20
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34
eme ging di ec o “Mic obiome.” Nu ien s. 2019;11(1):156. 719
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chain a y acid p opiona e and in an sleep. Eu J Clin Nu 2020 749. 722
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92. Ba Z, Lee Y, Meng H, e al. Ma ix E ec s on he deli e y e icacy o 724
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and sho -chain a y acids in heal hy young adul s. mSphe e. 2021;6(4):e00084-726
21. doi:10.1128/msphe e.00084-21 727
93. Lee Y, Ba Z, Robe s RF, e al. E ec s o Bi idobac e ium animalis subsp. lac is 728
BB-12® on he lipid/lipop o ein p o ile and sho chain a y acids in heal hy 729
young adul s: a andomized con olled ial. Nu J. 2017;16(1):1-9. 730
doi:10.1186/s12937-017-0261-6 731
732
733
35
Table Legend 734
Table 1. PIO c i e ia 735
Table 2. Summa y o ials selec ed o e iew 736
Figu e Legend 737
Figu e 1. Flowcha 738
Figu e 1. G aph o he me hodological quali y o he ials included in he s udy. 739
Figu e 2. Me hodological quali y o included clinical ials (n=25). 740
Figu e 4. Fo es plo showing he e ec s o GM modula ion on he quali y o sleep (n=18). 741
Figu e 5. Fo es plo e lec ing he e ec s o GM modula ion on sleep du a ion (n=5). 742
743
36
Table 1. PIO c i e ia 744
RCT: Randomized clinical ial 745
746
747
748
Pa ame e
C i e ia
Popula ion
Adolescen and adul popula ion (olde han 18 yea s old)
In e en ion
P obio ics and p ebio ics o mula ions
Ou comes
Quali y and du a ion o sleep
S udy design
RCT
Language
Spanish o English
37
Table 2. Summa y o ials selec ed o e iew 749
REFERENCE N INTERVENTION
USED
INTERVENTION
DURATION
(WEEKS)
VARIABLES
ANALYZED
DATA
COLLECTION
TOOLS
MAIN RESULTS
PROBIOTIC
Rode e al.
(2022)57
Heal hy
subjec s aged
20-28 (n=22)
Lac obacillus
hel e icus R0052
(2×109 CFU),
Lac iplan ibacillus
plan a um R1012
(8 × 108 CFU) and
Bi idobac e ium
longum R0175
(7×107 CFU)
Powde sache
4
Anxie y
S ess
Dep ession
Sleep quali y
Sleepiness
Awakening
HADS
PSS
STAI
KSD
The e we e no
signi ican
di e ences in sleep
quali y be ween he
p obio ic
in e en ion and
he placebo g oup
Sha ie e al
(2022)58
Pos menopausal
women aged
45-55 (n=66)
Lac obacillus
bulga icus,
S ep ococcus
he mophilus
Bi idobac e ium
lac is and L.
acidophilus
Yogu
6
Anxie y
S ess
Dep ession
Sleep quali y
PSQI
DASS-21
The use o
p obio ics had no
e ec on sleep
quali y
Da oodabadi
e al (2021)59
Females aged
18-40 su e ed
om cyclical
mas algia due
o b eas FCC
(n=45)
Lac obacillus
acidophilus, L.
e men um, L.
eu e i, and
Bi idiobac e ium
bi idum
2x109 CFU
Capsule
12
Dep ession
Anxie y
Sleep quali y
BDI
BAI
PSQI
The p obio ic
g oup did no
imp o e sleep
quali y
Wes e al
(2021)60
Nigh shi
wo ke s (n=87)
Lac obacillus
acidophilus DDS-1
and
Bi idobac e ium
animalis spp. lac is
UABla-12.
1x1010 CFU
Capsule
2 Sleep quali y
PSQI
Fi bi sleep ime
(min)
Signi ican changes
in sleep quali y in
he expe imen al
g oups
Calga o e al.
(2021)61
Heal hy
subjec s (n=33)
Limosil
ac obacillus
e men um LF16
(DSM 26956),
Lac icaseibacillus
hamnosus LR06
(DSM 21981),
Lac iplan ibacillus
plan a um LP01
(LMG P-21021),
and Bi idobac e im
longum 04 (DSM
23233). 4×109
CFU/AFU.
Sache
6 Sleep quali y PSQI
Signi ican
imp o emen in
sleep quali y
Lee e al
(2021)62
Heal hy adul s
aged 19-65
(n=156)
Lac obacillus
eu e i NK33 and
Bi idobac e im
adolescen is NK98
2.5 × 109 CFU/500
mg
Capsule
8
Sleep quali y
Symp oms o
insomnia
Mood
BAI
BDI-2
PSQI
ISI
SRI
Signi ican
educ ions in sleep
quali y and se e i y
o insomnia in he
expe imen al g oup

38
Ha ne e al
(2021)42
Eli e a hle es
(n=38)
Ul abio ic 60TMi
and
SBFlo ac i TMii
Table
17 Sleeping hou s
Sleep quali y
Sel - epo ed
sleep quali y
Sel - epo ed
numbe o hou s
o sleep
Sleep quali y and
quan i y imp o ed
in he expe imen al
g oup
Moloney e al
(2021)43
S uden s aged
18-40 (n=20)
Bi idobac e ium
longum AH1714.
1x109 CFU
Capsule
8
Dep ession
measu emen s
Sleep quali y
Mood
PSS
HADS-A,
HADS-D
PSQI
The p obio ic
Bi idobac e ium
longum imp o ed
sleep quali y and
du a ion in he
expe imen al g oup
Wang e al
(2021)44
Olde adul s
(n=120)
Bi idobac e ium
longum
Lac obacillus
acidophilus
En e ococcus
aecalis
Mo e o 1.0x107
CFU/g.
Capsule
1
Pos ope a i e
cogni i e
impai men
Pos ope a i e
sleep quali y
MMSE
NRS
No signi ican
di e ences we e
ound in sleep
quali y be ween he
expe imen al and
con ol g oup
Ma o a e al
(2019)45
Heal hy
s uden s (n=38)
Lac obacillus
e men um LF16
(DSM 26956)
L. hamnosus
LR06 (DSM
21981)
L. plan a um LP01
(LMG P-21021)
Bi idobac e ium
longum BL04
(DSM 23233)
4x109 CFU
Powde
9
P esence and
se e i y o
anxie y
symp oms and
p opensi y o be
anxious
Occu ence and
se e i y o
dep essi e
symp oms
Mood
Sleep quali y
LEIDS-R
STAI
BDI-2
POMS
PSQI
An inc ease in
sleep quali y was
obse ed in he
expe imen al g oup
Wäli aa a e al
(2019)46
Heal hy
pa ien s (n=61)
Lac obacillus
eu e i (DSM
17938 and ATCC
PTA 5289).
2x108 li e bac e ia
om he combined
s ains
Table
2 Sleep
Sel - epo ed
da a on
dis u bed sleep
The expe imen al
g oup was
associa ed wi h
ewe nigh s o
in e up ed sleep
Nishida e al
(2019)27
Heal hy
s uden s (n=60)
Lac obacillus
gasse i CP2305.
1x1010 bac e ial
cells pe 2 able s
Table
24
Men al and
physical
condi ion
Sleep quali y
STAI
GHQ-28
HADS
PSQI
In ake o he
p obio ic
signi ican ly
educed sleep
diso de s
Lei e al
(2018)47
Pa ien s wi h
simple ib
ac u e
(n=283)
Lac obacillus casei
Shi o a.
6x109 CFU
Milk
4
Sleep quali y NRS
The e was no
signi ican
imp o emen in
sleep quali y
Nishida e al
(2017)63
S uden s aged
18-34 (n=32)
Lac obacillus
gasse i CP2305.
1x1010 CFU
Canned milk
5
Men al and
physical
condi ion
Sleep
measu emen
and assessmen
GHQ-28
Zung-SDS
HADS
STAI
PSQI
Sleep quali y
imp o ed in he
p obio ic g oup,
sho ened sleep
la ency, and
inc eased sleep
du a ion
39
Sawada e al
(2017)49 S uden s (n.d.)
Lac obacillus
gasse i CP2305.
1.0x1010 CFU
Powde
4
Men al heal h
Sleep quali y
and dis u bances
GHQ-28
Zungs-SDS
HADS
STAI
PSQI
P obio ic inges ion
p e en ed he
de elopmen o
sleep diso de s and
imp o ed PSQI
sco es
Kelly e al
(2017)50
Heal hy
pa icipan s
aged 20-33
yea s (n=29)
Lac obacillus
hamnosus (JB-1)
1x109 CFU
Capsule
8
Psychobiological
esponseiii o an
acu e s esso
Cogni i e
pe o mance
Sleep quali y
CANTAB
SECPT
BDI-2
BAI
PSS
STAI
PSQI
P obio ic ea men
did no
signi ican ly a ec
sleep quali y
ela i e o placebo
ea men
Takada e al
(2017)26
Heal hy
s uden s
(n=124)
Lac obacillus casei
s ain Shi o a YIT
9029.
1.0x109 CFU/ml
Milk.
11
Anxie y le els
Sleep quali y
Sleep e iciency
Heal hy habi s
Psychological
well-being
STAI
PSQI
GHQ
OSA
HPI
Posi i e e ec on
sleep du a ion and
la ency
Culpeppe e al
(2016)51
Unde g adua e
s uden s
(n=581)
Lac obacillus
hel e icus R0052
(LH),
Bi idobac e ium
bi idum R0071
(BB) and B.
longum spp.
in an is R0033
(BI). 3×109 CFU.
Capsule
6
S ess le el
Sleeping hou s
Sel - epo ed
s ess sco es
Sel - epo ed
s ess and le els
o sleep
Nega i e
co ela ion be ween
hou s o sleep and
sel - epo ed s ess
alues
Wong e al
(2014)52
IBS pa ien s
(n=42)
Bi idobac e ium
longum,
B. in an is and B.
b e e,
Lac obacillus
acidophilus,
L. casei, L.
delb ueckii ssp.
bulga icus and L.
plan a um and
S ep ococcus
sali a ius ssp.
he mophilus
(VSL#3) 112.5
billion iable
lyophilized
bac e ia
Capsule
6
Sleep quali y
Day ime
sleepiness
HADS-A,
HADS-D
PSQI
ESS
No signi ican
di e ences we e
ound be ween he
p obio ic g oup and
placebo
Diop e al
(2008)28
Volun ee s wi h
s ess
symp oms aged
18-60 (n=75)
Lac obacillus
acidophilus Rosell-
52 and
Bi idobac e ium
longum Rosell-
175. (3 × 109 CFU)
Sache s ick
3 Sleep diso de s Sel - epo ed
le els o sleep
P obio ic
in e en ion did no
change s ess-
induced sleep
p oblems
PREBIOTIC
Saleh-Ghadimi
e al (2022)53
Female obese
ype 2 diabe ic
melli us
pa ien s aged
30–65 (n=63)
Nu iose®06
( esis an dex in) 8 Sleep quali y PSQI
P ebio ic
in e en ion
esul ed in
signi ican
imp o emen s in
sleep quali y when
40
compa ed o he
placebo g oup
Schaa sma e
al (2021)54
Adul s wi h
sleep
dis u bances
aged 30-50
(n=70)
P oduc con aining
p o ein, GOS,
i amins and
mine als
Sache
3 Sleep quali y PSQI
T ea men did no
imp o e sleep
quali y
Buigues e al
(2016)29
Ins i u ionalised
olde
popula ion
wi hou
demen ia
(n=50)
Da moca e P e®
(Inulin 3375mg
and uc o-
oligosaccha ides
3488mg (FOS))
Powde
13
E ec o he
p ebio ic on he
ail y synd ome
MMSE
AIS
No signi ican
changes in sleep
quali y we e
obse ed
SYNBIOTIC
Valle e al
(2021)55
Mili a y
unde going
ield aining
(n=65)
Lac obacillus
acidophilus LA-5
(2·1 × 108 CFU/g)
Bi idobac e ium
animalis BB-12
(2·7 × 109 CFU/g)
and inulin (2-
3g/60g)
Ice c eam
4 Sleep quali y
Sleepiness
WAM
PSQI
Sleep quali y did
no imp o e
signi ican ly in he
expe imen al g oup
Sleepiness
dec eased in he
synbio ic- ea ed
g oup
Que o e al
(2021)56
P o essional
socce playe s
and seden a y
s uden s (n=27)
Gas eel Plus®
(Bi idobac e ium
lac is CBP-
001010,
Lac obacillus
hamnosus CNCM
I-4036,
Bi idobac e ium
longum ES1
(≥1×109 CFU) and
FOS (200 mg))
S ick
4
Sleep quali y
Anxie y
S ess
Dep ession
Fa igue
HLPCQ.
STAI
PSS
BDI
BFI
The in e en ion
only imp o ed he
sleep quali y o he
a hle es
CFU: Colony-Fo ming Uni s; AIS: A hens Insomnia Scale; BDI-2: Beck Dep ession 750
In en o y; CANTAB: The Camb idge Neu opsychological Tes Au oma ed Ba e y; 751
GHQ: Gene al Heal h Ques ionnai e; GHQ-28: The 28-i em Gene al Heal h 752
Ques ionnai e; WAM: Well-being, Ac i i y, Mood ques ionnai e; BAI: The Beck Anxie y 753
In en o y; SRI: S ess Response In en o y; HADS-A, HADS-D: The Hospi al Anxie y 754
and Disease Scale; LEIDS-R: Leiden Index o Dep ession Sensi i i y-Re ised es ; ISI: 755
Insomnia Se e i y Index; MMSE: Mini-Men al S a e Examina ion; NRS: Nume ic Ra ing 756
Scale; OSA: The Ogu i-Shi akawa-Azumi sleep in en o y; POMS: P o ile o Mood S a e; 757
PSQI: Pi sbu gh Sleep Quali y Index; PSS: The Pe cei ed S ess Scale; SECPT: The 758
Socially E alua ed Cold P esso Tes ; STAI: The S a e T ai Anxie y In en o y; Zung-759
SDS: The Zung Sel -Ra ing Dep ession Scale; HPI: Heal h P ac ice Index; ESS: Epwo h 760
Sleepiness Scale; BFI: The B ie Fa igue In en o y; HLPCQ; The Sleep Quali y in 761
Heal hy Li es yle and Pe sonal Con ol Ques ionnai e; DASS-21: Dep ession, Anxie y, 762
and S ess Scale-21 i ems; IBS: i i able bowel synd ome; AFU: Ac i e Fluo escen Uni s; 763
KSD: Ka olinska Sleep Dia y. GOS: galac o-oligosaccha ides; FCC: ib ocy ic change. 764
MADRS: Mon gome y-Åsbe g Dep ession Ra ing Scale; QIDS-SR16: Quick In en o y o 765
Dep essi e Symp oma ology; GAD-7: Gene alized Anxie y Diso de 7-i em scale; MDD: 766
Majo Dep essi e Diso de . 767
41
i This o mula includes Lac obacillus acidophilus (CUL 21+CUL 60) 20 illion CFU, L.
hamnosus (CUL 63) 15.55 illion CFU, L. casei (CUL 06) 9.45 illion CFU, L.
plan a um (CUL 66) 3.15 illion CFU, L. e men um (CUL 67) 1.35 illion CFU,
Bi idobac e ium animalis ssp. lac is (CUL 34) 6.55 illion CFU, B. b e e (CUL 74) 1.35
illion CFU, B. bi idum (CUL 20) 345 million CFU, S ep ococcus he mophilus (CUL
68) 2.25 illion CFU.
ii This o mula consis s o Saccha omyces ce e isiae (boula dii) 5 illion CFU.
iii This o mula consis s o 112.5 billion iable lyophilized bac e ia: Bi idobac e ium
longum, B. in an is and B. b e e, Lac obacillus acidophilus, L. casei, L. delb ueckii ssp.
bulga icus and L. plan a um and S ep ococcus sali a ius ssp. he mophilus.