Anorexia nervosa and microbiota: systematic review and critical appraisal

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Ea ing and Weigh Diso de s - S udies on Ano exia, Bulimia and Obesi y (2023) 28:1
h ps://doi.o g/10.1007/s40519-023-01529-4
REVIEW
Ano exia ne osa andmic obio a: sys ema ic e iew andc i ical
app aisal
NaomiGa cia1· EmilioGu ie ez1,2
Recei ed: 1 No embe 2022 / Accep ed: 4 Janua y 2023
© The Au ho (s) 2023
Abs ac
Pu pose Recen s udies ha e epo ed a gu mic obio a imbalance o dysbiosis associa ed wi h ano exia ne osa (AN), which
has p omp ed an app aisal o i s ae iological ole, and he e o mula ion o AN as a me abo-psychia ic diso de . Thus, he
aim o his pape was o c i ically e iew he cu en scien i ic indings ega ding he ole o mic obio a in ano exia ne osa.
Me hods A sys ema ic s udy o pee - e iewed li e a u e published in ou da abases be ween 2009 and 2022 was conduc ed
acco ding o PRISMA guidelines. Bo h human and animal s udies we e included.
Resul s A o al o 18 s udies we e included. In animal models, bo h he p eclinical and clinical indings we e inconsis en
ega ding mic obio a composi ion, aecal me aboli e concen a ions, and he e ec s o human aecal mic obio a ansplan s.
Conclusion The me hodological limi a ions, lack o s anda disa ion, and concep ual ambigui y hinde he analysis o mic o-
bio a as a key explana o y ac o o AN.
Le el o e idence Le el I, sys ema ic e iew.
Keywo ds Ano exia ne osa· Mic obio a· Gu -b ain axis· Dysbiosis
In oduc ion
The e m in es inal mic obio a e e s o he se o mic oo -
ganisms (bac e ia, a chaea, ungi, and i uses) ha coex-
is in he gu [1]. In ecen yea s, in es inal mic obio a has
become he subjec o enewed in e es no only in he ield
o science, bu also ac oss socie y, and indus y. Thus, 96.8%
o he 53,921 publica ions in PubMed unde he label “gu
mic obio a” we e published in he las decade. Mo eo e ,
he mic obio a has become one o he scien i ic opics
ecei ing b oad co e age in he p ess [2, 3], and mic obio a-
based p oduc s ep esen a as -g owing ma ke oday, wi h
an es ima ed 275–400 $ million wo ldwide [4].
Cu en esea ch on mic obio a has p ima ily ocused on
bac e ia, mos o which belong o a small numbe o phyla
[5]. Fi micu es and Bac e oide es ep esen a ound 85–90%
o he o al mic obio a, whils Ac inobac e ia, Ve ucomi-
c obia, and P o eobac e ia appea in smalle p opo ions
[5]. Howe e , his composi ion is highly a iable be ween
indi iduals and in he same indi idual o e ime and can
be a ec ed by se e al ac o s, wi h die being he mos
esea ched o all [6]. Bo h long- e m and sho - e m die a y
pa e ns can p oduce changes in he s uc u e o mic obio a
by p o iding o emo ing nu ien s, and modi ying he con-
di ions o he gas oin es inal ecosys em su ounding bac e-
ia e.g., pH, bile acid con en , and so o h. [6]. Simila ly,
an ibio ics and psycho opic d ugs such as SSRIs ha e been
ound o ha e an impac on he mic obio a-gu -b ain axis
[6], and se e al s udies ha e shown he composi ion may
a y depending on age, s ess, BMI, and physical ac i i y
[6], among o he ac o s.
The su ge in he in e es in mic obio a has been mo i-
a ed by i s physiological po en ial, wi h an es ima ed 100
bac e ial genes o e e y human gene [1]. Mo eo e , gu
mic oo ganisms ha e been conside ed key playe s in he gu -
b ain axis [7], and i has been sugges ed hey may a ou
communica ion wi h he b ain ia he endoc ine, immune,
* Emilio Gu ie ez
emilio.gu ie [email p o ec ed]
1 Depa amen o de Psicología Clínica Y Psicobiología,
Facul ad de Psicología, Uni e sidad de San iago de
Compos ela, Campus Vida, 15782San iagodeCompos ela,
Spain
2 Unidad Ven es Clínicos, Facul ad de Psicologıa,
Uni e sidad de San iago de Compos ela, Campus Vida,
15782San iagodeCompos ela, Spain
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1 Page 2 o 24
o ne ous sys em [7]. Typically, he p ime candida es o
es ablishing his connec ion a e bac e ial me aboli es (espe-
cially SCFAs), neu o ansmi e s o immune in e media es
[6, 7]. Hence, i is easonable o sugges ha an imbalance in
gu mic obio a composi ion o dysbiosis may be linked o he
clinical ea u es o se e al men al heal h diso de s [7]. While
he idea ha gu mic oo ganisms may a ec beha iou is no
no el, da ing back o Boucha d’s au oin oxica ion heo y [8],
i is only wi h he eme gence and cheapening o sequencing
echniques and bioin o ma ics ha esea ch in he ield has
de eloped [7].
Se e al me hods ha e been applied o he analysis o
he mic obio a-gu -b ain axis [7]. Mic obiome s udies
ha e employed massi e sequencing echniques such as 16S
sequencing o compa e p o iles o mic obial communi ies
in indi iduals wi h and wi hou pa hology [9]. Al e na-
i e app oaches include Faecal Mic obio a T ansplan a ion
(FMT) [7] o humanised gno obio ic oden s, i.e., oden s
ha ha e been ansplan ed wi h he aecal mic obio a o
indi iduals wi h o wi hou pa hology [10]. Thus, esea ch
has examined he causal ole o mic obio a on men al heal h
[7] and, o da e, associa ions o au ism, psycho ic diso de s,
anxie y, dep ession, ADHD, pos - auma ic s ess diso de
and, mo e ecen ly, ea ing diso de s, including Ano exia
Ne osa (AN), ha e been p oposed [7].
AN a ec s 1% o he popula ion [11] wi h 90% o cases
being women [12]. I s onse is usually associa ed wi h
pube y o ea ly adul hood and, despi e i s low p e alence, i
has he highes mo ali y a e among men al diso de s [11].
Acco ding o he DSM-5, AN is cha ac e ized by ene gy
es ic ion esul ing in low body weigh , ea o gaining
weigh , and dis o ed body image [12]. Two sub ypes ha e
been es ablished i.e., es ic i e and pu ga i e.
O e all, AN is o en associa ed wi h physical signs
de i ed om malnu i ion such as b adyca dia, hypo en-
sion, lanugo, hypo he mia, and hype ac i i y [11]. The la -
e appea s in app oxima ely 70–80% o cases [13] hough
es ima es a y gi en he lack o consensus in i s de ini ion.
Fu he mo e, gas oin es inal symp oms, ma ked by abdomi-
nal pain and discom o , appea in he li e a u e since he
i s desc ip ions [14]. In ac , i has been es ima ed ha 90%
o AN cases p esen some ype o gas oin es inal complain
[15].
A p esen , he e is a lack o e icacious ea men s o
adul s wi h AN [11, 16, 17]. Al hough in e na ional guide-
lines [18] ecommend psychological in e en ion such as
CBT (cogni i e beha iou al he apy), he MANTRA p o-
ocol (Maudsley Model o Ano exia Ne osa T ea men o
Adul s), and SSCM (Specialis Suppo i e Clinical Man-
agemen ) as he ea men o choice, a ecen me a-analysis
conclude ha : “No signi ican di e ences be ween psy-
chological ea men and con ol condi ion we e ound on
weigh gain, on ea ing diso de pa hology, and on quali y o
li e.” [16, p.2]. In ac , his could be he ou come o a poo ly
unde s ood ae iology.
In an a emp o p og ess, Bulik e al. [19] sugges ed
e o mula ing/ e aming AN as a me abo-psychia ic diso -
de [19, 20]. This e o mula ion was g ounded in he ecen
s udy published by he Ea ing Diso de s Wo king G oup
wi hin he amewo k o he Psychia ic Genomics Con-
so ium (PGC), which concluded he exis ence o gene ic
associa ions be ween AN and me abolic/an h opome ic
ai s [20].
Unde he p emise o a me abo-psychia ic diso de ,
mic obio a would eme ge as a po en ial explana o y ac o
o key ea u es o AN [21]. The e o e, die a y educ ion,
psychosocial s ess, and ma ked weigh loss a e conside ed
o con ibu e o he es ablishmen o a selec i e in es inal
en i onmen o bac e ial su i al a ou ing he de elop-
men o dysbiosis [19]. So a , i has been sugges ed ha
his migh explain low weigh gain [19, 22], a ec i e symp-
oma ology [19, 22, 23], al e ed ea ing beha iou [23], and
e en hype ac i i y [22]. Thus, modi ica ions o mic obio a
composi ion using p o-, p ebio ics [22], FMT, o p ecision
nu i ion [19] ha e been p oposed as p omising he apeu ic
in e en ions.
In an e o o de e mine whe he al e ed composi ion
is mo e han a me e consequence o malnu i ion, se e al
au ho s ha e examined he unde lying causal mechanisms o
mic obio a in he ae iology o AN. In es inal dysbiosis has
been sugges ed o a ou yp ophan de iciency by al e ing
se o one gic pa hways ha inc ease physical ac i i y [22].
In he same ein, a ec i e symp oma ology has been associ-
a ed wi h al e ed gu -b ain communica ion due o inc eased
u emic oxins [22], and educed SCFAs [21]. Fe isso &
Hök el [23] de ine ea ing diso de s as he esul o al e ed
communica ion be ween mic obio a, he immune sys em,
and he neu oendoc ine sys em. Thus, hese au ho s ocus
on he ClpB p o ein (caseinoly ic pep idase B) gene a ed
by membe s o he En e obac e iaceae amily, p esen ing
a mime ic sequence wi h α-MSH [24]. These au ho s claim
ha a dysbiosis in ol ing an inc ease in hese bac e ia would
cause he seg ega ion o ClpB a ec ing he ae iology o AN
ei he by (a) a di ec e ec on he pe iphe al sa ie y ou es
-inc easing PYY [25, 26], o cen ally h ough MC4R [27];
o (b) an indi ec e ec om he o ma ion o an i-ClpB
IgG an ibodies c oss- eac i e wi h α-MSH ha would o m
immune complexes, ac i a ing ch onically he cen al MC4R
ecep o and inducing inc eased sa ie y and anxie y, o bo h.
Recen ly, F os ad [28] has emphasized he ole o CCK-4
as a complemen a y mechanism in eg a ed in o his model;
malnu i ion would cause dis up ion o he blood–b ain
ba ie , inc easing he sensi i i y o CCK2 ecep o s o he
CCK-4 pep ide gene a ed by en e oendoc ine I cells du ing
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Page 3 o 24 1
meals. Thus, an icipa o y anxie y would occu ha would
a ou psychological main enance mechanisms such as he
pu sui o hinness and weigh o e alua ion.
Bea ing in mind he abo e indings on he ea men and
ae iological unde s anding o AN, his wo k aimed o assess
he cu en scien i ic indings on he ole o in es inal mic o-
bio a in he de elopmen and main enance o he diso de in
human and animal s udies; hence, bo h human and animal
s udies we e included.
Me hod
Sea ch s a egy ands udy selec ion
A sys ema ic sea ch was conduc ed on No embe 5, 2021
(upda ed June 13, 2022) o all pape s e e ing o he opic
om 2009 o 2022 in he da abases PubMed, Web o Science
(Wos), PsycINFO, and ScienceDi ec . The sea ch consis ed
o he ollowing combina ion o e ms ((mic obio a) OR
(mic obiome)) OR (dysbiosis)) AND (Ano exia ne osa).
PICOS c i e ia o inclusion and exclusion o s udies a e
shown in Table1. This e iew was nei he egis e ed no
was a p o ocol published.
Only o iginal pee - e iewed published scien i ic pape s
we e included. The exclusion c i e ia we e as ollows:
Theses, con e ence pape s, le e s o he edi o , manuals,
li e a u e e iews; s udies wi h au ho s ha ing con lic s
o in e es . A icles a e w i en in a language o he han
English, Spanish, o F ench. S udies based on popula ions
wi h ano exia due o o he medical condi ions. A icles ha
exclusi ely e alua ed communi ies o mic oo ganisms o he
han bac e ia o a chaea. The sea ch yielded a o al o 400
pape s, o which 18 pape s we e inally selec ed ollow-
ing he guidelines o he PRISMA 2020 p o ocol [29], as
shown in Fig.1. Mo eo e , a manual sea ch was pe o med
om he bibliog aphy o he selec ed pape wi hou adding
u he e e ences. A icle sc eening was ca ied ou using
he Rayyan® web applica ion [30]. Ti les and abs ac s we e
independen ly e iewed by wo au ho s (NG and EG).
Da a ex ac ion andsyn hesis
Da a we e ex ac ed o an Excel sp eadshee . The ol-
lowing publica ion in o ma ion was sough : sample size
and desc ip ion, in e en ion o ea men (i applicable),
sequencing and analysis me hods, gu mic obio a ou come
da a ( axa, di e si y) o o he ou comes (e.g., me aboli e le -
els, associa ions be ween gu mic obio a and AN symp oms,
FMT ou comes). No s a is ical analysis was pe o med due
o he he e ogenei y o he included s udies.
Risk o bias
The Newscas le-O awa scale adap ed o c oss-sec ional
s udies [31], he SYRCLE’s RoB ool o animal s udies
[32], and he JBI c i ical app aisal ools ( o case epo and
case se ies) [33] we e used o assess he po en ial bias o
included s udies.
Table 1 PICOS s udy inclusion c i e ia
P eclinical s udies
(P)opula ion Animal model such as as ac i i y-based ano exia (ABA), o gno obio ic humanized oden s ansplan ed wi h gu mic obio a
o AN pa ien s (gAN)
(I)n e en ion ABA ( ood es ic ion and ee access o a unning wheel), o aecal mic obio a ansplan a ion (FMT) o AN pa ien s
(C)ompa ison Mice wi h adlibi um access o ood, wi hou ee access o a unning wheel as a con ol o ABA mice. Gno obio ic mice
ansplan ed wi h he gu mic obio a o no mal weigh indi iduals (gNW) as a con ol o gAN
(O)u comes Pheno ypical di e ences be ween gAN and gNW (beha iou , weigh , o o he s). Mic obio a composi ion in ABA model
(S) udy design Expe imen al design
Clinical s udies
(P)opula ion Indi iduals wi h AN
(I)n e en ion FMT, ea men wi h p e-, p obio ics o no speci ied in e en ion
(C)ompa ison NW (no mal-weigh ) con ol g oup o no con ol g oup
(O)u comes The p ima y ou comes collec ed we e in o ma ion ega ding mic obio a analysis in pa ien s wi h AN ( ela i e o abso-
lu e abundance, di e si y indices), di e ences be ween AN pa ien s and NW con ols o hese pa ame e s, co ela ions
be ween mic obio a composi ion and psychopa hological pa ame e s, aecal me aboli es concen a ions (SCFAs, BFCAs o
o he s), e ec s o FMT, o o he applied in e en ions
(S) udy design Randomized o non- andomized, c oss-sec ional, longi udinal, case se ies o single-case s udies
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Resul s
S udy selec ion and isk o bias
O he ini ial 400 pape s, 147 duplica e pape s we e excluded
as shown in Fig.1. A e he p ima y sc eening, 187 s ud-
ies we e excluded o no being ela ed o he subjec o he
s udy o no being speci ically ocused on AN. 65 o he
emaining 66 we e eco e ed. Finally, a ull- ex e iew
o hese was ca ied ou and 29 e iews we e excluded: 2
pape s w i en in a language o he han English, F ench o
Spanish; 1 doc o al hesis; 5 con e ence abs ac s; 1 le e
o he edi o ; 1 a icle wi h popula ion o he han he a ge ;
7 pape s wi h objec i es di e en o he aims o his e iew,
and 1 esea ch p o ocol.
The quali y o he included s udies is summa ized in Sup-
plemen a y Tables S1, S2, S3.
S udies inhumans
The p esen e iew included i e longi udinal s udies
[34–38], six c oss-sec ional s udies [39–44], wo single case
epo s [45, 46], and a case se ies design [47] he main ea-
u es o which a e summa ized in Table2.
One s udy aimed o analyse he composi ion o in es inal
mic obio a in pa ien s wi h AN [45]. The emaining s ud-
ies, apa om single-case and case-se ies s udies [45–47],
assessed di e ences in in es inal mic obio a be ween AN
and a no mal weigh con ol g oup (NW) adjus ed o age
and sex. O he s udies also compa ed mic obio a composi-
ion in an obese g oup [39, 41, 44], an o e weigh g oup
[41, 44], and a g oup o a hle es [44]. Se en s udies assessed
changes in mic obio a composi ion in pa ien s wi h AN in
esponse o FMT [46], o nu i ional ehabili a ion [34–38,
47]. Finally, wo s udies assessed di e ences in in es inal
Fig. 1 PRISMA lowcha (Page
e al., 2021) showing li e a u e
sea ch
Reco ds iden i ied om:
Da abases (n = 400)
PubMed (n= 105)
WoS (n=156)
ScienceDi ec (n=105)
Psycin o (n=34)
Reco ds emo ed be o e
sc eening:
Duplica ion
(n = 147)
Reco ds sc eened
(n = 253)
Reco ds excluded
I ele an i le (n = 187)
Reco ds sough o e ie al
(n = 66)
Reco ds no e ie ed
(n = 1)
Reco ds assessed o eligibili y
(n = 65) Reco ds excluded:
Re iew (n = 29)
Objec i e o s udy (n = 7)
Sample o s udy (n = 1)
Language (n=2)
Thesis (n=1)
Con e ence abs ac s (n=5)
Le e (n=1)
P o ocol (n=1)
S udies included in e iew
(n = 18)
Iden i ica ion o s udies ia da abases and egis e s
Iden i ica ion
Sc eening
Included
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Table 2 Main cha ac e is ics o human s udies included in he e iew
Au ho , yea S udy design Objec i es Sample cha ac e -
is ics T ea men Measu es Me hods Main esul s
A mougom e al.,
2009 [39]C oss-sec ional Iden i ica ion o
speci ic mic obial
communi ies associ-
a ed wi h AN, OB,
o NW
AN, n = 9
BMI:12.73 ± 1.602
Age: 19–36
OB, n = 20
BMI:47.09 ± 10.66
Age: 17–72
NW, n = 20
BMI:20.68 ± 2.014
Age: 13–68
n/a Mic obiological
Assessmen
Bac e ia copy num-
be / g o aeces
Real- ime qPCR
o mic obio a
species (s ool
sample)
↑ ela i e abundance o M. smi hii in
AN han in NW
P leide e e al., 2013
[45]Case Repo Cul u omic analysis o
AN s ool samples AN, n = 1
BMI: 10.4
Age: 21
n/a Mic obiological
Assessmen
Bac e ial iden i ica-
ion
Mass spec om-
e y (MALDI-
TOF)
Cul u e G ow h
Iden i ica ion o 11 new bac e ial spe-
cies
Million e al., 2013
[41]C oss-sec ional Compa ison o aecal
concen a ions o
Esche ichia coli, M.
smi hii, Bi idobac e-
ium animalis, and
Lac obacillus spp in
OB, OW, NW, and
AN
AN, n = 15
BMI:13.5
(11.7–14.6)
Age: 27.3 ± 10.8
NW, n = 76
BMI:22.4
(20.7–23.7)
Age: 49.5 ± 18.6
OW, n = 38
BMI: 27.1
(25.9–28.6)
Age: 54.1 ± 17.8
OB, n = 134
BMI: 40.0
(36.4–46.8)
Age: 51.8 ± 14.7
n/a Mic obiological
Assessmen
P e alence o each
bac e ial axo-
nomic g oup
Concen a ion
(log10 copies o
DNA / ml)
Real- ime PCR
o mic obio a
species (s ool
sample)
BMI was nega i ely co ela ed o M.
smi hii, E.coli, and B. animalis
BMI was posi i ely co ela ed o Lac o-
bacillus eu e i

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Table 2 (con inued)
Au ho , yea S udy design Objec i es Sample cha ac e -
is ics T ea men Measu es Me hods Main esul s
Mo i a e al., 2015
[43]C oss-sec ional Compa ison o
in es inal mic obio a
composi ion in NW,
ANBP, and ANR
ANR, n = 14
BMI: 12.7 ± 1.5
Age: 28.1 ± 10.7
ANBP, n = 11
BMI: 13.0 ± 1.2
Age: 32.5 ± 9.4
NW, n = 21
BMI: 20.5 ± 2.1
Age: 31.5 ± 7.4
n/a Mic obiological
Assessmen
P e alence o each
bac e ial axo-
nomic g oup
log10 cells / g o
aeces
Biochemical pa am-
e e s
SCFAs
Yakul In es inal
Flo a-SCAN
(YIF-SCAN®):
Re e se an-
sc ip ion-qPCR
o mic obio a
species (s ool
sample) based
on 16S and 23S
RNA analysis
Biochemical
analysis o
blood samples
High-pe o mance
liquid ch o-
ma og aphy
(HPLC) o s ool
samples
↓ bac e ial coun o S ep ococcus, C.
coccoides, C. lep um, B. agilis, and
L. plan a um in AN han in NW
↓ C. coccoides in ANR han in NW
↓ B. agilis in ANR and ANBP han
in NW
↓ ace ic and p opionic acid in AN han
in NW
No signi ican di e ences we e ound
in bu y a e concen a ions be ween
AN and NW
Kleiman e al., 2015
[34]Longi udinal E alua ion o changes
o in es inal mic o-
bio a in AN pa ien s
a e hospi al-based
weigh es o a ion
Compa ison o
in es inal mic obio a
composi ion in AN
and in a no mal
weigh g oup
Assessmen o he
associa ion be ween
mic obial composi-
ion, dep ession,
anxie y, and ea ing
diso de psychopa-
hology
AN0, n = 16
BMI: 16.2 ± 1.5
Age:28 ± 11.7
AN1, n = 10
BMI: 17.4 ± 0.9
NW, n = 12
BMI: 21.5 ± 1.9
Age:29.8 ± 11.6
Du a ion
No speci ied
Type o ea men
Weigh es o a ion
O he unspeci ied
pha macological/
psychological
ea men
Mic obiological
Assessmen
Taxa ela i e abun-
dance
α-di e si y (spe-
cies ichness,
Chao-1 index) and
β-di e si y (Uni-
F ac dis ances)
Psychological
assessmen
Speci ic psycho-
pa hological
cha ac e is ics
ela ed o ea ing
diso de s and,
anxious o dep es-
si e symp oms
16S RNA
sequencing
(V1-V3) (s ool
sample)
BAI, BDI, EDE-Q
↓ gene a o Co iobac e iaceae,
Pa abac e oide es and ↑ gene a o
Ruminococcaceae in AN1 han NW
↑ Bacilli, Co iobac e iales and ↓
Clos idiales, Clos idia, Anae o-
s ipes, Faecalibac e ium in AN0 han
NW
↓ α-di e si y in AN0 and AN1 han NW
Signi ican di e ence in β-di e si y
be ween AN and NW ha no malized
a e ea men
α-di e si y was nega i ely associa ed
o EDE-Q o al sco es, BDI, and
subscales sco es o shape and weigh
conce n
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Table 2 (con inued)
Au ho , yea S udy design Objec i es Sample cha ac e -
is ics T ea men Measu es Me hods Main esul s
Mack e al., 2016 [35] Longi udinal Compa ison o
in es inal mic obio a
composi ion in AN
and NW
E alua ion o changes
in mic obio a
composi ion in pos -
weigh gain and/
o no malisa ion o
ea ing beha iou
Assessmen o SCFAs
p o iles (p e- and
pos -weigh gain)
die a y in ake, and
gas oin es inal
symp oms
AN0, n = 55
BMI: 15.3 ± 1.4
Age: 23.8 ± 6.8
AN1, n = 44
BMI: 17.7 ± 1.4
NW, n = 55
BMI: 21.6 ± 2.0
Age: 23.7 ± 6,7
Du a ion
3,5 ± 1,7mon hs
Type o ea men
Weigh es o a ion
No malized ea ing
habi s
O he unspeci ied
pha macological/
psychological
ea men
Mic obiological
Assessmen
Rela i e abundance
o bac e ial axa
P e alence o bac e-
ial axa
α-di e si y (Spe-
cies ichness,
Chao-1 index,
Shannon index)
and β-di e si y
(unweigh ed
UniF ac dis ance,
B ay–Cu is dis-
simila i y)
SCFAs
Gas oin es inal
symp oms
16S RNA
sequencing (V4)
(s ool sample)
Gas ch oma og-
aphy
Gas o-ques ion-
nai e
↓ Bac e oide es o Fi micu es a io in
AN0 han NW, u he dec easing
a e ea men
↑ Ac inobac e ia in AN0 han in NW
↑ Ve ucomic obia in AN0 han in NW,
no malizing a e ea men
AN0 shows ↑ ela i e abundance o
M. smi hii (bu ↓ p e alence), mucin
deg ading bac e ia (Anae os ipes,
Anae o uncus, Akke mansia),
Clos idium clus e I, XI, XVIII, and
Bi idobac e ium
No signi ican di e ences in α-di e si y
be ween AN and NW
Signi ican ly lowe β-di e si y in he
same AN indi idual a di e en imes
(AN0-AN1) han in di e en subjec s
in he espec i e g oups
↑ ale a e, iso-bu y a e and, BFCAs
concen a ions in AN0 and AN1 as
comp ed o NW
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Table 2 (con inued)
Au ho , yea S udy design Objec i es Sample cha ac e -
is ics T ea men Measu es Me hods Main esul s
Mö kl e al., 2017 [44] C oss-sec ional Compa ison o in es-
inal mic obio a in
AN, AT, NW, OW,
and OB g oups
AN, n = 18
BMI: 15.3 ± 1.3
Age: 22.44 ± 3.20
AT, n = 20
BMI:22.14 ± 1.76
Age: 22.15 ± 3.86
NW, n = 26
BMI:21.89 ± 1.73
Age: 24.93 ± 3.75
OW, n = 22
BMI:26.99 ± 1.13
Age: 25.32 ± 3.98
OB, n = 20
BMI:34.55 ± 4.43
Age: 26.9 ± 6.10
n/a Mic obiological
Assessmen
Rela i e abundance
o bac e ial axa
α-di e si y (spe-
cies ichness,
Chao-1 index,
Shannon index)
and β-di e si y
(weigh ed and
unweigh ed Uni-
F ac dis ance)
Psychological
assessmen
Dep essi e symp-
oms
An h opome ic
assessmen
(%) body a
Body a dis ibu-
ion
Biochemical Pa am-
e e s
16S RNA
sequencing
(V1-V2) (s ool
sample)
BDI, HAMD
BIA, ul asound
measu emen s
↑ Co iobac e iaceae in AN han in NW
No signi ican di e ences in α- and
β-di e si y be ween AN and NW, bu
signi ican di e ences be ween AN
and AT
α-di e si y was nega i ely co ela ed
o BDI sco es when all g oups we e
included in he analysis
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Table 2 (con inued)
Au ho , yea S udy design Objec i es Sample cha ac e -
is ics T ea men Measu es Me hods Main esul s
Bo go e al., 2017 [40] C oss-sec ional E alua ion o he
ela ionship be ween
in es inal mic o-
bio a composi ion,
nu i ional s a us,
and psychological
cha ac e is ics in
ANR
ANR, n = 15
BMI:13.82 ± 1.80
Age: 25.6 ± 7.97
NW, n = 15
BMI:22.06 ± 2.55
Age: 24.4 ± 5.79
n/a Mic obiological
Assessmen
Rela i e abundance
o bac e ial axa
P e alence o M.
smi hii
M. smi hii copy
numbe
α-di e si y and
β-di e si y (OTU-
based me hods)
Psychological
assessmen
Gene al psychopa-
hology, ypical
cogni i e and
beha iou al
cha ac e is ics o
ea ing diso de s,
and anxious o
dep essi e symp-
oms
SCFAs
16S RNA
sequencing
(V3-V4) (s ool
sample)
Real- ime qPCR
o M. smi hii
SCL-90, EDI-2,
STAI-Y, BDI-II
Gas ch oma og-
aphy
↓ Fi micu es, Ruminococcus, Rose-
bu ia, Clos idium, and ↑ P o eo-
bac e ia, En e obac e iaceae in AN
han NW
↑ p e alence and absolu e abundance o
M. smi hii in AN han NW
No signi ican di e ences in α- and
β-di e si y be ween AN and NW
BMI was nega i ely associa ed o
obsession-compulsion sco e (SCL-
90), s a e anxie y sco e (STAI-Y),
ai anxie y sco e (STAI-Y), and BDI
o al sco e
Clos idium spp. was nega i ely co -
ela ed wi h BDI sco e
↓ bu y a e and p opiona e le els in AN
han in NW
No di e ences in ace a e, iso- ale a e
and iso-bu y a e le els be ween AN
and NW
Bu y a e was nega i ely co ela ed o
dep ession and anxie y sco es
Kleiman e al., 2017
[47]Case se ies Cha ac e iza ion o
daily changes in
in es inal mic obio a
composi ion and
di e si y in h ee
acu e AN pa ien s
du ing hospi al-
based enou ishmen
AN0, n = 3
BMI: 15.6,
17.6,13.7
Age: 25,29,16
AN1,
BMI: 20.2, 21.1,
15.4
Du a ion
Be ween 34 and
73days
Type o ea men
Weigh es o a ion
O he unspeci ied
pha macological/
psychological
ea men
Mic obiological
Assessmen
Rela i e abundance
o bac e ial axa
α-di e si y (Shan-
non index) and
β-di e si y
(unweigh ed Uni-
F ac dis ance)
Biochemical pa am-
e e s
16S RNA
sequencing (V4)
(s ool sample)
Pa ien -speci ic changes in in es inal
mic obio a composi ion and di e si y
du ing enou ishmen
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1 Page 16 o 24
FMT in a case o AN ound signi ican changes in s uc u e,
in es inal pe meabili y, di e si y, and ela i e abundances
o A. muciniphila and M. smi hii ha we e un ela ed o
imp o ed gas oin es inal symp oma ology, mood, o ea -
ing beha iou [46].
One s udy e alua ing daily changes in in es inal mic o-
bio a composi ion and di e si y in h ee pa ien s obse ed
hese changes we e speci ic o each indi idual [47]. Ano he
s udy assessing gas ic symp oma ology and i s e olu ion in
esponse o nu i ional ehabili a ion ound no imp o emen
o e en a wo sening o symp oms o he uppe ac a e
ea men such as abdominal pain, in es inal noises, and a
sensa ion o incomple e e acua ion despi e he changes in
ela i e abundances [35]. Finally, ano he s udy obse ed a
educ ion in aecal GABA and dopamine concen a ions in
ANR0 ela i e o NW con ols [37].
Animal s udies
As shown in Table5, ou s udies wi h di e en animal mod-
els examined he causal ole o mic obio a in he de elop-
men o AN [64–67].
Two o hese s udies employed ge m- ee mouse mod-
els (Mus musculus), C57BL/6 [65], and BALB/c [66]. One
s udy employed C57Bl/6JRj mice [64], while ano he used
Wis a a s [67]. The e we e also di e ences ega ding he
sex o he animals i.e., wo s udies employed emales [66,
67], one s udy used males [64], and ano he mixed g oups
[65].
Two s udies pe o med human aecal mic obio a ans-
plan s in animal models [65, 66]. One s udy colonized
he same gene a ion o ally om ozen aeces [65], while
ano he colonized he pa en gene a ion om esh aeces,
using o sp ing as pa o he expe imen [66]. The main
objec i es o hese s udies we e o examine di e ences in
weigh gain [65, 66], and beha iou [66] in mice econs i-
u ed wi h aecal mic obio a om AN pa ien s (gAN) as
compa ed o mice wi h no mal weigh con ol mic obio a
(gNW); and o analyse he ela ionship be ween bac e ial
axa and weigh gain o beha iou [65].
Mo eo e , wo s udies e alua ed di e ences in in es inal
mic obio a composi ion in animal models unde he ABA
p o ocol as compa ed o con ol g oups in di e en nu i ion
and ac i i y condi ions [64, 67]. Thus, da a a e epo ed o
di e en con ol g oups: a con ol g oup wi hou ood o
ac i i y es ic ions (C) [64, 67]; a con ol g oup wi h ac i -
i y and ood es ic ion [64]; a educed body weigh con ol
g oup ( educ ion o ood o main ain a 25% lowe ing in body
weigh wi hou physical ac i i y), and a con ol g oup wi h-
ou ood es ic ion and wheel access (CRW) [67].
In all expe imen s, mic obio a analysis was pe o med
by 16S RNA sequencing using he V3-V4 egion [66, 67],
V4 [65] as he p ime , o V5–V6 [64]. Fu he mo e, 5-HT
and 5-HIAA concen a ions in b ain issue [66], educ ions
in b ain olume and in he numbe o as ocy es [64], and
di e ences in anxie y le els we e assessed using beha iou al
es s (open ield es o ma ble bu ying es ), as well as he
e ec s o p obio ic ea men (Bac e oides ulga us) on
beha iou [66].
Faecal mic obio a ansplan expe imen s yielded incon-
sis en esul s i.e., one s udy ound gAN animals exhibi ed
signi ican ly less weigh gain han gNW animals, wi h longe
imes in he pe iphe al quad an s in he open ield es , and
a highe numbe o bu ied ma bles, indica ing highe le els
o anxie y [66], bu ano he s udy ound no signi ican di -
e ences be ween he wo g oups [65].
S udies e alua ing aecal mic obio a in animal models
unde he ABA p o ocol showed ha in he a model he e
we e signi ican di e ences in composi ion and di e si y
be ween he expe imen al g oups, which we e mainly linked
o educed in ake a he han hype ac i i y [67]. Howe e ,
no signi ican di e ences in alpha di e si y we e obse ed
in mice, bu a highe ela i e abundance o Clos idium clo-
clea um was ound in he ABA model, as well as a posi i e
co ela ion be ween he ela i e abundance o Bu kholde-
iales and body weigh , ood in ake, and he pe cen age o
lean mass [65].
Discussion
In ecen yea s, nume ous s udies ha e claimed mic o-
bio a is a po en ial causal explana o y ac o o AN. This
esea ch is based on he desc ip ion o an in es inal dysbio-
sis associa ed o pa hology, a deduc ion unde lying mos o
he human s udies included in his e iew (Supplemen a y
TableS5), which con as s wi h he inconsis ency in he
esul s ob ained (Table2). The de ini ion o dysbio ic s a e in
AN di e s om one s udy o ano he and has been explained
in di e en ways: due o he imma u i y o he echniques,
he me hodological di e ences be ween he s udies, and he
ambigui y o he e m i sel .
As indica ed by Hooks & O'Malley [68], “ he b oade
he de ini ion, he easily i is de ec ed.” (p.6). The concep
o dysbiosis in he cu en li e a u e poses p oblems in bo h
p ecision and consensus and is usually associa ed wi h
mic obio a “imbalance” in e ms o di e ences in he ela-
i e abundances and di e si y pa ame e s. Howe e , owing
o he high in e -indi idual a iabili y in mic obio a compo-
si ion in humans [5, 9], he e is a lack o no ma i e da a on
wha is heal hy o no mal [68]. Fu he mo e, he compa ison
wi h heal hy indi iduals c ea es a ci cula allacy whe eby a
pa hological p ocess causes dysbiosis which, in u n, leads
o a pa hological p ocess [4]. Hence, i would be eason-
able o ask whe he he compa ison wi h a no mal weigh
g oup does eally p o ide ele an in o ma ion ega ding he

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Table 5 Main cha ac e is ics o animal s udies included in he e iew
Au ho , yea Objec i es Sample cha ac e is ics In e en ion/T ea men Measu es Me hods Main esul s
Ha a e al., 2019 [66] Compa ison o body
weigh gain and beha -
iou al cha ac e is ics
be ween gAN and gNW
AN, n = 4
BMI: 13.7 ± 0.1kg/m2
Age: 23.0 ± 3.4
NW, n = 4
BMI: 21.6 ± 1.2kg/m2
Age: 25.3 ± 0.8
Animal model
Female GF BALB/c mice
Sample o mic obiologi-
cal assessmen
ngAN = 40
ngNW = 40
Sample o weigh gain
and ood e iciency
analysis
ngAN = 35
ngNW = 37
Sample o beha iou al
assessmen
ngAN = 35
ngNW = 37
Sample o analysis o
5-HT and 5-HIIA le els
ngAN = 10
ngNW = 10
Expe imen al in e en ion
T ansplan a ion o aecal
mic obio a om AN o
NW in o pa en al GF
mice
P obio ic ea men o
gAN (Bac e oides
ulga us, 5 × 108 UFC/
once a week)
Mic obiological assess-
men
Rela i e abundance o
bac e ial axa
Beha iou al analysis
ime spen in he 12
pe iphe al subsqua es
o 20min
numbe o ma bles bu ied
mo o ac i i y ( o al
dis ance a elled o
20min)
O he measu es
5-HT and 5-HIAA le els
in b ain issue
% o body weigh change
Cumula i e ood in ake
Food e iciency
16S RNA sequencing
(V3-V4) (s ool sample)
Open- ield es
Ma ble bu ying es
↓ Rela i e abundance o
Bac e oide es and B. a-
gilis in AN han in NW
↓ body weigh gain in gAN
han in gNW
↓ ood e iciency in gAN
han in gNW
Food e iciency was sig-
ni ican ly co ela ed o
Odo ibac e o Su e ella
gAN spen signi ican ly
mo e ime in pe iphe al
subsqua es han gNW in
an open- ield es
gAN bu ied mo e ma bles
han gNW in ma ble bu y-
ing es
↓ 5-HT le els in gAN
b ains em
No signi ican changes in
5-HIAA le els
Adminis a ion o B. ulga-
us ↓ nº o bu ied ma bles
in gAN mice
No signi ican di e ences
in mo o ac i i y be ween
gAN and gNW mice
T inh e al., 2021
[67]Analysis o al e a ions
in aecal mic obio a in
a s using he modi ied
ABA-model wi h con ol
g oups unde di e en
s a a ion and ac i i y
condi ions
Animal model
Female Wis a a s
C, n = 12
CRW, n = 12
RBW, n = 12
ABA, n = 13
Expe imen al condi ions
CRW
RBW
ABA
Mic obiological assess-
men
Rela i e abundance o
bac e ial axa
α-di e si y (Species ich-
ness, Shannon index)
and β-di e si y (UniF ac
dis ances)
O he measu es
Body weigh (mean g/day)
Running-wheel ac i i y
(mean dis ance (km)/
day)
Food in ake (mean g/day)
His ological b ain olume
GFAP-posi i e cells pe
mm2
mRNA exp ession o
GFAP
16S RNA sequencing
(V3-V4) (s ool sample)
Re e se ansc ip ion-
qPCR
Real ime-PCR
an i-GFAP an ibody
s aining
Ch onic ood es ic ion ↑
α-di e si y
β-di e si y in RBW and
ABA g oups we e signi i-
can ly di e en om hose
in he C and CRW g oups
↓ P e o ella, ↑ Odo ibac e ,
Lac obacillus, Akke -
mansia, Bi idobac e ium,
Ruminococcus in animals
wi h educed bodyweigh
in compa ison o con ol
a s
Ch onic ood es ic ion had
a signi ican in luence on
gu mic obio a composi-
ion
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Table 5 (con inued)
Au ho , yea Objec i es Sample cha ac e is ics In e en ion/T ea men Measu es Me hods Main esul s
B e on e al., 2021
[64]Cha ac e iza ion o gu
mic obio a dysbiosis in
an ABA model
Co ela ions be ween he
in es inal bac e ial com-
posi ion and he le els o
neu opep ides POMC,
o NPY
Animal model
Male C57Bl/6JRj mice
C, n = 6–8
LFA, n = 6–8
ABA, n = 6–8
Expe imen al condi ions
LFA
ABA
Mic obiological assess-
men
Rela i e abundance o
ASV
α-di e si y (Species ich-
ness and Shannon index)
Quan i ica ion o neu o-
pep ide exp ession
NPY and POMC mRNA
le els
O he measu es
Body weigh (mean g/day)
Food in ake (mean g/day)
Running dis ance o ABA
mice (mean dis ance
(km)/ day)
16S RNA sequenc-
ing (V5-V6) in mouse
cecum
qPCR
quan i ica ion o mRNA
le els
The e a e no signi ican
di e ences in α-di e si y
be ween C, LFA and ABA
mice
↑ ela i e abundance
o Bu kholde iales,
Clos idium clús e XVIII
and Lac obacillus in C
han in ACL and ABA
↑ C. cloclea um in ABA
and ACL han in C
No signi ican di e ences in
he ela i e abundance o
Rosebu ia spp., A. mucin-
iphila and M. smi hii
be ween g oups
Bu kholde iales was posi-
i ely co ela ed o body
weigh , ood in ake, and
lean mass
Lac obacillales was nega-
i ely co ela ed o body
weigh , ood in ake and
lean mass
11 bac e ial uni s we e
posi i ely co ela ed o
he POMC hypo halamic
le el
3 bac e ial uni s we e nega-
i ely co ela ed o NPY
hypo halamic le els
All bac e ial uni s we e
posi i ely co ela ed o
body weigh and ood
in ake
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Table 5 (con inued)
Au ho , yea Objec i es Sample cha ac e is ics In e en ion/T ea men Measu es Me hods Main esul s
Glenny e al., 2021
[65]E alua ion o he e ec s
AN in es inal mic obio a
on body composi ion
and weigh gain in gno-
obio ic mice
AN0, n = 4
BMI: 13.8 ± 0.8kg/m2
Age: 18.3 ± 0.3
AN1, n = 4
BMI: 18.0 ± 0.9kg/m2
NW, n = 4
BMI: 22.0 ± 0.7kg/m2
Age: 18.5 ± 0.3
Animal model
Male and emale GF
C57BL/6 mice
ngAN0 = 50
ngAN1 = 53
ngNW = 50
AN ea men
Weigh es o a ion
Expe imen al in e en ion
T ansplan a ion o mic o-
bio a de i ed om AN0,
AN1, and NW in o GF
mice
(Thawed human s ool,
o al adminis a ion)
Mic obiological assess-
men
Rela i e abundance o
bac e ial axa
log10 no malized coun
α-di e si y (Shannon
index) and β-di e si y
(non-me ic mul idimen-
sional scaling, B ay–
Cu is dissimila i y)
Ano he measu es
% change in body com-
posi ion
% change in body weigh
A e age daily ood in ake
(g/day)
16S RNA sequenc-
ing (V4) (human and
colonized mice s ool
samples)
qPCR
No ela ionship be ween
AN-associa ed in es inal
mic obio a and changes
in body weigh , a mass,
lean mass, o daily ood
consump ion
No signi ican di e ences
in α- and β-di e si y
be ween gAN0 and gAN1
Age and BMI measu emen s a e epo ed, when equi ed, as mean ± SD. AN0 (indi iduals wi h ano exia ne osa be o e ea men ), AN1 (indi iduals wi h ano exia ne osa a e ea men ), NW
(no mal weigh con ol g oup), gAN (gno obio ic mice econs i u ed wi h gu mic obes de i ed om indi iduals wi h AN), gNW (gno obio ic mice ansplan ed wi h gu mic obio a o no mal
weigh emale subjec s), gAN0 (gno obio ic mice ansplan ed wi h gu mic obio a om AN0), gAN1 (gno obio ic mice ansplan ed wi h he gu mic obio a om AN1), C (con ol animals wi h
adlibi um access o ood, wi hou ee access o a unning wheel), CRW (con ol animals wi h adlibi um access o ood and ee access o a unning wheel), RBW (con ol animals wi h a 25%
educ ion in body weigh ), ABA (expe imen al g oup exposed o ood es ic ion and ee access o a unning wheel), LFA (con ol g oup wi h es ic ed access o ood and wi hou access o a
unning wheel), GF (ge m- ee), ASV (amplicon sequence a ian ), HIAA (5-hyd oxyindoleace ic acid), 5-HT (se o onin), POMC (p o-opiomelanoco in), NPY (neu opep ide Y), GFAP (glial
ib illa y acidic p o ein)
↓ Signi ican dec ease
↑ Signi ican inc ease
Ea ing and Weigh Diso de s - S udies on Ano exia, Bulimia and Obesi y (2023) 28:1
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1 Page 20 o 24
ae iology o AN. Fo mic obio a o be ega ded as an ae io-
logical ac o in AN, i no only has o be di e en om ha
o no mal weigh people bu also di e en om o he s a es
o malnu i ion.
Fu he mo e, ield s udies a e s ill in hei in ancy, wi h
no clea ly es ablished p o ocols and wi h majo obs acles
o o e come in he analyses [69, 70]. Massi e sequencing
echniques p o ide da a o a composi ional na u e, collec ed
as ela i e abundance, which poses a challenge o s a is ical
analysis [69–71]. Thus, an absolu e abundance canno be
in e ed since he o al numbe o eads pe sample p o ided
by he sequencing pla o ms e lec a echnical a i ac , un e-
la ed o an ac ual biological composi ion [69, 71]. Conse-
quen ly, he da a a e no independen o each o he , and he
inc ease in he ela i e abundance o one axon au oma ically
causes changes in ha o o he s [69, 71, 72]. This implies he
need o be p uden in analysing he esul s. I can be mislead-
ing o say ha a axon inc eases because o a physiological
dis u bance, wi hou conside ing a speci ic e e ence poin
[71, 72]. In addi ion, he p obabili y o alse posi i es, and
spu ious co ela ions will inc ease [69]. A p esen , e en
hough di e en analy ical solu ions ha e been p oposed, he
con ol o hese a iables has no been comple ely esol ed
[70, 71], aising se ious doub s ega ding he au hen ici y o
he co ela ions epo ed in he s udies e iewed, as well as
he di e ences ob ained be ween g oups.
Mo eo e , quan i a i e echniques (qPCR) ha e been used
o ob ain absolu e da a wi h espec o a speci ic numbe o
axa. Though se e al s udies ha e ound a high abundance o
M. smi hii, he biological implica ions o his inding emain
con o e sial. Thus, i may be in ol ed in cons ipa ion o en
obse ed in AN, o unc ion as an adap i e ac o o low
nu i ion inc easing ene gy e iciency [73].
In he es ablishmen o causal ela ionships, ha is, in he
sea ch o explana o y mechanisms, wo me hodologies ha e
been used i.e., humanized gno obio ic animal models and
FMT. As o he o me , Wal e e al. [10] ecen ly poin ed
ou he lack o igo in hese designs. A small numbe o
dono s a e usually used, whose mic obio a is ans e ed o
a much la ge numbe o animals, a i icially in la ing he
sample size. This, on he one hand, does no allow ep esen -
ing he high in e -indi idual a iabili y exis ing in he com-
posi ion o he human mic obio a and, on he o he hand,
a ou s pseudo eplica ion, inc easing he p obabili y o
alse posi i es [10]. The humanized gno obio ic animal s ud-
ies included in his e iew [65, 66] showed his weakness in
design, in addi ion o di e gen esul s ha cas easonable
doub on he conclusions d awn.
In his e iew, he FMT ea men was adminis e ed o
only one pa ien in one s udy [46], wi hou posi i e esul s in
ood in ake, weigh , o a ec i e and gas oin es inal symp-
oms ega dless o he modi ica ion in mic obio a composi-
ion. In he li e a u e, ano he publica ion epo ing posi i e
esul s wi h he same me hodology was excluded due o a
decla ed con lic o in e es [74].
Bea ing in mind he abo e indings, claims o an in es i-
nal dysbiosis associa ed o AN a e a bes specula i e gi en
ha he cu en e idence on he p oposed heo e ical mecha-
nisms is a he sca ce [1, 7]. Thus, e en hough mul iple
s udies ha e unde sco ed he possible ole o SCFAs, he
esul s we e highly inconsis en , and ailed o suppo his
assump ion, as shown in Table3. As o Fe isso & Hök-
el ’s [23] p oposal, inc eases in En e obac e iaceae canno
be subs an ia ed due o i s widesp eaddis ibu ion in he
human in es ine, hough i migh be a sou ce o an igens
e en in he absence o any al e a ion. Thus, his model has
wo main weaknesses. Fi s , he e is he assump ion o a
common o igin o AN, bulimia ne osa, and binge ea ing
diso de [23]. This assump ion has been s ongly challenged
[75, 76], on he g ounds o hinde ing he in eg a ion o bio-
logical e idence [76], and he homogeniza ion o ea ing dis-
o de s [75] ha dilu e he impo ance o undamen al ac o s
o unde s anding he ae iology o AN, such as malnu i ion
and i s in e ac ion wi h physical ac i i y [77]. Thus, he e
is no consis en e idence suppo ing Fe isso & Hök el ’s
[23] assump ion as he da a was ob ained om he e ogene-
ous samples composed o se e al o hese h ee ca ego ies.
Second, co ela ions be ween au oan ibodies o ClpB and
AN ha e no been es ablished wi h he mos objec i e AN
diagnos ic signs, bu wi h subjec i e symp oms [24, 78, 79],
such as he pu sui o hinness. Howe e , as poin ed ou by
Gu ié ez & Ca e a [14, 80], his ea u e is no ep esen a-
i e o all AN cases.
Hence, hese wo sho comings may explain why IgG
au oan ibodies agains α-MSH ha e been ound in AN
pa ien s and no mal weigh con ols [24, 81–83], he high
in e -indi idual a iabili y ha has been obse ed [79, 83],
and he inconsis en da a ega ding he e y exis ence o a
g ea e concen a ion o his bac e ia in AN [24, 79, 83].
Mo eo e , di e ences in molecula a ini y p ope ies a e
inconclusi e, as some imes he dissocia ion a e may be
highe [84], o lowe [83] in AN han in a no mal weigh
con ol g oup.
Mo eo e , u he esea ch on he ole o ClpB in pe iph-
e al and cen al sa ie y pa hways is equi ed since i s in ol e-
men in PYY sec e ion comes om in i o s udies [26], o
om s udies wi h low sample size [25, 26]. Fu he mo e,
one s udy epo ed a agmen o he ClpB molecule wi h
an α-MSH homologous sequence wi h no ac i i y on MC3R
and MC4R ecep o s [85], and no signi ican di e ences in
concen a ions be ween AN pa ien s and no mal weigh con-
ols [78].
Finally, u he esea ch is equi ed o asce ain i hese
molecules a e anspo ed h ough he blood–b ain ba ie ,
and o de e mine he mechanisms enabling hem o c oss
he in es inal ba ie , as he e idence ega ding in es inal
Ea ing and Weigh Diso de s - S udies on Ano exia, Bulimia and Obesi y (2023) 28:1
1 3
Page 21 o 24 1
hype pe meabili y in AN pa ien s is inconsis en [83, 86,
87]. Likewise, he ecen in eg a ion o he ole o CCK-4
in his model [27] is also con o e sial. The anxiogenic
cha ac e o his pep ide was obse ed in he 70s o he
XX cen u y and was a ibu ed o an agonis ic ac ion on he
CCK2 b ain ecep o [88]. Howe e , e agas in is a syn-
he ic molecule whose na u al endogenous syn hesis has no
been demons a ed [88, 89]. In addi ion, he main o ms o
cholecys okinin (CCK) p esen in plasma (CCK-58, 33, 22
and 8) [90] ha e been ound in low concen a ions, in he
ange o pMol/L, a om peak in he nanomola ange gen-
e a ed by CCK-4, and i emains o be de e mined whe he
hey can c oss he blood–b ain ba ie signi ican ly o a ec
CCK2 ecep o s and ha e panicogenic ac i i y [88].
A u he con o e sial issue is Sudo’s [22] explana ion o
hype ac i i y in AN, which was inconsis en wi h he ind-
ings o he p esen e iew. The animal s udies e iewed [64,
67] showed a bac e ial composi ion mainly associa ed wi h
die a y es ic ion qui e di e en om he es ic i e eed-
ing schedule o he ABA model. Despi e obse ing a lowe
le el o se o onin in he b ains em o he gAN g oup, Ha a
e al. [66] epo ed no signi ican di e ences in mo o ac i -
i y. Al e a ions in he se o one gic pa hways associa ed wi h
AN ha e been desc ibed in he li e a u e, bu hey ha e no
been es ablished as exclusi e o he condi ion [91]. Se o o-
nin (5-HT) could be in ol ed in inc eased ac i i y h ough
pa icipa ion in he a e si e mo i a ional sys em, opposi e
o he dopamine gic one [92]. Howe e , 5-HT- ela ed in e -
en ions es ed in he ABA model we e pa ially e ec i e,
whe eas in humans, hey we e no [91–93].
S eng h andlimi s.
The main limi a ion o his e iew es on i s quali a i e
na u e, as well as di icul ies in in e p e ing he esul s
gi en he b oad me hodological di e si y, and he lack
o concep ual consensus. Mo eo e , he dea h o s udies
e alua ing he unc ionali y o mic obio a, and he small
samples mos ly composed o Eu opean women, p o ide a
pa ial iew o he issue. Ne e heless, his e iew seeks o
p o ide insigh in o he cu en sho comings in he ield,
and o add ess he explana o y di icul ies associa ed wi h
he assump ion o mic obio a as a cen al ae iological agen
o AN.
Wha we al eady know on his subjec ?
In ecen yea s, he e iological ole o mic obio a in AN has
unde gone a e i al, and s udies ha e unde sco ed he ole o
in es inal dysbiosis, which has p omp ed i s econcep ualiza-
ion as a me abo-psychia ic diso de .
Wha does his s udy add?
This e iew includes clinical and p eclinical e idence pub-
lished in June 2022 ega ding he ela ionship be ween gu
mic obio a and AN. The inconsis ency in he esul s ailed o
subs an ia e he iew o mic obio a as an explana o y ac o
o AN. Sho comings such as poo consensus, me hodologi-
cal limi a ions, and ambiguous de ini ions a e inhe en o a
ield ha is jus s a ing o eme ge/mo e.
Conclusions
Owing o he lassi ude o he e m dysbiosis, and he lack
o s udies e alua ing di e ences be ween AN and o he
cases o malnu i ion, he exis ence o a pa hologically
speci ic mic obio a composi ion associa ed wi h AN
has no been subs an ia ed o da e, which unde mines i s
ae iological ole. Fu he esea ch and new p o ocols a e
equi ed o ad ance a e ou unde s anding and gene a e
new da a o ully elucida e he ole o mic obio a. How-
e e , his accomplishmen should no o e look he cau-
ious wo ds o Hanage [94], when he wa ned, “In p e-sci-
en i ic imes when some hing happened ha people did no
unde s and, hey blamed i on spi i s. We mus esis he
u ge o ans o m ou mic obial passenge s in o mode n-
day phan oms” (p. 248).
Supplemen a y In o ma ion The online e sion con ains supplemen-
a y ma e ial a ailable a h ps:// doi. o g/ 10. 1007/ s40519- 023- 01529-4.
Au ho con ibu ions Bo h au ho s con ibu ed equally o he
manusc ip .
Funding Open Access unding p o ided hanks o he CRUE-CSIC
ag eemen wi h Sp inge Na u e. Suppo ed by he esea ch budge o
he Unidad Ven es Clinicos, Uni e si y o San iago de Compos ela.
Da a a ailabili y The da ase s gene a ed du ing and/o analysed du -
ing he cu en s udy a e a ailable om he co esponding au ho on
easonable eques .
Decla a ions
Con lic o In e es s The au ho s decla e ha hey ha e no compe ing
in e es s.
Open Access This a icle is licensed unde a C ea i e Commons A i-
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Ea ing and Weigh Diso de s - S udies on Ano exia, Bulimia and Obesi y (2023) 28:1
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