oyalsocie ypublishing.o g/jou nal/ s b
Re iew
Ci e his a icle: Ma i an E, Quaglia iello A,
F ago E, Pa a nello T, Ma ino ME. 2024 The
ole o animal hos s in shaping gu
mic obiome a ia ion. Phil. T ans. R. Soc. B
379: 20230071.
h ps://doi.o g/10.1098/ s b.2023.0071
Recei ed: 10 July 2023
Accep ed: 10 Oc obe 2023
One con ibu ion o 18 o a heme issue
‘Sculp ing he mic obiome: how hos ac o s
de e mine and espond o mic obial
coloniza ion’.
Subjec A eas:
mic obiology, ecology, immunology, e olu ion
Keywo ds:
hos –mic obe in e ac ion, gu mic obio a,
holobion
Au ho o co espondence:
Ma ia Elena Ma ino
e-mail: [email p o ec ed]
The ole o animal hos s in shaping gu
mic obiome a ia ion
Elisa Ma i an
1
, And ea Quaglia iello
1
, En ic F ago
2
, Tomaso Pa a nello
1
and
Ma ia Elena Ma ino
1
1
Depa men o Compa a i e Biomedicine and Food Science, Uni e si y o Pado a, 35020 Pado a, I aly
2
CIRAD, UMR CBGP, INRAE, Ins i u Ag o, IRD, Uni e si é Mon pellie , 34398 Mon pellie , F ance
MEM, 0000-0001-5038-5605
Millions o yea s o co-e olu ion be ween animals and hei associa ed
mic obial communi ies ha e shaped and di e si ied he na u e o hei
ela ionship. S udies con inue o e eal new laye s o complexi y in hos –
mic obe in e ac ions, he a e o which depends on a a ie y o di e en ac-
o s, anging om neu al p ocesses and en i onmen al ac o s o local
dynamics. Resea ch is inc easingly in eg a ing ecosys em-based app oaches,
me agenomics and ma hema ical modelling o disen angle he indi idual
con ibu ion o ecological ac o s o mic obiome e olu ion. Wi hin his
amewo k, hos ac o s a e known o be among he dominan d i e s o
mic obiome composi ion in di e en animal species. Howe e , he ex en
o which hey shape mic obiome assembly and e olu ion emains unclea .
In his e iew, we summa ize ou unde s anding o how hos ac o s d i e
mic obial communi ies and how hese dynamics a e conse ed and a y
ac oss axa. We conclude by ou lining key a enues o esea ch and highligh
he need o implemen a ion o and key modi ica ions o exis ing heo y o
ully cap u e he dynamics o hos -associa ed mic obiomes.
This a icle is pa o he heme issue ‘Sculp ing he mic obiome: how
hos ac o s de e mine and espond o mic obial coloniza ion’.
1. In oduc ion
All animals a e chime ic c ea u es, co e ed inside and ou wi h mic o-
o ganisms, collec i ely called ‘mic obio a’. The collec ion o genomes o such
mic obial communi ies, oge he wi h hei s uc u al elemen s and me aboli es,
is e e ed o as he ‘mic obiome’[1]. Hos -associa ed mic obiomes make
essen ial con ibu ions o animal heal h by ex ac ing nu ien s om die a y
subs a es, p omo ing hos de elopmen , s imula ing he immune sys em, and
p o ec ing he hos om in asion by pa hogens and o he na u al enemies. In
e u n, he hos p o ides a nu ien - ich en i onmen and addi ional de ence
sys ems agains mic obial compe i o s [2].
One o he cen al goals o hos –mic obe esea ch is o unde s and he
ecological ac o s ha d i e he composi ion o hos -associa ed mic obiomes.
T adi ionally, esea che s ha e used heo e ical models and expe imen al obse -
a ions o ask unde wha condi ions local dynamics (selec ion by hos ac o s)
ou weigh neu al dynamics (i.e. ansmission, d i , p io i y e ec s) in explain-
ing a ia ion in hos mic obiomes. In his ega d, hos ac o s, such as
de elopmen al s age and gene ic backg ound, ha e been shown o in luence
gu mic obiome composi ion ac oss di e en animal species (e.g. humans,
mice, zeb a ish, chicken, ca le, swine) [3]. A he same ime, neu al models
and en i onmen al ac o s (e.g. die , biogeog aphy, d ugs) ha e been ound
o bes desc ibe gu mic obiome composi ion in animals, including humans
[4]. Howe e , despi e la ge-scale sampling e o s, he ela i e con ibu ion
o such ecological ac o s and how hey con e ge o de e mine mic obiome
a ia ion ac oss animals is s ill elusi e. As a esul , he main o ces ha
de e mine hos -associa ed mic obiome a ia ion emain poo ly unde s ood.
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In his e iew, we summa ize ou cu en unde s anding
o how hos - ela ed ac o s d i e a ia ion in he gu mic o-
biome. Ou goal h oughou is o highligh conse ed
mechanisms as well as di e ences in he complex hos -le el
selec ion o mic obio a composi ion ac oss animal hos s.
To b eak down his complexi y, we ocus on ou main
hos - ela ed ac o s: ana omy, geno ype, e ical ansmission
and immune esponse. Finally, we discuss he di ec ion o
u u e esea ch in hos –mic obe symbiosis and he impo -
ance o in eg a ing concep s and app oaches o explain he
dynamics o hos –mic obe in e ac ions.
2. Ana omy
Mic obiome assembly in animal hos s begins a bi h and,
du ing hos de elopmen , i unde goes a a ie y o dynamic
p ocesses ha in luence i s es ablishmen , unc ion and
e olu ion. One o he main ac o s explaining he a ia ion
in gu mic obiome ac oss animals is based on hei ana om-
ical di e ences. O gan and epi helial peculia i ies (e.g.
leng h, su ace a ea, ansi ime), oge he wi h a ia ions
in physico-chemical condi ions (e.g. pH, edox po en ial,
oxygen a ailabili y, an imic obial compounds) along he
gas oin es inal (GI) ac a e c ucial egula o s o mic obial
homeos asis, shaping he composi ion, densi y and coloniza-
ion a e o gu mic obiome ac oss e eb a e and in e eb a e
axa ( igu e 1aand able 1).
All animals, including humans, sha e signi ican mic o-
biome he e ogenei y along he in es ine, wi h mic obes
dis ibu ed along a g adien o in ensi y, s a ing om he
low numbe s o mic obial cells pe g am o gu con en in
he uppe GI egions o signi ican ly highe alues in he
dis al pa s o he gu . In he uppe GI egions, his dis i-
bu ion is mainly d i en by he acidic condi ions (luminal
pH < 3), coupled wi h he high concen a ions o hos
sec e ions (e.g. an imic obial e ec o s, bile acids, panc ea ic
(a)in es ine
100 Pm
pha ynx
1 mm p o en iculus
ca dia R1 R2 R3
R4
R5
c op
c op midgu ileum
pylo us
an e io in es ine
s omach
middle in es ine
pos e io in es ine
ec um 1 mm
midgu
hindgu
Malpighian
ubules
o egu
C. elegans
D osophila
honeybee
ish
100
C. elegans D osophila honeybee ish mice humans P o obac e ia
Fi micu es
Bac e oide es
Acidobac e ia
Ac inobac e ia
C ema chaeo a
o he s
ela i e abundance (%)
0
(b)
Figu e 1. (a) Di e en ial in e e ence con as mic oscopy (DIC) image o he body o C. elegans [5] and dissec ed gu s o adul D osophila [6], honeybee [7] and
Se iola dume ilii [8]. The di e en gu egions a e labelled in each igu e. (b) Rela i e abundance o he majo gu mic obio a phyla ac oss in e eb a es
(i.e. C. elegans [9], D osophila [10], honeybee [11]) and e eb a es (i.e. ish [12], mice and humans [13]).
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luids) and sho ansi imes ( ables 1and 2)[69]. In insec s,
pH may be an impo an de e minan o di e ences in gu
mic obial communi ies among insec g oups. Ca e pilla s o
bu e lies and mo hs, o ins ance, ha e gu s ha a e e y
poo in e ms o mic obial di e si y, some s udies sugges ing
ha his g oup does no ha e esiden mic obes. One o he
easons is hough o be he ha sh condi ions o as ood
passage and high pH le els in he midgu [70]. S udies in
D osophila melanogas e (he ea e e e ed o as D osophila)
ha e shown ha gene ic abla ion o he coppe cells (i.e.
he cells o he acidic compa men o he midgu ) o o he
V-ATPase, which media es he acidi ica ion o his egion,
esul s in inc eased pH and a highe abundance o gu
mic obes in bo h la ae and adul s [59,71]. Acidi ica ion o
Table 1. Main ana omical ac o s shaping gu mic obiome composi ion ac oss he main hos s co e ed in he e iew. C. elegans,Caeno habdi is elegans;
P, p esen ; A, absen ; –, no a ailable; TLR, Toll-like ecep o ; NLRs, NOD-like ecep o s; AM, an imic obial; AMPs, an imic obial pep ides; fip, ungal-induced
pep ides; DUOX, dual oxidase; PGRPs, pep idoglycan ecogni ion p o eins; MAMPs, mic obe-associa ed molecula pa e ns.
hos
ana omical ea u es
physico-chemical/molecula ac o sepi helial s uc u e niche me amo phosis
Hyd a glycocalix wi h mucus-
like p ope ies [14]
A A an imic obial pep ides (hyd amacin, pe iculin, a minin pep ide
amilies); TLR-domain-con aining p o ein p ecu so s NLRs [15]
C. elegans pe i ophic ma ix [16]P[17] A AM e ec o s (lysozymes, caenacins/neu opep ide-like p o eins, C- ype
lec in domain-con aining p o eins, de ensin-like AMPs, fip and
fip- ela ed pep ides, hauma in-like p o eins [18]
DUOX sys em [19]
Tol-1, pa hogen a oidance beha iou [20]
D osophila pe i ophic ma ix [21]P[22]P[23] AMPs (d osocin, dip e icin and d osomycin) [24]
PGRPs [25]
DUOX sys em [26]
TLRs, no di ec ly in ol ed in MAMPs ecogni ion [27]
honeybee pe i ophic ma ix [28]P[29]P[23] AMPs (apidaecin Ia, apidaecin Ib, apidacein 2, apidacin, abaecin,
de ensin-1, de ensin-2, hymenop aecin, jellein 1, jellein 2,
jellein 4)
PGRPs, TLRs [30]
fish mucus laye [31]–A AMPs [32,33]
DUOX sys em [34]
NLRs, TLRs [35]
bile acids [36]
B cells [37]
T cells [38]
mouse mucus laye [39]P[40] A PGRPs [41]
AMPs [42]
DUOX sys em [43]
NLRs [44]
TLRs [45]
bile acids [46]
B cells [47]
T cells [48]
human mucus laye [49]P[50] A PGRPs [51]
AMPs [52]
DUOX sys em [53]
NLRs [44]
TLRs [45]
bile acids [54]
B cells [55]
T cells [56]
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he su ounding en i onmen is also used by commensal bac-
e ia as a mechanism o con ol mic obial in asion and
p o ec he hos [72]. On he con a y, he inc ease in pH, he
high ansi ime in he ileum and ec um and he esul ing
accumula ion o ood con en a ou mic obial p oli e a ion
[29]( able 2). Simila o he mic obial he e ogenei y o he GI
axis in insec s and mammals, a gene al p og essi e inc ease
in he bac e ial popula ion size and a ia ion in communi y
composi ion om he s omach o he hindgu has also been
obse ed in ish [73]( able 2). Howe e , in con as o mam-
mals o insec s, whe e mic obial di e si y is highes in he
hindgu , in ish, he highes o e all di e si y is ound in he
midgu [74]. This esul may be due o di e ences in he domi-
nan mic obial axa be ween ish and o he e eb a es (i.e.
ep iles, bi ds and mammals): while he la e a e mainly domi-
na ed by Bac e oide es and Fi micu es, he mic obiome in ish
is mainly composed o P o eobac e ia and Fi micu es [12]
( igu e 1b). I has been shown ha selec i e p essu es a ising
om a wide ange o hos ac o s, including hos ana omical
ea u es, play a unique ole in he ecology o ish mic obiomes
[74]. S a ing wi h he seminal s udy by Roesele s e al.showing
s iking simila i ies be ween he gu mic obial composi ion
o labo a o y- ea ed and wild-caugh zeb a ish [75], hos -
media ed selec ion o gu mic obiome has been obse ed in
many ish species, including Eu opean seabass (Dicen a chus
lab ax), A lan ic cod (Gadus mo hua), ainbow ou , salmon
and se e al ca p species (i.e. g ass ca p, c ucian ca p and big-
head ca p) [76,77]. Howe e , he speci ic mechanisms
esponsible o such selec ion lag behind ou knowledge o
hose ope a ing in humans and o he mammals, la gely
owing o he high biodi e si y o ish and, consequen ly, he
high a ia ion in mo phology and unc ion o hei GI ac
[73,74,78].
Ano he c i ical ac o shaping he composi ion and
a ia ion o he gu mic obiome in he GI ac is he edox
po en ial o he gu lumen. In con as o he ex ensi e
anoxic egions o he mammalian gu , he D osophila gu
epi helium is endowed wi h an ae obic me abolism owing o
an ex ensi e ne wo k o acheal cells ha allow oxygen ans-
e [79]. He e, oxygen di usion om he epi helium esul s in
a p edominan ly oxic/hypoxic gu lumen, which is a ou able
o ae obic/ae o ole an mic oo ganisms, bu hos ile o
obliga e anae obes [79]. In addi ion, die a y mic obes (e.g.
Lac obacillus spp.) a e able o induce he NADPH oxidase
DUOX p oduc ion o epi helial eac i e oxygen species
(ROS), which in u n a e in ol ed in con olling hei densi y
in he gu [80]. In mammals, a ia ions in edox po en ial
along he GI ac di ec ly con ol mic obial composi ion and
me abolic capaci y. Whe eas in he absence o oxygen, obliga e
anae obic bac e ia ca abolize complex ca bohyd a es in o
e men a ion p oduc s (e.g. sho -chain a y acids) ha
con ibu e o hos nu i ion, in he p esence o oxygen, acul a-
i e anae obic bac e ia ca abolize e men a ion p oduc s in o
ca bon dioxide, which would ins ead in e e e wi h hos nu i-
ion. Thus, o ensu e ha he mic obiome emains bene icial,
he hos main ains colonocy es in a s a e o hypoxia, ensu ing
he dominance o obliga e anae obic bac e ia [81].
Beyond physico-chemical ac o s, he animal in es inal
epi helium p o ides a physical ba ie ha con ibu es o
main aining a balance be ween p o ec ing he hos om pa ho-
gens and ole a ing bene icial mic obes. In he ubula
body s uc u e o Hyd a, mic oo ganisms mus o e come he
Table 2. Physico-chemical and molecula ac o s shaping he gu mic obiome composi ion ac oss he main hos s co e ed in he e iew.Fo each gu sec ion,
pH, oxygen and mic obial load a e epo ed. CFU, colony- o ming uni s; C. elegans,Caeno habdi is elegans;–, no a ailable.
gu sec ion
pha ynx in es ine
hos pH CFU pH CFU
C. elegans 5.96 ± 0.31 [57]–3.59 ± 0.09 [57]ca 10
2
wo m
−1
[58]
o egu midgu hindgu
pH CFU pH CFU pH CFU
D osophila ca 7[59]10
4
mm
−3
[22] midgu : ca 7–9;
coppe cell
egion: <3 [59]
10
3
mm
−3
[22]ca 5[59]10
3
mm
−3
[22]
honeybee 4.82 ± 0.08 [60] 10 ( o al copies o
16S RNA)
[29]
3
5.6–7[60]10
4
( o al copies
o 16S RNA)
[29]
ileum: 5.1–6.7; ec um:
5.2–5.3 [61]
10
8
–10
9
( o al
copies o 16S
RNA) [29]
s omach small in es ine la ge in es ine
pH CFU pH CFU pH CFU
fish 4.2–5.2 [62]ca 2.2 × 10
3
g
−1
[63]
7.6–8.6 [62] 3.1 × 10
3
g
−1
[63] 8.2–8.7 [62]10
4
g
−1
[64]
mouse 2.7–4.1 [65]ca 10
3
g
−1
[66]ca 5[65]10
4
–10
7
ml
−1
[66] 7.0–7.6 [65]10
9
–10
10
ml
−1
[67]
human 1.0–2.5 [68]ca 10
3
–10
5
g
−1
[69]
6.0–7.4 [68]10
8–
10
9
g
−1
[69] colon: 7.1–7.5;
caecum: 5.6; ec um:
7.4 [68]
colon: 10
8
–10
11
g
−1
[69]
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physico-chemical ba ie ep esen ed by he mul ilaye ed
glycocalyx co e ing he ec ode mal epi helium [14]. The
glycocalyx, which is also conse ed in he nema ode
Caeno habdi is elegans [16], has wo unc ionally dis inc com-
pa men s: an inne s a i ied laye ha ac s as a physico-
chemical ba ie and p oduces as amoun s o an imic obial
pep ides (AMPs) ( able 2), and an ou e laye composed o con-
s an ly enewed ansmemb ane glycop o eins, p o eoglycans
and glycolipids, which p o ide he habi a o he symbio ic
bac e ial communi y [82]. Fo his eason, i has been p oposed
ha he ou e laye o Hyd a’s glycocalyx (as po en ially in
o he animals) has mucus-like p ope ies a he han being a
pa o he memb ane-ancho ed glycocalyx. This ana omical
o ganiza ion likely unc ions as a de ence because bac e ia
ha e ne e been obse ed o each he dense inne laye s o
he glycocalyx o e en he ec ode mal cell memb ane [14].
S ikingly, a simila obse a ion was made in he mammalian
colon. An inne i mly adhe en laye wi h a s a i ied o ganiz-
a ion was de oid o bac e ia, whe eas he ou e loose laye
appea ed o be colonized by symbion s [83]. In insec s, an ana-
omical ba ie is p o ided by he e y close apposi ion
be ween he epi helial cells, media ed by sep a e junc ions,
which a e unc ionally equi alen o he igh junc ions in he
mammalian gu epi helium [79]. In addi ion, insec s appea
o ha e e ol ed speci ic epi helium-associa ed mechanisms
ha e ec i ely sepa a e he mic obes om he hos issue, p e-
sumably as adap i e s a egies o u he ensu e mic obiome
con ol in he absence o he adap i e immune sys em o
highe me azoans. The mos e iden example o such adap-
a ions in mos insec s is p o ided by he pe i ophic
memb ane, a igh ly a anged semi-pe meable memb ane
ha p o ec s he o egu and hindgu and p e en s he anslo-
ca ion o pa hogenic mic oo ganisms and mic obial oxins o
he epi helium [84]. The pe i ophic memb ane consis s o
chi in-binding p o eins ha a e ex ensi ely glycosyla ed and
s uc u ally simila o he mucins o he e eb a e mucus. I
has been sugges ed ha he D osophila mic obiome, like some
mucus-associa ed bac e ia in he mammalian gu , may di ec ly
in e ac wi h hese p o eins [85]. In he dis al GI ac (e.g. he
p oximal colon in mammals), he mucosal bio ilm o ma ion is
indeed conse ed om mammals o amphibians, albei wi h
s uc u al di e ences, sugges ing an ancien e olu iona ily
conse ed o igin o his egion as a ba ie and habi a o
he mic obiome [14]. A di e gence in mic obial composi ion
be ween he mucosal and diges a-associa ed colonic commu-
ni ies has been obse ed in se e al mammals, including
humans [86], macaques [87], mice [88], cows [89] and lying
squi els [67]. Howe e , some bac e ia can pene a e he
mucus and bind di ec ly o he epi helium. Acine obac e and
P o eobac e ia ha e been ound in a signi ican p opo ion o
he small in es ine and colonic c yp s in heal hy mice [40]
and humans [90]. Some in e eb a es a e also endowed wi h
speci ic ana omical niches ha a ou he coloniza ion o ben-
e icial mic oo ganisms and allow hem o exe s ong con ol
o e hei associa ed mic obes h ough compa men aliza ion
[91–93]. Many examples come om insec s, a well-s udied
one being he bean bug, Rip o us pedes is,whicho ally
acqui es a speci ic Bu kholde ia symbion , which o ms dense
colonies in midgu c yp s [94]. A simila physical niche is
also c ea ed in he adul D osophila o egu , which is speci i-
cally colonized by wild bene icial s ains o Lac obacillus and
Ace obac e s ains. Bac e ial coloniza ion appea s o be
a ou ed by he ly i sel in a highly speci ic manne , in ol ing
speci ic molecules (p obably mucins) in he ex acellula
ma ix o he p o en iculus ha a e able o bind exclusi ely
o he bac e ial su ace o colonizing compe en s ains, bu
no o non-colonizing s ains [22]. In he all a mywo m (Spo-
dop e a ugipe da), he p o ec i e laye s o gu mic obes can be
weakened by oxic plan chemicals, hus al e ing he p o ec i e
pe i ophic ma ix and ul ima ely allowing gu esiden s o
leak in o he body ca i y and cause disease [95].
Age and s age o de elopmen a e o he common ac o s
ha con ibu e o mic obiome a ia ion in di e en animal
hos s. This has la gely been demons a ed in honeybees
[96], D osophila [97], ish (bo h wild and aquacul u e) [98],
mice and humans [99]. Pa icula ly in humans, he di e si y
o he mic obiome inc eases wi h age and becomes ixed a
a ound 3 yea s o age, when he composi ion o he gu
mic obiome mo e closely esembles ha o adul s [99]. No a-
bly, in many holome abolous insec s (i.e. bee les, lies, wasps,
an s, bees, bu e lies, mo hs and o he s), me amo phosis also
imposes se e al cons ain s on he assembly and pe sis ence
o gu mic obes [23]. In many insec s, he la al gu (includ-
ing he mic obes in he gu lumen) is pu ged p io o
pupa ion and newly eme ging adul s exc e e he emnan s
o he la al gu as meconium [100]. This pe u ba ion can
cause gu -associa ed symbion s o be eloca ed wi hin he
hos , supp essed o los al oge he [101]. Simila es uc u ing
o he mic obiome occu s in o he animals unde going
me amo phosis, such as lamp eys [102], ogs [103] and
sponges [104].
Finally, s udies in bo h in e eb a e and mammalian
model sys ems ha e demons a ed sex-speci ic di e ences in
he composi ion o he gu mic obiome [105,106]. In mam-
mals, his has been linked o di e ences in sex s e oid
ho mones be ween males and emales [107]. Howe e , he
noise in oduced by con ounding ac o s such as die , age
and hos gene ic backg ound has obscu ed sex di e ences
in many di e en model sys ems [105].
In summa y, al hough animals ca y di e en mic obial
species in hei gu , ana omical ea u es (e.g. pH g adien
along he gu , edox po en ial, de elopmen al s ages) ep-
esen conse ed ac o s ha shape he ecology o he gu
mic obio a in all animals ( igu e 2).
3. Geno ype
Much o he esea ch on hos –mic obe symbioses has ocused
on unde s anding he impac o hos gene ics on he compo-
si ion o animal-associa ed mic obiomes. To his end,
esea ch s udies ha e p ima ily used genome-wide associ-
a ion s udies (GWASs), quan i a i e ai locus (QTL)
analyses and 16S RNA gene amplicon sequencing. Hos gen-
o ype has been ound o be signi ican ly associa ed wi h gu
mic obial composi ion in a wide ange o species and axa,
om nema odes o mammals. Unde en i onmen ally con-
olled condi ions, QTL mapping s udies coupled wi h 16S
RNA gene sequencing and he use o inb ed mouse s ains
and e e ence popula ions showed ha hos gene ic a ia ion
can explain a subs an ial p opo ion o he a ia ion in gu
mic obiome composi ion (i.e. om 1.6 o 9%). This sugges s
a symbio ic ela ionship ha has co-e ol ed o e millions
o yea s whe eby hos s il e equi ed mic obes [108]. Such
an es ima e appea s o be conse ed in humans, whe e hos
gene ics has been es ima ed o explain be ween 1.9 and
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8.1% o a ia ion in he gu mic obiome [4,109]. By pe o m-
ing 16S gene sequencing and unc ional assessmen o he gu
mic obiome in di e en Caeno habdi is species, spanning a
ime ame o 200–300 My o e olu ion, Be g e al.[110]
obse ed a consis en clus e ing o mic obiome based on
geno ype. In addi ion, a s udy by Zhang e al. exposed gene i-
cally dis inc C. elegans s ains o a 63-membe model
mic obiome and showed ha se e al genomic egions a e
associa ed wi h he abundance o speci ic mic obial axa
ac oss hos s ains, wi h he mos signi ican o e lap obse ed
o genes in ol ed in hos insulin signalling pa hways [111].
In D osophila, esea ch s udies in es iga ing he link
be ween speci ic genes and he mic obiome ha e iden i ied
se e al immune- ela ed genes (e.g. nubbin,D osophila homol-
ogue o he mammalian ansc ip ion ac o Oc 1/Pou2 l,
caudal), as well as genes in ol ed in neu al and cellula
g ow h and de elopmen , as key egula o s o gu mic obial
coloniza ion [112,113]. A he same ime, by using 36 ly lines
om he D osophila Gene ic Re e ence Panel (DGRP), Ea ly
e al. showed ha gu mic obiome a ia ion in D osophila
commensal bac e ial load, bo h in composi ion and abun-
dance, can be la gely a ibu ed o physical aspec s o gu
cell g ow h and de elopmen , including neu onal unc ion,
neu onal mo phogenesis and de elopmen [114]. A GWAS
conduc ed c ossing di e en bac e ia species and s ains
and honeybee geno ypes e ealed a signi ican associa ion
be ween gu mic obiome composi ion, pa icula ly Bi idobac-
e ium spp., and hos ecep o genes, such as he glu ama e
ecep o gene and he G p o ein-coupled ecep o gene,
speci ically exp essed in he bee b ain [115]. While hese
s udies a e p ima ily based on associa ions be ween hos
genes and he p esence o speci ic gu bac e ial species, expe -
imen al wo k s udying hos con ol o e gu mic obial
s uc u e a e also popula . Recip ocal ansplan a ion o gu
humans
cop ophagy
social con ac /
passi e dispe sal
en i onmen al/
die acquisi ion
T cells
IgA
(B-cell p oduc s)
mice
ish
honeybees
D osophila
C
.
e
l
e
g
a
n
s
Hyd a
N
O
D
-
l
i
k
e
e
c
e
p
o
s
PGRP
AMPs
T
o
l
l
-
l
i
k
e
e
c
e
p
o
s
e
g
e
a
i
e
e
p
o
d
u
c
i
o
n
m
a
e
n
a
l
p
o
i
s
i
o
n
i
n
g
e
m
a
l
e
g
e
m
c
e
l
l
s
Figu e 2. Summa y o he main hos - ela ed (geno ype, ana omy, e ical ansmission, immuni y) and en i onmen al ac o s d i ing gu mic obio a a ia ion ac oss
animals. Each ci cle e e s o he main hos species co e ed in he e iew. Colou ed cells indica e he p esence o he espec i e ac o s, while emp y cells indica e he
absence o he ac o in he espec i e hos . Fu he de ails on each ac o can be ound in ables 1and 2.C. elegans,Caeno habdi is elegans; AMPs, an imic obial
pep ides; PGRP, pep idoglycan ecogni ion p o ein; IgA, immunoglobulin A. Image c edi s: Joana C. Ca alho.
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mic obiome in o ge m- ee (GF) zeb a ish and mouse ecipi-
en s has shown ha he ansplan ed communi ies e ain
simila i ies o he o iginal communi y in e ms o he lineages
p esen . Howe e , he ela i e abundance o hese lineages
changes o esemble he no mal gu mic obial communi y
composi ion o he ecipien hos [116]. O he s udies ha e
shown s ong co ela ions be ween ish hos geno ype and
mic obiome composi ion in s ickleback popula ions (whe e
mo e gene ically di e se popula ions ha e mo e di e se gu
mic obiomes) [117], cyp inids [118] and salmonids [119],
and on hyb id indi iduals [120]. Speci ically, by using 16S
RNA gene sequencing on ish lineages de i ed om pa en s
wi h di e en eeding habi s (i.e. he he bi o ous Megalo-
b ama amblycephala, and he ca ni o ous Cul e albu nus), Li
e al. disco e ed a s ong co ela ion be ween geno ype and
gu mic obial assemblages. The dominan mic obial axa
showed a signi ican ly posi i e co ela ion wi h he gene ic
ac o s o bo h ecip ocal hyb ids and bo h pa en s. These
indings no only sugges ha hos gene ics signi ican ly
in luence gu mic obial communi ies, bu also imply ha
genomic in e ac ions may di ec ly o indi ec ly in luence he
die a y adap a ion and e olu ion o ish, and ul ima ely
shape he composi ion o he gu mic obiome [120].
He i abili y s udies ha e been widely used o es ima e
he ex en o which hos gene ics con ibu e o a ia ion
in he gu mic obiome. In humans, he he i abili y o gu
mic obiome was ini ially demons a ed in win s udies.
These s udies assumed ha i he gene ic backg ound o he
hos in luences a pa icula pheno ype, measu es o he pheno-
ypic ai o in e es would be mo e simila wi hin
monozygo ic win pai s han wi hin dizygo ic win pai s
[121]. Howe e , he esea ch ca ied ou on wins has so a
been inconclusi e, wi h se e al s udies coming o di e en
conclusions [122]. Among he di e en mic obes s udied,
some ha e s onge he i abili ies, o example hose in he
amily Ch is ensenellaceae (phylum Fi micu es) [123]. In
addi ion, GWAS app oaches, and mo e ecen ly ancien
DNA da a (box 1), ha e been used in la ge popula ions o
un ela ed indi iduals wo ldwide o explo e associa ions
be ween hos gene ic a ian s, gu mic obial species, and phe-
no ypic ai s. Examples o human genes ound o be
associa ed wi h gu mic obiome composi ion include
he i amin D ecep o [129], he ORA6A2 gene esponsible
o he soapy as e o co iande expe ienced by some indi id-
uals, CD36 associa ed wi h he abili y o as e long-chain
a y acids on he ongue [109], and immune genes, such as
ABO and FUT2 [130,131]. Howe e , he mos consis en ly
eplica ed associa ion o da e is be ween gene ic a ian s o
he lac ase gene (LCT) and he abundance o Bi idobac e ia in
he human gu [3,132]. (Fo ex ensi e de ails abou his
opic, e e o [133].) In e es ingly, his associa ion is speci i-
cally obse ed in indi iduals who epo consuming dai y
p oduc s, highligh ing a gene-by-en i onmen in e ac ion
in ol ing he mic obiome.
(a) Phylosymbiosis: when hos –mic obe ela ionship
mi o s hos phylogeny
Mic obes ha e shaped he e olu iona y landscapes o all
mul icellula o ganisms o e billions o yea s. In his con ex ,
co-e olu iona y pa e ns ha e been iden i ied in he case o
mu ualis ic symbioses be ween animals and hei gu mic o-
biome, whe e hei in ima e in e ac ion equi es mu ual
adap a ions o he bene i o each pa ne [134]. The o e all
s uc u e and composi ion o he gu mic obial ecosys em
e lec na u al selec ion a bo h he hos and mic obial
le els, which may esul in a unc ionally s able, co-e ol ed
coope a ion cha ac e ized by mu ual adap a ion and bene i s
[135]. In his scena io, he ield o mic obiome esea ch has
been expanded o include an e olu iona y pe spec i e
Box 1. The con ibu ion o ancien DNA o unde s anding hos -media ed selec ion on mic obiome e olu ion.
O e he pas h ee decades, he ield o ancien DNA (aDNA), ecen ly honou ed by he Nobel P ize o S an e Pääbo, has
d ama ically imp o ed ou echnical abili y o econs uc ou pas . I is now possible o in es iga e speci ic key s eps in he
e olu ion o di e en o ganisms, including hos mic obiomes, and o ob ain di ec in o ma ion on he co-e olu iona y
ela ionship be ween hos and mic obes [124]. Using ancien cop oli e da a, a ecen s udy by Sande s e al. has shown
how humans, along wi h o he non-human p ima es, co-e ol ed wi h hei symbion s [125]. The collec ed e idence
shows ha he gu mic obial communi y in humans has expe ienced s ong selec i e p essu es linked o gene ic and phys-
iological changes ha ha e occu ed du ing ou e olu ion as a species, bu which a e independen o he popula ion’s
li es yle. In o al, 10 di e en bac e ial phyla we e ound o ha e co-di e si ied du ing ou e olu ion, wi h a ying deg ees
o co a ia ion be ween phyla. Human-associa ed mic obes showed signals o s ong posi i e and pu i ying selec ion wi h
espec o pan-associa ed symbion s, wi h se e al clus e s o o hologous genes (COGs) showing signi ican co-di e si ica ion
signa u es. This suppo s he hypo hesis ha , despi e bac e ial phylogene ic his o y, mul iple bac e ial unc ions ha e been
selec ed o o e millions o yea s. The human o al mic obiome also appea s o show signals o co-e olu ion wi h he hos .
E idence om aDNA s udies has highligh ed he exis ence o 10 di e en bac e ial gene a ha ha e been main ained
h oughou he e olu iona y his o y o all A ican hominids, sugges ing ha hey a e likely o ha e been impo an membe s
o he o al en i onmen since a ound 40 Ma [126]. In addi ion, as epo ed o he gu mic obiome, he Homo lineage (includ-
ing Neande hals) shows unc ional and axonomic di e ences om non-human p ima es. An imp essi e example o he
co-e olu ion o Homo mic obes came om he analysis o ancien and mode n o al s ep ococci. Indeed,
human S ep ococcus spp. (i.e. S ep ococcus mi is, S ep ococcus sanguinis and S ep ococcus sali a ius) a e able o exclusi ely
bind human alpha-amylase (AMY1 gene), which is one o he mos abundan enzymes in human sali a, h ough he
ac ion o he abpA and abpB genes [127]. AMY1 has di e en copy numbe s in mode n human popula ions and is conside ed
o be a gene ic ai selec ed as a esul o changes in he die a y choices o ou species o e ime [128]. The abili y o human
S ep ococcus spp. o ap human amylase hus sugges s how hese species ha e co-e ol ed in ela ion o bo h hos gene ic
and hos die a y changes.
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called phylosymbiosis, de ined as ‘mic obial communi y
ela ionships ha ecapi ula e he phylogeny o hei hos ’
[136]. When s able, long- e m and in ima e hos –mic obe
associa ions occu o e e olu iona y ime, a phylosymbio ic
pa e n may eme ge om co-specia ion o co-phylogene ic
e en s, whe e he wo species specia e simul aneously, esul -
ing in pa allel e olu iona y his o ies and cong uen
phylogenies [137]. This may be he case o hos –mic obe
in e ac ions wi h s ong unc ional in e dependence, o cing
he wo en i ies o di e ge in conce o a oid ex inc ion,
and has been desc ibed in se e al insec species ha co-
e ol e and co-specia e wi h hei endosymbion [138]. One
o he i s e idences linking phylosymbio ic pa e ns comes
om he cnida ian Hyd a [139]. In Hyd a, hos -associa ed bac-
e ial communi ies e lec he phylogene ic ela ionship o
hei hos , and knockdown o he Hyd a a minin amily o
an imic obial pep ides has been shown o dis up phylosym-
biosis [140]. In D osophila, a ecen s udy has shown ha shi s
in mic obiome composi ion lead o di e gence in D osophila
allele equencies in as ew as i e gene a ions, wi h mo e
common alleles in ly popula ions expe imen ally en iched
o a pa icula mic obial g oup also being mo e common
in na u al popula ions wi h a high ela i e abundance o
ha mic obial g oup. This sugges s ha mic obiomes could
ac as a selec i e o ce in luencing he pa e n and p ocess
o adap a ion e en on sho imescales [141]. Howe e , pa -
e ns o phylosymbiosis a e weakly suppo ed in bo h
labo a o y s ains and wild ui ly popula ions, p obably
owing o D osophila’s cons an need o eplenish gu mic obes
om he en i onmen [142]. In social co bicula e bees (honey-
bees, bumblebees and s ingless bees), i e co e lineages o he
gu mic obiome show phylogenies ha la gely ma ch hose o
he hos s, suppo ing co-di e si ica ion o e abou 80 My
[143]. Howe e , some o hese bee hos lineages ha e los
o gained gu bac e ia o e his pe iod, and some membe s
o he bee gu mic obiome appea o be oppo unis ic
en i onmen al bac e ia o pa hogens [144]. Among aqua ic
in e eb a es, se e al lines o e idence ha e highligh ed phy-
losymbio ic pa e ns in sponges, ascidians, c us aceans and
co als [145–148]. This con as s wi h inconsis en e idence
o phylosymbiosis in ishes [74,149].
In g ea apes, including humans, chimpanzees, go illas
and o angu ans, ma ke s om p o ein-coding genes (sensi-
i e enough o disc imina e s ains ha ha e di e ged o e
millions o yea s) p o ide e idence o co-di e si ica ion o
hos s and some lineages o gu bac e ia, implying long- e m
e ical associa ion [144,150]. By in eg a ing he exis ing
da a desc ibing phylosymbiosis in animal sys ems, Mallo
& Ama o ound ha , while phylosymbiosis appea s o
become less common as mic obiomes become axonomically
iche ac oss he animal kingdom, mammals a e he only
excep ion o his gene al pa e n [151]. One possible expla-
na ion o his pa e n is ha in mammals he e is a
combina ion o ai s ha acili a e e ical mic obial ans-
mission (i.e. i ipa ous bi h, pa en al ca e and milk
p oduc ion) and hos con ol o mic obial coloniza ion (adap-
i e immune sys em and adap a ions o placen a and milk).
Al hough o he e eb a es ha e some o hese cha ac e is ics,
only mammals ha e all o hem [151]. Mammals hus show
phylosymbiosis despi e ha ing ich symbio ic communi ies
p obably because he men ioned hos ai s o se he s ochas-
ici y associa ed wi h he dispe sal and selec ion o ich
mic obiomes. Phylosymbiosis is hus acili a ed in mammals
because mic obial communi y assembly is less s ochas ic
han in o he e eb a es.
Despi e hese exci ing disco e ies, ecen claims sugges
ha phylosymbiosis can also a ise h ough simple and non-
adap i e hos il e ing p ocesses. This means ha closely
ela ed hos s sha e simila pheno ypic ai s (e.g. die , gu
pH, gu mo phology) ha il e simila bac e ia p esen in
ood and o he en i onmen al sou ces, as seen in C. elegans
[152] and ca e pilla s (e.g. Manduca sex a species [153]).
Wi hin his ame, G oussin e al. ecen ly a gued ha co-
e olu ion is unlikely o explain he co-phylogene ic pa e n
in he mammalian gu mic obiome, and in addi ion o hos
il e ing e ec s, he obse ed co-phylogene ic pa e ns a e
likely o esul om a geog aphical model o hos specia ion
wi h educed symbion dispe sal and acquisi ion o
symbion s om local species pool [154].
In summa y, he ex ensi e esea ch on hos –mic obe sym-
bioses unde sco es he signi ican in luence o hos gene ics
on he composi ion o all animal-associa ed mic obiomes
( igu e 2), wi h di e en axa showing a consis en co ela ion
be ween hos geno ype and gu mic obial s uc u e. These
indings sugges long-s anding and e ol ing symbio ic
ela ionships be ween animals and hei gu mic obes,
spanning millions o yea s, in which hos s ac as il e s o
essen ial mic obes.
4. Ve ical ansmission
Bac e ial symbion s can be ans e ed di ec ly om pa en o
o sp ing wi hou mixing wi h mic obes in he en i onmen .
This p ocess is called e ical ansmission and i plays a
c ucial ole in es ablishing and shaping he mic obial compo-
si ion and di e si y o he gu [155]. I is he p ima y ou e
by which o sp ing acqui e hei i s gu mic obes. In animals,
e ical ansmission can occu by a a ie y o mechanisms,
including he ansmission h ough emale ge m cells (i.e.
eggs and emb yos), asexual ep oduc ion (e.g. budding in
Hyd a)[156] o di ec con ac wi h pa en s (e.g. ia b eas
milk) [157]. O he indi ec mechanisms a e also common,
including egu gi a ion o ood [158], o egg smea ing (and
associa ed beha iou s) in insec s (box 2). In gene al, he
mode by which a mu ualis is ansmi ed om one gene a ion
o he nex is s ic ly ela ed o he impo ance o he se ices
ha i p o ides o he hos [170]. Fo hos s ha show a
s ong dependence on hei symbion s (e.g. endosymbion s),
e ical ansmission ensu es ha mic oo ganisms pe o ming
c i ical nu i ional unc ions o o he unc ions essen ial o
hei own su i al a e main ained, while allowing an op imal
niche o he symbion o pe sis [171]. Many insec species
main ain obliga e endosymbion s h ough e ical ans-
mission. This ansmission can occu anso a ially in he
egg, on/nea he egg, o by di ec associa ion wi h la ae
eleased in o he en i onmen [172]. Fo example, in ca pen e
an s, Blochmania is ansmi ed e ically by acu e in acellula
in ec ion o he o a ies and subsequen inco po a ion in o he
eggs [173]. Simila ly, in aphids, Buchne a is anso a ially
ansmi ed o de eloping eggs h ough a highly selec i e
mechanism a he o a y ips [174]. In se se lies, he B i a-
min-supplying symbion Wiggleswo hia is ans e ed ia
mamma y gland sec e ions du ing la al de elopmen in
u e o [175]. The bac e ia Wolbachia and Spi oplasma, which
in ec ge mline issues in acellula ly and/o occu in he
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haemolymph, ha e been epo ed as he only he i able
symbion s in Lepidop e a and D osophila species [176,177].
Howe e , unlike in acellula symbion s, gu -associa ed
bac e ia in insec s a e gene ally ho izon ally acqui ed
du ing and a e bi h ia ho izon al ans e om he su -
ounding en i onmen . Indeed, D osophila emb yos a e
s e ile, bu he eggshells ca y low mic obial loads wi h
high phylogene ic di e si y, mos likely om adul aeces
[142,178], a mechanism also epo ed in He e op e a [179]
and se e al s ink bugs [180]. As la ae consume bac e ia
om he egg o he en i onmen , he bac e ial densi y in
he gu inc eases h oughou he la al s age, eaching a pla-
eau in hi d-ins a wande ing la ae [181]. Like D osophila,
C. elegans ha bou s a lexible gu mic obial pool ha is
la gely dependen on en i onmen al a ailabili y. Howe e ,
ecen s udies ha e sugges ed he p esence o a co e mic o-
biome in he wo m ha may be po en ially main ained
h ough e ical ansmission [182]. P elimina y da a also
sugges ha such ansmission may be acili a ed by he
i ellogenin Vi -2, a amily o yolk p o eins ha a e pa icu-
la ly abundan in o ipa ous animals and a e capable o
binding bac e ia [183]. In mos ish, he o ipa ous beha iou
means ha gu mic obiome symbion s a e acqui ed mainly
ho izon ally om mul iple en i onmen al sou ces, including
he eggs, he su ounding wa e and he i s eed [73],
al hough e ical ansmission has been epo ed in some
cases [151,184].
By con as , in humans and o he animals (i.e. apes [185],
ba s [186], mice [187], a s [188], bee les [189]) he consensus
on e ical ansmission om mo he o in an has been la gely
es ablished by cul u e-based me hods [190], species-le el esol-
u ion s udies [191] and mic obial s ain- acking analyses
[192]. In humans, mo he - o-in an ansmission is one o he
mos in luen ial a iables in mic obiome composi ion, as i
has been es ima ed ha app oxima ely 50% o he o al
in an gu mic obiome sha es exac ly he same bac e ial s ains
as he espec i e mo he s [193]. Al hough he exac iming
o he i s gu mic obial colonize s and he con ibu ion o
di e en sou ces o mic obial seeding ha e been a ma e
o deba e, i is widely accep ed ha he i s majo
exposu e o he neona e o mic oo ganisms occu s a bi h,
speci ically a he up u e o he amnio ic memb anes [194].
Nume ous s udies ha e also shown ha he mode o
deli e y is a c i ical ac o in de e mining he ea ly coloniza-
ion o he neona al mic obiome, wi h signi ican di e ences
epo ed be ween aginally and Caesa ean-deli e ed in an s.
Vaginally deli e ed in an s end o ha e mic obial communi-
ies ha esemble hose o he mo he ’s aginal mic obiome,
whe eas Caesa ean-deli e ed in an s ha e bac e ial commu-
ni ies (ac oss all body si es) ha mos closely esemble
Box 2. Hos selec ion o gu mic obes h ough beha iou al ea u es in insec s.
To unde s and he ecology and di e si y o symbion s in insec gu s, i is necessa y o conside he p ocess o symbion acqui-
si ion. Symbion s can be acqui ed e ically om mo he o o sp ing wi h a ying deg ees o ideli y, ho izon ally om
conspeci ic o he e ospeci ic indi iduals, o om he en i onmen . In each o hese si ua ions, as we will explain in he ol-
lowing, insec s o en exhibi sophis ica ed beha iou s o ensu e symbion acquisi ion. In many hemip e an s ink bugs,
e ical ansmission o gu symbion s equi es mo he s o smea eggs wi h symbion capsules o aecal d ople s, om
which newbo ns eed di ec ly [159]. In o he hemip e ans, howe e , mo he s do no p o ide such s uc u es, as is he case
in he squash bug, Anasa is is. In his species, o sp ing equi e bac e ial symbion s o he genus Caballe onia o ensu e suc-
cess ul de elopmen , bu he bac e ium is no p o ided di ec ly by he emales. Ins ead, o sp ing a e able o loca e he
symbion wi h high ideli y in A. is is aeces o in he en i onmen [160]. Acquisi ion o gu symbion s om he soil is
also common bo h in ca e pilla s and s ink bugs. Hannula e al.[161] showed ha he gu mic obial communi ies o ca e -
pilla s o he cabbage mo h, Mames a b assicae, we e simila o hose ound in soil, bu only when ca e pilla s wande ed on
he soil su ace [161]. This beha iou hus ensu es he acquisi ion o many bac e ia, including some de ensi e ones wi h
known an i-pa hogenic p ope ies. Simila ly, in he s ink bug Rip o us pedes is, speci ic beha iou s ha allow hese insec s
o acqui e bac e ia om he soil a e key o inco po a ing bac e ia capable o deg ading insec icides in o hei symbio ic epe -
oi e [162,163]. These beha iou s include o al acquisi ion o he bac e ium pa icula ly by second- and hi d-ins a nymphs
[159]. In he bi o es, plan s p o ide an ideal sou ce o symbion s, and phylogene ic e idence has also elucida ed he po ous
na u e o symbion s ha inhabi bo h he gu and plan issues [164,165]. Fo example, in he bee le Lag ia illosa, symbion s o
he genus Bu kholde ia a e equi ed o he de elopmen and su i al o he insec . These symbion s a e ela ed o plan
pa hogens and hey s ill e ain he abili y o colonize plan s and cause disease. In his species, symbion s a e acqui ed ans-
o a ially, bu speci ic beha iou s ha inc ease he acquisi ion o plan -inhabi ing s ains a e likely o allow he inco po a ion
o no el bac e ial isola es. Beha iou al changes b ough by symbion s in social insec s can also al e he composi ion o gu
symbion s. Fo example, symbion s ha e been epo ed o educe agg essi e in e ac ions among nes -ma es in he lea -cu ing
an Ac omy mex echina io [166] and he Ge man cock oach, Bla ella ge manica [167]. Conside ing ha social con ac is one o
he main means by which symbion s a e acqui ed in an s, bees, cock oaches and e mi es [168], educed agg ession could
ul ima ely inc ease ho izon al ansmission o symbion s. Al oge he , he examples p esen ed he e show ha many insec s
acqui e mu ualis ic gu symbion s h ough sophis ica ed beha iou s, and i is likely ha new exci ing simila beha iou s
a e ye o be disco e ed. As he acqui ed symbion s a e in many cases obliga e, such a s a egy is likely o be e icien in ensu -
ing ansmission o he nex gene a ion. Howe e , ela i e o anso a ial ansmission, his s a egy may be less eliable
because he w ong symbion may be acqui ed, o pa hogens may hijack he mode o ansmission o ensu e pe sis ence.
This la e isk has been obse ed in he ypanosoma id pa asi e Lep omonas py hoco is, which a acks he i ebug, Py ho-
co is ap e us [169]. Howe e , ho izon al symbion up ake may o e new oppo uni ies, as use ul symbion s may be acqui ed
de no o om o he species, o om soil o plan su aces, whe e hey may be p e-adap ed o s esso s, such as insec icides o
ex eme abio ic condi ions.
oyalsocie ypublishing.o g/jou nal/ s b Phil. T ans. R. Soc. B 379: 20230071
9
Downloaded om h ps:// oyalsocie ypublishing.o g/ on 26 Sep embe 2025
104. Fie h RA, Gau hie M-EA, Bayes J, G een KM,
Degnan SM. 2016 On ogene ic changes in he
bac e ial symbion communi y o he opical
demosponge Amphimedon queenslandica:
me amo phosis is a new beginning. F on . Ma . Sci.
3, 228. (doi:10.3389/ ma s.2016.00228)
105. O g E, Meh abian M, Pa ks BW, Shipko a P, Liu X,
D ake TA, Lusis AJ. 2016 Sex di e ences and
ho monal e ec s on gu mic obio a composi ion in
mice. Gu Mic obes 7, 313–322. (doi:10.1080/
19490976.2016.1203502)
106. Wan X, Jiang Y, Cao Y, Sun B, Xiang X. 2020
Di e gence in gu bac e ial communi y s uc u e
be ween male and emale s ag bee les Odon olabis
allaciosa (Coleop e a, Lucanidae). Animals 10,
2352. (doi:10.3390/ani10122352)
107. Ma kle JGM e al. 2013 Sex di e ences in he gu
mic obiome d i e ho mone-dependen egula ion o
au oimmuni y. Science 339, 1084–1088. (doi:10.
1126/science.1233521)
108. Benson AK e al. 2010 Indi iduali y in gu
mic obio a composi ion is a complex polygenic
ai shaped by mul iple en i onmen al and hos
gene ic ac o s. P oc. Na l Acad. Sci. USA 107,
18 933–18 938. (doi:10.1073/pnas.1007028107)
109. Good ich JK e al. 2016 Gene ic de e minan s o he
gu mic obiome in UK wins. Cell Hos Mic obe 19,
731–743. (doi:10.1016/j.chom.2016.04.017)
110. Be g M, Zhou XY, Shapi a M. 2016 Hos -speci ic
unc ional signi icance o Caeno habdi is gu
commensals. F on . Mic obiol. 7, 1622. (doi:10.
3389/ micb.2016.01622)
111. Zhang F e al. 2021 Na u al gene ic a ia ion d i es
mic obiome selec ion in he Caeno habdi is elegans
gu . Cu . Biol. 31, 2603–2618. (doi:10.1016/j.cub.
2021.04.046)
112. Vazquez-A eguin K, Bensa d C, Schell JC, Swanson
E, Chen X, Ru e J, Tan in D. 2019 Oc 1/Pou2 1 is
selec i ely equi ed o colon egene a ion and
egula es colon malignancy. PLoS Gene . 15,
e1007687. (doi:10.1371/jou nal.pgen.1007687)
113. Dan o W, Da is MM, Lind all JM, Tang X, U ell H,
Junell A, Beskow A, Engs öm Y. 2013 The Oc 1
homolog Nubbin is a ep esso o NF-κB-dependen
immune gene exp ession ha inc eases he
ole ance o gu mic obio a. BMC Biol. 11, 99.
(doi:10.1186/1741-7007-11-99)
114. Ea ly AM, Shanmuga ajah N, Buchon N, Cla k AG.
2017 D osophila geno ype in luences commensal
bac e ial le els. PLoS ONE 12, e0170332. (doi:10.
1371/jou nal.pone.0170332)
115. Wu J, Lang H, Mu X, Zhang Z, Su Q, Hu X, Zheng H.
2021 Honey bee gene ics shape he s ain-le el
s uc u e o gu mic obio a in social ansmission.
Mic obiome 9, 225. (doi:10.1186/s40168-021-
01174-y)
116. Rawls JF, Mahowald MA, Ley RE, Go don JI. 2006
Recip ocal gu mic obio a ansplan s om zeb a ish
and mice o ge m- ee ecipien s e eal hos habi a
selec ion. Cell 127, 423–433. (doi:10.1016/j.cell.
2006.08.043)
117. Smi h CCR, Snowbe g LK, Capo aso JG, Knigh R,
Bolnick DI. 2015 Die a y inpu o mic obes and hos
gene ic a ia ion shape among-popula ion
di e ences in s ickleback gu mic obio a. ISME J. 9,
2515–2526. (doi:10.1038/ismej.2015.64)
118. Li T, Long M, Li H, Ga esoupe F-J, Zhang X, Zhang
Q, Feng D, Li A. 2017 Mul i-omics analysis e eals a
co ela ion be ween he hos phylogeny, gu
mic obio a and me aboli e p o iles in cyp inid
ishes. F on . Mic obiol. 8, 454. (doi:10.3389/ micb.
2017.00454)
119. Rasmussen JA e al. 2021 Genome- esol ed
me agenomics sugges s a mu ualis ic ela ionship
be ween Mycoplasma and salmonid hos s. Commun.
Biol. 4,1–10. (doi:10.1038/s42003-021-02105-1)
120. Li W e al. 2018 Gene ic e ec s on he gu
mic obio a assemblages o hyb id ish om pa en s
wi h di e en eeding habi s. F on . Mic obiol. 9,
2972. (doi:10.3389/ micb.2018.02972)
121. Tu nbaugh PJ e al. 2009 A co e gu mic obiome in
obese and lean wins. Na u e 457, 480–484.
(doi:10.1038/na u e07540)
122. Sanna S, Ku ilshiko A, Van De G aa A, Fu J,
Zhe nako a A. 2022 Challenges and u u e
di ec ions o s udying e ec s o hos gene ics on
he gu mic obiome. Na . Gene . 54, 100–106.
(doi:10.1038/s41588-021-00983-z)
123. Good ich JÂK e al. 2014 Human gene ics shape he
gu mic obiome. Cell 159, 789–799. (doi:10.1016/j.
cell.2014.09.053)
124. O lando L e al. 2021 Ancien DNA analysis. Na .
Re . Me hods P ime s1, 14. (doi:10.1038/s43586-
020-00011-0)
125. Sande s JG e al. 2023 Widesp ead ex inc ions o co-
di e si ied p ima e gu bac e ial symbion s om
humans. Na . Mic obiol. 8, 1039–1050. (doi:10.
1038/s41564-023-01388-w)
126. Fellows Ya es JA e al. 2021 The e olu ion
and changing ecology o he A ican
hominid o al mic obiome. P oc. Na l Acad.
Sci. USA 118, e2021655118. (doi:10.1073/pnas.
2021655118)
127. Haase EM, Kou Y, Sabha wal A, Liao Y-C, Lan T,
Lindq is C, Scannapieco FA. 2017 Compa a i e
genomics and e olu ion o he amylase-binding
p o eins o o al s ep ococci. BMC Mic obiol. 17, 94.
(doi:10.1186/s12866-017-1005-7)
128. Pe y GH e al. 2007 Die and he e olu ion o
human amylase gene copy numbe a ia ion. Na .
Gene . 39, 1256–1260. (doi:10.1038/ng2123)
129. Wang J e al. 2016 Genome-wide associa ion
analysis iden i ies a ia ion in i amin D ecep o
and o he hos ac o s in luencing he gu
mic obio a. Na . Gene . 48, 1396–1406. (doi:10.
1038/ng.3695)
130. Rühlemann MC e al. 2021 Genome-wide
associa ion s udy in 8,956 Ge man indi iduals
iden i ies in luence o ABO his o-blood g oups on
gu mic obiome. Na . Gene . 53, 147–155. (doi:10.
1038/s41588-020-00747-1)
131. Qin Y e al. 2022 Combined e ec s o hos
gene ics and die on human gu mic obio a and
inciden disease in a single popula ion coho . Na .
Gene . 54, 134–142. (doi:10.1038/s41588-021-
00991-z)
132. Blekhman R e al. 2015 Hos gene ic a ia ion
impac s mic obiome composi ion ac oss human
body si es. Genome Biol. 16, 191. (doi:10.1186/
s13059-015-0759-1)
133. Good ich JK, Da enpo ER, Cla k AG, Ley RE. 2017
The ela ionship be ween he human genome and
mic obiome comes in o iew. Annu. Re . Gene . 51,
413–433. (doi:10.1146/annu e -gene -110711-
155532)
134. O’B ien PA, Webs e NS, Mille DJ, Bou ne DG. 2019
Hos -mic obe coe olu ion: applying e idence om
model sys ems o complex ma ine in e eb a e
holobion s. mBio 10, 10-128. (doi:10.1128/mbio.
02241-18)
135. Van Den Abbeele P, Van De Wiele T, Ve s ae e W,
Possemie s S. 2011 The hos selec s mucosal and
luminal associa ions o coe ol ed gu
mic oo ganisms: a no el concep . FEMS Mic obiol.
Re . 35, 681–704. (doi:10.1111/j.1574-6976.2011.
00270.x)
136. Lim SJ, Bo dens ein SR. 2020 An in oduc ion o
phylosymbiosis. P oc. R. Soc. B 287, 20192900.
(doi:10.1098/ spb.2019.2900)
137. G oussin M, Mazel F, Alm EJ. 2020 Co-e olu ion and
co-specia ion o hos -gu bac e ia sys ems. Cell Hos
Mic obe 28,12–22. (doi:10.1016/j.chom.2020.06.
013)
138. Mo an NA. 2001 The coe olu ion o bac e ial
endosymbion s and phloem- eeding insec s. Ann.
MO Bo . Ga d. 88,35–44. (doi:10.2307/2666130)
139. F aune S, Bosch TCG. 2007 Long- e m main enance
o species-speci ic bac e ial mic obio a in he basal
me azoan Hyd a.P oc. Na l Acad. Sci. USA 104,
13 146–13 151. (doi:10.1073/pnas.0703375104)
140. F anzenbu g S, Wal e J, Künzel S, Wang J, Baines
JF, Bosch TCG, F aune S. 2013 Dis inc an imic obial
pep ide exp ession de e mines hos species-speci ic
bac e ial associa ions. P oc. Na l Acad. Sci. USA 110,
E3730–E3738. (doi:10.1073/pnas.1304960110)
141. Rudman SM e al. 2019 Mic obiome composi ion
shapes apid genomic adap a ion o D osophila
melanogas e .P oc. Na l Acad. Sci. USA 116,
20 025–20 032. (doi:10.1073/pnas.1907787116)
142. Blum JE, Fische CN, Miles J, Handelsman J. 2013
F equen eplenishmen sus ains he bene icial
mic obiome o D osophila melanogas e .mBio 4,
e00860-13. (doi:10.1128/mBio.00860-13)
143. Kwong WK, Medina LA, Koch H, Sing K-W, Soh EJY,
Asche JS, Ja é R, Mo an NA. 2017 Dynamic
mic obiome e olu ion in social bees. Sci. Ad . 3,
e1600513. (doi:10.1126/sciad .1600513)
144. Mo an NA, Ochman H, Hamme TJ. 2019
E olu iona y and ecological consequences o gu
mic obial communi ies. Annu. Re . Ecol. E ol. Sys .
50, 451–475. (doi:10.1146/annu e -ecolsys-110617-
062453)
145. O’B ien PA e al. 2020 Di e se co al ee in e eb a es
exhibi pa e ns o phylosymbiosis. ISME J. 14,
2211–2222. (doi:10.1038/s41396-020-0671-x)
146. Thomas T e al. 2016 Di e si y, s uc u e and
con e gen e olu ion o he global sponge
mic obiome. Na . Commun. 7, 11870. (doi:10.1038/
ncomms11870)
oyalsocie ypublishing.o g/jou nal/ s b Phil. T ans. R. Soc. B 379: 20230071
16
Downloaded om h ps:// oyalsocie ypublishing.o g/ on 26 Sep embe 2025
147. Tang Y, Ma KY, Cheung MK, Yang C-H, Wang Y, Hu
X, Kwan HS, Chu KH. 2021 Gu mic obio a in
decapod sh imps: e idence o phylosymbiosis.
Mic ob. Ecol. 82, 994–1007. (doi:10.1007/s00248-
021-01720-z)
148. Pollock FJ, Mcminds R, Smi h S, Bou ne DG, Willis
BL, Medina M, Thu be RV, Zane eld JR. 2018 Co al-
associa ed bac e ia demons a e phylosymbiosis and
cophylogeny. Na . Commun. 9, 4921. (doi:10.1038/
s41467-018-07275-x)
149. Syl ain F-É, Holland A, Bouslama S, Aude -Gilbe É,
La oie C, Val AL, De ome N. 2020 Fish skin and gu
mic obiomes show con as ing signa u es o hos
species and habi a . Appl. En i on. Mic obiol. 86,
e00789. (doi:10.1128/AEM.00789-20)
150. Moelle AH e al. 2016 Cospecia ion o gu
mic obio a wi h hominids. Science 353, 380–382.
(doi:10.1126/science.aa 3951)
151. Mallo EK, Ama o KR. 2021 Hos speci ici y o he
gu mic obiome. Na . Re . Mic obiol. 19, 639–653.
(doi:10.1038/s41579-021-00562-3)
152. Samuel BS, Rowedde H, B aendle C, Félix M-A,
Ru kun G. 2016 Caeno habdi is elegans esponses o
bac e ia om i s na u al habi a s. P oc. Na l Acad.
Sci. USA 113, E3941–E3949. (doi:10.1073/pnas.
1607183113)
153. Hamme TJ, Janzen DH, Hallwachs W, Ja e SP,
Fie e N. 2017 Ca e pilla s lack a esiden gu
mic obiome. P oc. Na l Acad. Sci. USA 114,
9641–9646. (doi:10.1073/pnas.1707186114)
154. G oussin M, Mazel F, Sande s JG, Smillie CS,
La e gne S, Thuille W, Alm EJ. 2017 Un a eling he
p ocesses shaping mammalian gu mic obiomes
o e e olu iona y ime. Na . Commun. 8, 14319.
(doi:10.1038/ncomms14319)
155. Rosenbe g E, Zilbe -Rosenbe g I. 2021
Recons i u ion and ansmission o gu mic obiomes
and hei genes be ween gene a ions.
Mic oo ganisms 10, 70. (doi:10.3390/
mic oo ganisms10010070)
156. Bosch TCG. 2022 Beyond Lynn Ma gulis’g een
hyd a. Symbiosis 87,11–17. (doi:10.1007/s13199-
022-00849-w)
157. No a ba olo V, Giu è M, Mon an e C, Co sello G,
Ca a M. 2022 Composi ion o human b eas milk
mic obio a and i s ole in child en’s heal h. Pedia .
Gas oen e ol. Hepa ol. Nu . 25, 194–210. (doi:10.
5223/pghn.2022.25.3.194)
158. Wallace EK, He elko ES, Koski SE, Vick S-J,
Buchanan-Smi h HM, Slocombe KE. 2019
Explo a ion o po en ial igge s o sel -di ec ed
beha iou s and egu gi a ion and einges ion in
zoo-housed chimpanzees. Appl. Anim. Beha . Sci.
221, 104878. (doi:10.1016/j.applanim.2019.104878)
159. Kikuchi Y, Hosokawa T, Fuka su T. 2011 Speci ic
de elopmen al window o es ablishmen o an
insec -mic obe gu symbiosis. Appl. En i on. Mic obiol.
77,4075–4081. (doi:10.1128/AEM.00358-11)
160. Villa SM, Chen JZ, Kwong Z, Acos a A, Vega NM,
Ge a do NM. 2023 Specialized acquisi ion beha io s
main ain eliable en i onmen al ansmission in an
insec -mic obial mu ualism. Cu . Biol. 33,
2830–2838. (doi:10.1016/j.cub.2023.05.062)
161. Hannula SE, Zhu F, Heinen R, Bezeme TM. 2019
Folia - eeding insec s acqui e mic obiomes om he
soil a he han he hos plan . Na . Commun. 10,
1254. (doi:10.1038/s41467-019-09284-w)
162. Kikuchi Y, Haya su M, Hosokawa T, Nagayama A,
Tago K, Fuka su T. 2012 Symbion -media ed
insec icide esis ance. P oc. Na l Acad. Sci. USA 109,
8618–8622. (doi:10.1073/pnas.1200231109)
163. Almeida-Da-Sil a CLC, Sa io LEB, Cou inho-Sil a R,
Ojcius DM. 2023 The ole o NOD-like ecep o s in
inna e immuni y. F on . Immunol. 14, 1122586.
(doi:10.3389/ immu.2023.1122586)
164. Fló ez LV, Sche lach K, Gaube P, Ross C, Si e E,
He mes C, Rod igues A, He weck C, Kal enpo h M.
2017 An ibio ic-p oducing symbion s dynamically
ansi ion be ween plan pa hogenici y and insec -
de ensi e mu ualism. Na . Commun. 8, 15172.
(doi:10.1038/ncomms15172)
165. Kim D-R, Cho G, Jeon C-W, Welle DM, Thomashow
LS, Pauli z TC, Kwak Y-S. 2019 A mu ualis ic
in e ac ion be ween S ep omyces bac e ia,
s awbe y plan s and pollina ing bees. Na .
Commun. 10, 4802. (doi:10.1038/s41467-019-
12785-3)
166. Teseo S, Van Zweden JS, Pon ie i L, Kooij PW,
Sø ensen SJ, Wenselee s T, Poulsen M, Boomsma JJ,
Sapoun zis P. 2019 The scen o symbiosis: gu
bac e ia may a ec social in e ac ions in lea -cu ing
an s. Anim. Beha . 150, 239–254. (doi:10.1016/j.
anbeha .2018.12.017)
167. Wada-Ka suma a A, Zu ek L, Nalyanya G, Roelo s
WL, Zhang A, Schal C. 2015 Gu bac e ia media e
agg ega ion in he Ge man cock oach. P oc. Na l
Acad. Sci. USA 112, 15 678–15 683. (doi:10.1073/
pnas.1504031112)
168. D ew GC, Budge GE, F os CL, Neumann P, Siozios S,
Yañez O, Hu s GDD. 2021 T ansi ions in symbiosis:
e idence o en i onmen al acquisi ion and social
ansmission wi hin a clade o he i able symbion s. ISME
J. 15,2956–2968. (doi:10.1038/s41396-021-00977-z)
169. Salem H, Onchu u TO, Baue E, Kal enpo h M. 2015
Symbion ansmission en ails he isk o pa asi e
in ec ion. Biol. Le . 11, 20150840. (doi:10.1098/
sbl.2015.0840)
170. Fishe RM, Hen y LM, Co nwallis CK, Kie s ET, Wes
SA. 2017 The e olu ion o hos -symbion
dependence. Na . Commun. 8, 15973. (doi:10.1038/
ncomms15973)
171. Russell JA, Funa o CF, Gi aldo YM, Goldman-Hue as
B, Suh D, K onaue DJC, Mo eau CS, Pie ce NE. 2012
A e i able menage ie o he i able bac e ia om
an s, bu e lies, and beyond: b oad molecula
su eys and a sys ema ic e iew. PLoS ONE 7,
e51027. (doi:10.1371/jou nal.pone.0051027)
172. Nyholm SV. 2020 In he beginning: egg–mic obe
in e ac ions and consequences o animal hos s.
Phil. T ans. R. Soc. B 375, 20190593. (doi:10.1098/
s b.2019.0593)
173. Feldhaa H, S aka J, K ischke M, Be hold K, S oll S,
Muelle MJ, G oss R. 2007 Nu i ional upg ading o
omni o ous ca pen e an s by he endosymbion
Blochmannia.BMC Biol. 5, 48. (doi:10.1186/1741-
7007-5-48)
174. Koga R, Meng X-Y, Tsuchida T, Fuka su T. 2012
Cellula mechanism o selec i e e ical
ansmission o an obliga e insec symbion a he
bac e iocy e–emb yo in e ace. P oc. Na l Acad. Sci.
USA 109, E1230–E1237. (doi:10.1073/pnas.
1119212109)
175. A a do GM, Lohs C, Heddi A, Alam UH, Yildi im S,
Aksoy S. 2008 Analysis o milk gland s uc u e and
unc ion in Glossina mo si ans: milk p o ein
p oduc ion, symbion popula ions and ecundi y.
J. Insec Physiol. 54, 1236–1242. (doi:10.1016/j.
jinsphys.2008.06.008)
176. Anbu su H, Fuka su T. 2011 Spi oplasma as a model
insec endosymbion . En i on. Mic obiol. Rep. 3,
144–153. (doi:10.1111/j.1758-2229.2010.00240.x)
177. Ma eos M, Cas ezana SJ, Nanki ell BJ, Es es AM,
Ma kow TA, Mo an NA. 2006 He i able
endosymbion s o D osophila.Gene ics 174,
363–376. (doi:10.1534/gene ics.106.058818)
178. B ode ick NA, Lemai e B. 2012 Gu -associa ed
mic obes o D osophila melanogas e .Gu Mic obes
3, 307–321. (doi:10.4161/gmic.19896)
179. Salem H, Flo ez L, Ge a do N, Kal enpo h M. 2015
An ou -o -body expe ience: he ex acellula
dimension o he ansmission o mu ualis ic
bac e ia in insec s. P oc. R. Soc. B 282, 20142957.
(doi:10.1098/ spb.2014.2957)
180. Hosokawa T, Kikuchi Y, Fuka su T. 2007 How many
symbion s a e p o ided by mo he s, acqui ed by
o sp ing, and needed o success ul e ical
ansmission in an obliga e insec –bac e ium
mu ualism? Mol. Ecol. 16, 5316–5325. (doi:10.
1111/j.1365-294X.2007.03592.x)
181. Douglas AE. 2011 Lessons om s udying insec
symbioses. Cell Hos Mic obe 10, 359–367. (doi:10.
1016/j.chom.2011.09.001)
182. Zhang F, Be g M, Die king K, Félix M-A, Shapi a M,
Samuel BS, Schulenbu g H. 2017 Caeno habdi is
elegans as a model o mic obiome esea ch.
F on . Mic obiol. 8, 485. (doi:10.3389/ micb.
2017.00485)
183. Zheng J, Meng X, Fan J, Yang D. 2021 Ve ical
ansmission o issue mic obio a in Caeno habdi is
elegans.bioRxi , 2021.12.06.471348. (doi:10.1101/
2021.12.06.471348)
184. Abdelha iz Y, Fe nandes JMO, Dona i C, Pindo M,
Ki on V. 2022 In e gene a ional ans e o
pe sis en bac e ial communi ies in emale Nile
ilapia. F on . Mic obiol. 13, 879990. (doi:10.3389/
micb.2022.879990)
185. Hau e HC, Ba elli C. 2019 Conse e he ge ms: he
gu mic obio a and adap i e po en ial. Conse .
Gene . 20,19–27. (doi:10.1007/s10592-019-01150-y)
186. Ingala MR, Simmons NB, Pe kins SL. 2018 Ba s a e
an un apped sys em o unde s anding mic obiome
e olu ion in mammals. mSphe e 3,10–128. (doi:10.
1128/mSphe e.00397-18)
187. Moelle AH, Suzuki TA, Phi e -Rixey M, Nachman
MW. 2018 T ansmission modes o he mammalian
gu mic obio a. Science 362, 453–457. (doi:10.
1126/science.aa 7164)
188. Inoue R, Ushida K. 2003 Ve ical and ho izon al
ansmission o in es inal commensal bac e ia in he
oyalsocie ypublishing.o g/jou nal/ s b Phil. T ans. R. Soc. B 379: 20230071
17
Downloaded om h ps:// oyalsocie ypublishing.o g/ on 26 Sep embe 2025
a model. FEMS Mic obiol. Ecol. 46, 213–219.
(doi:10.1016/S0168-6496(03)00215-0)
189. Pa ke ES, Du y GJ, Moczek AP. 2019
T ansgene a ional de elopmen al e ec s o species-
speci ic, ma e nally ansmi ed mic obio a in
On hophagus dung bee les. Ecol. En omol. 44,
274–282. (doi:10.1111/een.12703)
190. Makino H e al. 2011 T ansmission o in es inal
Bi idobac e ium longum subsp. longum s ains om
mo he o in an , de e mined by mul ilocus
sequencing yping and ampli ied agmen leng h
polymo phism. Appl. En i on. Mic obiol. 77,
6788–6793. (doi:10.1128/AEM.05346-11)
191. Bäckhed F e al. 2015 Dynamics and s abiliza ion o
he human gu mic obiome du ing he i s yea o
li e. Cell Hos Mic obe 17, 690–703. (doi:10.1016/j.
chom.2015.04.004)
192. Yassou M e al. 2018 S ain-le el analysis o
mo he - o-child bac e ial ansmission du ing he
i s ew mon hs o li e. Cell Hos Mic obe 24,
146–154. (doi:10.1016/j.chom.2018.06.007)
193. Valles-Colome M e al. 2023 The pe son- o-pe son
ansmission landscape o he gu and o al
mic obiomes. Na u e 614, 125–135. (doi:10.1038/
s41586-022-05620-1)
194. Kennedy KM e al. 2023 Ques ioning he e al
mic obiome illus a es pi alls o low-biomass
mic obial s udies. Na u e 613, 639–649. (doi:10.
1038/s41586-022-05546-8)
195. Reyman M e al. 2019 Impac o deli e y mode-
associa ed gu mic obio a dynamics on heal h in
he i s yea o li e. Na . Commun. 10, 4997.
(doi:10.1038/s41467-019-13014-7)
196. Wampach L e al. 2018 Bi h mode is associa ed wi h
ea lies s ain-con e ed gu mic obiome unc ions
and immunos imula o y po en ial. Na . Commun. 9,
5091. (doi:10.1038/s41467-018-07631-x)
197. Du an i S e al. 2017 Ma e nal inhe i ance o
bi idobac e ial communi ies and bi idophages in
in an s h ough e ical ansmission. Mic obiome 5,
66. (doi:10.1186/s40168-017-0282-6)
198. S inson LF, Sindi ASM, Cheema AS, Lai CT,
Mühlhäusle BS, Wlodek ME, Payne MS, Geddes DT.
2021 The human milk mic obiome: who, wha ,
when, whe e, why, and how? Nu . Re . 79,
529–543. (doi:10.1093/nu i /nuaa029)
199. Zheng D, Liwinski T, Elina E. 2020 In e ac ion
be ween mic obio a and immuni y in heal h and
disease. Cell Res. 30, 492–506. (doi:10.1038/
s41422-020-0332-7)
200. Hancock RE, Sco MG. 2000 The ole o
an imic obial pep ides in animal de enses. P oc. Na l
Acad. Sci. USA 97, 8856–8861. (doi:10.1073/pnas.
97.16.8856)
201. F aune S, Augus in R, An on-E xleben F, Wi lieb J,
Gelhaus C, Klimo ich VB, Samoilo ich MP, Bosch
TCG. 2010 In an ea ly b anching me azoan, bac e ial
coloniza ion o he emb yo is con olled by
ma e nal an imic obial pep ides. P oc. Na l Acad.
Sci. USA 107, 18 067–18 072. (doi:10.1073/pnas.
1008573107)
202. Kuma A, Ba uah A, Tomioka M, Iino Y, Kali a MC,
Khan M. 2020 Caeno habdi is elegans: a model o
unde s and hos –mic obe in e ac ions. Cell. Mol. Li e
Sci. 77, 1229–1249. (doi:10.1007/s00018-019-
03319-7)
203. Fo d SA, D ew GC, King KC. 2022 Immune-media ed
compe i ion bene i s p o ec i e mic obes o e
pa hogens in a no el hos species. He edi y 129,
327–335. (doi:10.1038/s41437-022-00569-3)
204. Fo d SA, Kao D, Williams D, King KC. 2016 Mic obe-
media ed hos de ence d i es he e olu ion o
educed pa hogen i ulence. Na . Commun. 7,
13430. (doi:10.1038/ncomms13430)
205. Ma a A, Hanson MA, Kondo S, E kosa B, Lemai e
B. 2021 D osophila an imic obial pep ides and
lysozymes egula e gu mic obio a composi ion and
abundance. mSphe e 12, 16. (doi:10.1128/mbio.
00824-21)
206. Buchon N, B ode ick NA, Lemai e B. 2013 Gu
homeos asis in a mic obial wo ld: insigh s om
D osophila melanogas e .Na . Re . Mic obiol. 11,
615–626. (doi:10.1038/n mic o3074)
207. Ia senko I, Kondo S, Mengin-Lec eulx D, Lemai e B.
2016 PGRP-SD, an ex acellula pa e n- ecogni ion
ecep o , enhances pep idoglycan-media ed ac i a ion
o he D osophila Imd pa hway. Immuni y 45,
1013–1023. (doi:10.1016/j.immuni.2016.10.029)
208. Pa edes JC, Welchman DP, Poide in M, Lemai e B.
2011 Nega i e egula ion by amidase PGRPs shapes
he D osophila an ibac e ial esponse and p o ec s
he ly om innocuous in ec ion. Immuni y 35,
770–779. (doi:10.1016/j.immuni.2011.09.018)
209. B ode ick NA, Buchon N, Lemai e B. 2014
Mic obio a-induced changes in D osophila
melanogas e hos gene exp ession and gu
mo phology. mBio 5, e01117-14. (doi:10.1128/
mBio.01117-14)
210. Cha oux B, Capo F, Ku z CL, Peslie S, Chaduli D,
Vialla -Lieu aud A, Roye J. 2018 Cy osolic and
sec e ed pep idoglycan-deg ading enzymes in
D osophila espec i ely con ol local and sys emic
immune esponses o mic obio a. Cell Hos Mic obe
23, 215–228. (doi:10.1016/j.chom.2017.12.007)
211. Ryu J-H e al. 2008 Inna e immune homeos asis by
he homeobox gene Caudal and commensal-gu
mu ualism in D osophila.Science 319, 777–782.
(doi:10.1126/science.1149357)
212. Hanson MA, G ollmus L, Lemai e B. 2023 Ecology-
ele an bac e ia d i e he e olu ion o hos
an imic obial pep ides in D osophila.Science 381,
eadg5725. (doi:10.1126/science.adg5725)
213. Lee W-J, Kim S-H. 2014 Role o DUOX in gu
in lamma ion: lessons om D osophila model o
gu -mic obio a in e ac ions. F on . Cell. In ec .
Mic obiol. 3, 116. (doi:10.3389/ cimb.2013.00116)
214. Lemai e B, Nicolas E, Michau L, Reichha J-M,
Ho mann JA. 1996 The do so en al egula o y
gene casse e spä zle/Toll/cac us con ols he
po en an i ungal esponse in D osophila adul s.
Cell 86, 973–983. (doi:10.1016/S0092-
8674(00)80172-5)
215. F anzenbu g S, F aune S, Künzel S, Baines JF,
Domaze -Lošo T, Bosch TCG. 2012 MyD88-de icien
Hyd a e eal an ancien unc ion o TLR signaling in
sensing bac e ial colonize s. P oc. Na l Acad. Sci.
USA 109, 19 374–19 379. (doi:10.1073/pnas.
1213110109)
216. Rako -Nahoum S, Paglino J, Eslami-Va zaneh F,
Edbe g S, Medzhi o R. 2004 Recogni ion o
commensal mic o lo a by oll-like ecep o s is
equi ed o in es inal homeos asis. Cell 118,
229–241. (doi:10.1016/j.cell.2004.07.002)
217. Vijay-Kuma M e al. 2010 Me abolic synd ome and
al e ed gu mic obio a in mice lacking Toll-like
ecep o 5. Science 328, 228–231. (doi:10.1126/
science.1179721)
218. Die king K, Pi a L. 2020 Recep o s media ing hos -
mic obio a communica ion in he me ao ganism:
he in e eb a e pe spec i e. F on . Immunol. 11,
1251. (doi:10.3389/ immu.2020.01251)
219. Hibino T e al. 2006 The immune gene epe oi e
encoded in he pu ple sea u chin genome. De . Biol.
300, 349–365. (doi:10.1016/j.ydbio.2006.08.065)
220. Chapman JA e al. 2010 The dynamic genome o
Hyd a.Na u e 464, 592–596. (doi:10.1038/
na u e08830)
221. Pu nam NH e al. 2007 Sea anemone genome
e eals ances al eume azoan gene epe oi e and
genomic o ganiza ion. Science 317,86–94. (doi:10.
1126/science.1139158)
222. Mo a V, Soa es F, Sun T, Philpo DJ. 2015 NOD-like
ecep o s: e sa ile cy osolic sen inels. Physiol. Re .
95, 149–178. (doi:10.1152/phys e .00009.2014)
223. Chuphal B, Rai U, Roy B. 2022 Teleos NOD-like
ecep o s and hei downs eam signaling pa hways:
a b ie e iew. Fish Shell ish Immunol. Rep. 3,
100056. (doi:10.1016/j. si ep.2022.100056)
224. Howe K, Schi e PH, Zielinski J, Wiehe T, Lai d GK,
Ma ioni JC, Soylemez O, Kond asho F, Lep in M.
2016 S uc u e and e olu iona y his o y o a la ge
amily o NLR p o eins in he zeb a ish. Open Biol. 6,
160009. (doi:10.1098/ sob.160009)
225. Rehman A, Sina C, Ga ilo a O, Häsle R, O S,
Baines JF, Sch eibe S, Rosens iel P. 2011 Nod2 is
essen ial o empo al de elopmen o in es inal
mic obial communi ies. Gu 60, 1354–1362.
(doi:10.1136/gu .2010.216259)
226. Zhang H, Luo XM. 2015 Con ol o commensal
mic obio a by he adap i e immune sys em. Gu
Mic obes 6, 156–160. (doi:10.1080/19490976.2015.
1031946)
227. Flajnik MF, Du Pasquie L. 2004 E olu ion o inna e
and adap i e immuni y: can we d aw a line? T ends
Immunol. 25,640–644. (doi:10.1016/j.i .2004.10.001)
228. Pa a D, Takizawa F, Sunye JO. 2013 E olu ion o B
cell immuni y. Annu. Re . Anim. Biosci. 1,65–97.
(doi:10.1146/annu e -animal-031412-103651)
229. Pe e son DA, Mcnul y NP, Gu uge JL, Go don JI.
2007 IgA esponse o symbio ic bac e ia as a
media o o gu homeos asis. Cell Hos Mic obe 2,
328–339. (doi:10.1016/j.chom.2007.09.013)
230. S ugnell RA, Wijbu g OLC. 2010 The ole o
sec e o y an ibodies in in ec ion immuni y. Na . Re .
Mic obiol. 8, 656–667. (doi:10.1038/n mic o2384)
231. Nagaishi T e al. 2022 Immunoglobulin A–speci ic
de iciency induces spon aneous in lamma ion
speci ically in he ileum. Gu 71, 487–496. (doi:10.
1136/gu jnl-2020-322873)
oyalsocie ypublishing.o g/jou nal/ s b Phil. T ans. R. Soc. B 379: 20230071
18
Downloaded om h ps:// oyalsocie ypublishing.o g/ on 26 Sep embe 2025
232. Suzuki K, Meek B, Doi Y, Mu ama su M, Chiba T,
Honjo T, Faga asan S. 2004 Abe an expansion o
segmen ed ilamen ous bac e ia in IgA-de icien
gu . P oc. Na l Acad. Sci. USA 101, 1981–1986.
(doi:10.1073/pnas.0307317101)
233. Rollenske T, Bu khal e S, Mue ne L, Von Gun en S,
Lukasiewicz J, Wa demann H, Macphe son AJ. 2021
Pa allelism o in es inal sec e o y IgA shapes
unc ional mic obial i ness. Na u e 598, 657–661.
(doi:10.1038/s41586-021-03973-7)
234. Takeuchi T, Ohno H. 2022 IgA in human heal h and
diseases: po en ial egula o o commensal
mic obio a. F on . Immunol. 13, 1024330. (doi:10.
3389/ immu.2022.1024330)
235. Shapi o JM e al. 2021 Immunoglobulin A a ge s a
unique subse o he mic obio a in in lamma o y
bowel disease. Cell Hos Mic obe 29,83–93. (doi:10.
1016/j.chom.2020.12.003)
236. Sel anan ham T e al. 2016 NKT cell–de icien mice
ha bo an al e ed mic obio a ha uels in es inal
in lamma ion du ing chemically induced coli is.
J. Immunol. 197, 4464–4472. (doi:10.4049/
jimmunol.1601410)
237. B ugman S e al. 2014 T lymphocy es con ol
mic obial composi ion by egula ing he
abundance o Vib io in he zeb a ish gu .
Gu Mic obes 5, 737–747. (doi:10.4161/19490976.
2014.972228)
238. Mille ET, S anbäck R, Bohannan BJM. 2018
Mic obiomes as me acommuni ies: unde s anding
hos -associa ed mic obes h ough me acommuni y
ecology. T ends Ecol. E ol. 33, 926–935. (doi:10.
1016/j. ee.2018.09.002)
239. Sa ka A e al. 2020 Mic obial ansmission in
animal social ne wo ks and he social mic obiome.
Na . Ecol. E ol.4, 1020–1035. (doi:10.1038/s41559-
020-1220-8)
240. Kwong WK, Mo an NA. 2016 Gu mic obial
communi ies o social bees. Na . Re .
Mic obiol. 14, 374–384. (doi:10.1038/n mic o.
2016.43)
241. Deb ay R, He be RA, Ja e AL, C i s-Ch is oph A,
Powe ME, Koskella B. 2022 P io i y e ec s in
mic obiome assembly. Na . Re . Mic obiol. 20,
109–121. (doi:10.1038/s41579-021-00604-w)
242. Vega NM, Go e J. 2017 S ochas ic assembly
p oduces he e ogeneous communi ies in
he Caeno habdi is elegans in es ine. PLoS
Biol. 15, e2000633. (doi:10.1371/jou nal.pbio.
2000633)
243. Obadia B, Gü ene ZT, Zhang V, Ceja-Na a o JA,
B odie EL, Ja WW, Luding on WB. 2017 P obabilis ic
in asion unde lies na u al gu mic obiome s abili y.
Cu . Biol. 27, 1999–2006. (doi:10.1016/j.cub.2017.
05.034)
244. Co by-Ha is V, Pon a oli AC, Shimke s LJ, Benne zen
JL, Habel KE, P omislow DE. 2007 Geog aphical
dis ibu ion and di e si y o bac e ia associa ed wi h
na u al popula ions o D osophila melanogas e .
Appl. En i on. Mic obiol. 73, 3470–3479. (doi:10.
1128/AEM.02120-06)
245. Ellegaa d KM, Engel P. 2019 Genomic di e si y
landscape o he honey bee gu mic obio a.
Na . Commun. 10, 446. (doi:10.1038/s41467-019-
08303-0)
246. Ellegaa d KM, Suenami S, Miyazaki R, Engel P. 2020
Vas di e ences in s ain-le el di e si y in he gu
mic obio a o wo closely ela ed honey bee species.
Cu . Biol. 30, 2520–2531. (doi:10.1016/j.cub.2020.
04.070)
247. Bu ns AR, S ephens WZ, S agaman K, Wong S,
Rawls JF, Guillemin K, Bohannan BJ. 2016
Con ibu ion o neu al p ocesses o he assembly o
gu mic obial communi ies in he zeb a ish o e
hos de elopmen . ISME J. 10, 655–664. (doi:10.
1038/ismej.2015.142)
248. Ma ãNez I e al. 2018 Expe imen al e alua ion o
he impo ance o coloniza ion his o y in ea ly-li e
gu mic obio a assembly. eLi e 7, e36521. (doi:10.
7554/eLi e.36521)
249. Mo ai ou M, Fo sy he A, Fellows Ya es JA, B ealey
JC, Wa inne C, Guschanski K. 2022 Ecology, no
hos phylogeny, shapes he o al mic obiome in
closely ela ed species. Mol. Biol. E ol. 39, msac263.
(doi:10.1093/molbe /msac263)
250. B ode ick NA, Ra a KF, Goodman RM, Handelsman
J. 2004 Census o he bac e ial communi y o he
gypsy mo h la al midgu by using cul u ing and
cul u e-independen me hods. Appl. En i on.
Mic obiol. 70, 293–300. (doi:10.1128/AEM.70.1.293-
300.2004)
251. Xiang H, Wei G-F, Jia S, Huang J, Miao X-X, Zhou Z,
Zhao L-P, Huang Y-P. 2006 Mic obial communi ies
in he la al midgu o labo a o y and ield
popula ions o co on bollwo m (Helico e pa
a mige a). Can. J. Mic obiol. 52, 1085–1092.
(doi:10.1139/w06-064)
252. Klamms eine T, Wal e A, Boga aj T, Heussle CD,
S es B, S eine FM, Schlick-S eine BC, A ho e W,
Insam H. 2020 The co e gu mic obiome o black
soldie ly (He me ia illucens) la ae aised on low-
biobu den die s. F on . Mic obiol. 11, 993. (doi:10.
3389/ micb.2020.00993)
253. Zhang J, Holdo AD, Walhou AJ. 2017 C. elegans
and i s bac e ial die as a model o sys ems-le el
unde s anding o hos –mic obio a in e ac ions. Cu .
Opin. Bio echnol. 46,74–80. (doi:10.1016/j.copbio.
2017.01.008)
254. Ma ino ME, Joncou P, Leenay R, Ge ais H, Shah
M, Hughes S, Gille B, Beisel C, Leulie F. 2018
Bac e ial adap a ion o he hos ’s die is a key
e olu iona y o ce shaping D osophila-Lac obacillus
symbiosis. Cell Hos Mic obe 24, 109–119. (doi:10.
1016/j.chom.2018.06.001)
255. Obadia B, Keebaugh ES, Yamada R, Luding on WB,
Ja WW. 2018 Die in luences hos –mic obio a
associa ions in D osophila.P oc. Na l Acad. Sci.
USA 115, E4547–E4548. (doi:10.1073/pnas.
1804948115)
256. Chen J-S, Tsau S-C, Ting C-T, Fang S. 2022 Die a y
u iliza ion d i es he di e en ia ion o gu bac e ial
communi ies be ween specialis and gene alis
d osophilid lies. Mic obiol. Spec . 10, e01418–22.
(doi:10.1128/spec um.01418-22)
257. Walbu n J W, Wemheue B, Thomas T, Copeland E,
O’Conno W, Boo h M, Fielde S, Egan S. 2019 Die
and die -associa ed bac e ia shape ea ly mic obiome
de elopmen in yellow ail king ish (Se iola lalandi).
Mic ob. Bio echnol. 12, 275–288. (doi:10.1111/
1751-7915.13323)
258. Ca mody RN, Ge be GK, Lue ano JM, Ga i DM,
Somes L, S enson KL, Tu nbaugh PJ. 2015 Die
domina es hos geno ype in shaping he mu ine
gu mic obio a. Cell Hos Mic obe 17,72–84.
(doi:10.1016/j.chom.2014.11.010)
259. Dapa T, Rami o RS, Ped o MF, Go do I, Xa ie KB.
2022 Die lea es a gene ic signa u e in a keys one
membe o he gu mic obio a. Cell Hos
Mic obe 30, 183–199. (doi:10.1016/j.chom.2022.01.
002)
260. Da id LA e al. 2014 Die apidly and ep oducibly
al e s he human gu mic obiome. Na u e 505,
559–563. (doi:10.1038/na u e12820)
261. Chandle JA, Mo gan Lang J, Bha naga S, Eisen JA,
Kopp A. 2011 Bac e ial communi ies o di e se
D osophila species: ecological con ex o a hos –
mic obe model sys em. PLoS Gene . 7, e1002272.
(doi:10.1371/jou nal.pgen.1002272)
262. Ley RE e al. 2008 E olu ion o mammals and hei
gu mic obes. Science 320, 1647–1651. (doi:10.
1126/science.1155725)
263. Muegge BD, Kuczynski J, Knigh s D, Clemen e JC,
Gonzalez A, Fon ana L, Hen issa B, Knigh R,
Go don JI. 2011 Die d i es con e gence in gu
mic obiome unc ions ac oss mammalian phylogeny
and wi hin humans. Science 332, 970–974. (doi:10.
1126/science.1198719)
264. Ley RE, Lozupone CA, Hamady M, Knigh R, Go don
JI. 2008 Wo lds wi hin wo lds: e olu ion o he
e eb a e gu mic obio a. Na . Re . Mic obiol. 6,
776–788. (doi:10.1038/n mic o1978)
265. Fos e KR, Schlu e J, Coy e KZ, Rako -Nahoum S.
2017 The e olu ion o he hos mic obiome as an
ecosys em on a leash. Na u e 548,43–51. (doi:10.
1038/na u e23292)
oyalsocie ypublishing.o g/jou nal/ s b Phil. T ans. R. Soc. B 379: 20230071
19
Downloaded om h ps:// oyalsocie ypublishing.o g/ on 26 Sep embe 2025
