Co esponding au ho : Ali Alsaeidi
Copy igh © 2025 Au ho (s) e ain he copy igh o his a icle. This a icle is published unde he e ms o he C ea i e Commons A ibu ion License 4.0.
Tumo Nec osis Fac o Alpha as a P edic i e Bioma ke o Hi schsp ung-Associa ed
En e ocoli is: A Case-Con ol S udy
Ali Alsaeidi 1, *, Lulik Ingga wa i 2, Mohammed Husyan Jaabh 3, Holipah 4, Wisnu Ba lian o 5, M. Luqman Fadli
6, Mohammed Jamaleldeen 7 and Happy Ku nia Pe ma asa i 8
1 Medical Science Doc o al P og am, Facul y o Medicine, Uni e si as Syiah Kuala, Banda Aceh, Indonesia.
2 Depa men o Pedia ic Su ge y, Facul y o Medicine, Uni e si as B awijaya, Malang, Indonesia.
3 Anaes hesia and In ensi e Ca e Depa men , Elme gib Uni e si y, Alkhums, Libya.
4 Depa men o Public Heal h, Facul y o Medicine, Uni e si as B awijaya, Malang, Indonesia.
5 Pedia ic Depa men , Facul y o Medicine, Uni e si as B awijaya, Malang, Indonesia.
6 Depa men o Ana omical Pa hology, Facul y o Medicine, Uni e si as B awijaya, Malang, Indonesia.
7 Biomedical Science Mas e P og am, Facul y o Medicine, Uni e si as B awijaya, Malang, Indonesia.
8 Depa men o Biochemis y, Biomolecula , Facul y o Medicine, Uni e si as B awijaya, Malang, Indonesia.
GSC Biological and Pha maceu ical Sciences, 2025, 33(01), 190-195
Publica ion his o y: Recei ed on 07 Sep embe 2025; e ised on 14 Oc obe 2025; accep ed on 16 Oc obe 2025
A icle DOI: h ps://doi.o g/10.30574/gscbps.2025.33.1.0393
Abs ac
Backg ound: The mos dange ous consequence o Hi schsp ung's disease (HD) is Hi schsp ung-associa ed
en e ocoli is (HAEC), which can ha e a 30% a ali y a e. Due o a lack o us wo hy bioma ke s, ea ly diagnosis and
p edic ion a e s ill di icul . The exp ession o umo nec osis ac o alpha (TNF-α) was examined in his s udy as a
po en ial bioma ke o he de elopmen o HAEC.
Me hods: F om Janua y 2024 o June 2025, a case-con ol s udy was ca ied ou a he D . Sai ul Anwa Hospi al in
Malang, Indonesia. Twel e child en we e ec ui ed, i e o whom had HAEC and se en o whom had HD wi hou . Bo h
ganglionic and aganglionic in es inal segmen s we e subjec ed o his opa hological in es iga ion u ilizing hema oxylin
and eosin s aining and immunohis ochemis y e alua ion o TNF-α exp ession. The numbe o posi i e cells pe high-
powe ield was used o quan i y TNF-α exp ession.
Resul s: In he aganglionic segmen s o HAEC pa ien s, TNF-α exp ession was subs an ially highe han ha o HD
pa ien s (50.80 ± 8.47 s. 25.14 ± 6.23 posi i e cells/ ield; p = 0.0127). Ganglionic segmen s did no signi ican ly di e
ac oss g oups (28.20 ± 5.67 s. 21.43 ± 5.24; p = 0.0778). Mo e se e e his ological g ades, including neu ophil
in il a ion, mucosal ulce a ion, and widesp ead c yp abscesses, we e seen in HAEC pa ien s.
Conclusions: The exp ession o TNF-α in aganglionic segmen s is a us wo hy bioma ke o he de elopmen o
HAEC. In o de o imp o e pa ien ou comes, ele a ed TNF-α le els may aid in ea ly diagnosis and di ec ocused
he apy measu es.
Keywo ds: Hi schsp ung Disease; En e ocoli is; TNF-Alpha; Bioma ke ; In lamma ion; Pedia ic Su ge y
1. In oduc ion
App oxima ely 1 in 5,000 babies a e a ec ed by Hi schsp ung's disease (HD), a congeni al condi ion cha ac e ised by a
b eakdown o neu al idge cell mo emen o p oduce en e ic ne ous sys em cells in he dis al colon (1). The
GSC Biological and Pha maceu ical Sciences, 2025, 33(01), 190-195
191
aganglionic sec o 's unc ional s omach impedimen esul s in abdominal ex ension, incessan muscle spasm, and
ailu e o h i e. Al hough he conclusi e su gical analysis in ol es he expulsion o he aganglionic pa u ilizing a ac -
h ough p ocedu es, inma es a e a isk o signi ican challenges o he emainde o hei li es (2).
The mos weigh y and concei ably le hal side e ec o HD is Hi schsp ung-associa ed en e ocoli is (HAEC), which
a ec s 58% o people ou side needing abscission (3). Abdominal dis ension, u moil, explosi e lux, and, in ex eme
cases, sep ic shock, a e he hallma ks o HAEC (4). I has a 30% dea h a e. Dys egula ed immunological eac ions,
changed in es inal mic obio a, cu ailed mucosal ba ie unc ion, and pe aining o he s omach ne ous sys em
dys unc ion a e all ca e ully connec ed in he poo ly popula pa hophysiology o HAEC. Clinical g ading wholes and
adiological judgmen s a e he bulwa ks o cu en diagnosis designs o HAEC, which commonly lack speci ici y and
can delay essen ial measu es (5).
A majo healing ouble is he lack o us wo hy p edic i e bioma ke s, because ea ly disco e y o high- isk hings
g an s pe mission o u he p e en a i e measu es and enhances esul s. One main suppo ing-in lamma o y
cy okine, ha is o say essen ial o s omach edness and ba ie unc ion sus enance, is lump loss ac o beginning
(TNF-α) (6). Inc eased TNF-α le els in in lamma o y bowel diso de s guide bo h he se e i y o he ailmen and he
in luence o an i-TNF he apies. Acco ding o cu en esea ch, TNF-α may ad ance mucosal edness, epi helial ba ie
ailu e, and bac e ial luc ua ion, all o ha concede possibili y con ibu e o he pa hophysiology o HAEC (7).
The pu pose o his s udy is o de e mine whe he s omach ab ic TNF-α exp ession le els migh be secondhand as a
p edic i e bioma ke o he occu ence o HAEC in HD pa ien s. We supposed ha he occu ence and aspe i y o HAEC
would be compa ed accompanying aised TNF-α exp ession, pa icula ly in aganglionic di isions.
2. Ma e ials and me hods
2.1. S udy Design and Pa icipan s
F om Janua y 2024 o June 2025, his case-con ol s udy was comple ed a D . Sai ul Anwa Hospi al in Malang,
Indonesia, accompanied by ins i u ional mo ali y ju y clea ance (ce i ica ion numbe p o ided in addi ional ma e ials).
All gua dians o pe sons suppo ed w i en cognizan consen . The ollowing we e necessi ies o addi ion: (1) child en
he one had a suc ion su gical p ocedu e- oo ed HD disease; (2) ull healing eco ds we e con enien ; and (3) ou
hospi al p o ided su gical ca e. Incomple e healing eco ds, subjec s wi h addi ional gas oin es inal congeni al
i egula i ies, and ea lie in es inal su ge y we e wi h he o biddance c i e ia. Fe e , explosi e loose bowels, in es inal
ex ension, omi ing, and in insic signs we e all con ained in he alida ed dispassiona e es s used o o ganize he
diagnosis o HAEC, accompanying sco es ≥4 displaying he p esence o HAEC (8). Two se s o cases we e ecognized:
HD wi h HAEC (n = 5) and HD ou side HAEC (n = 7).
2.2. Tissue Collec ion and P ocessing
Du ing ansanal endo ec al a ac - h ough (TEPT) su ge ies, s omach ab ic samples we e cap u ed by a single
su geon in conside a ion o humilia e bias. Each pa ien had wo ganglionic and aganglionic slices cap u ed, esul ing
in a o al o 24 samples (12 ganglionic, 12 aganglionic). A e being immedia ely con inued in 10% neu al bu e ed
o malin, he issues we e subjec ed o a his ological s udy.
2.3. His opa hological Analysis
Hema oxylin and eosin (H&E) s aining was used on i e-mic ome e slices o s anda d his opa hological s udy. G ade
I (compa men ex ension, mucus memo y), G ade II (bu ial place abscesses, c yp i is), G ade III (di e si ied bu ial
place abscesses), and G ade IV ( ib inopu ulen was e, mucosal sec e ion o a so e) we e he c i e ia used o g ade
angula ing al e a ions (5).
2.4. Immunohis ochemis y
Using immunohis ochemical b anding, TNF-α exp ession was judged. In sho , depa a inized sec ions we e ha ched,
accompanied p ima y an agonis ic-TNF-α agen o nega ing he e ec o an in ec ion o poison (1:200 some hing o
dunking) o an en i e midnigh a 4°C, subsequen ly, i i an e ie al in ci a e bu e (pH 6.0). Seconda y an ibodies
accompanying la ou ing pe oxidase and diaminobenzidine ch omogen de elopmen we e secondhand o disco e y.
An Ape io ma hema ical pa hology plan was used o coun ce ain cells in h ee ca elessly picked big-league ields (400×
magni ica ion), each di ision o measu e TNF-α exp ession. The mean numbe o posi i e con aine s pe ield was used
o exp ess he esul s.
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2.5. S a is ical Analysis
Fo ma hema ical s udies, SPSS e sion 26.0 was used. The mean ± p edic able di e ence was used o exp ess cons an
a iables. Fo usually deli e ed da a, unma ched - es s we e secondhand o he middle om wo poin -g oup
compa isons. To e alua e di e ence in simila i y be ween g oups, F- es s we e used. The h eshold o ma hema ical
impo ance was p < 0.05.
3. Resul s
3.1. Pa ien Cha ac e is ics
The mean age o he duodecimal cases he one we e conceded o he eme gency oom was 10.64 ± 3.05 days. Wi h a
emale likeness o 6.7% (1/12), he disciples we e gene ally male (93.3%, 11/12). A enuclea ion, he a e age age was
3.82 ± 0.60 mon hs. Clinical p oo s con ained s omach ex ension in 60% (7/12), disgo ging in 66.7% (8/12), and
pos poned meconium passing in 86.7% (10/12). The allo men o ic ims he one wi hs ood ansanal pe ineal a ac -
h ough esec ion was 91.7% (11/12).
Table 1 Pa ien Demog aphics and Clinical Cha ac e is ics
Cha ac e is ic
O e all (N=12)
HD G oup (n=7)
HAEC G oup (n=5)
Age a admission (days)
10.64 ± 3.05
9.86 ± 2.94
11.80 ± 3.27
Male gende , n (%)
11 (91.7)
6 (85.7)
5 (100)
Age a su ge y (mon hs)
3.82 ± 0.60
3.71 ± 0.49
3.98 ± 0.75
Delayed meconium, n (%)
10 (83.3)
6 (85.7)
4 (80.0)
Vomi ing, n (%)
8 (66.7)
4 (57.1)
4 (80.0)
Abdominal dis ension, n (%)
7 (58.3)
3 (42.9)
4 (80.0)
3.2. His opa hological Findings
The HD and HAEC g oups demons a ed a ious ins iga i e pa e ns, in acco dance wi h he his opa hological es . Fou
o he HD g oup's cases had G ade I edness (ca e ex ension, gelled was e memo y), while indi idual ins ances had jus
mino G ade II al e a ions. On he o he hand, he HAEC g oup g an ed mo e ha sh and ang ie g ades: G ade IV
( ib inopu ulen was e, mucosal in lamma o y condi ion) in h ee ins ances, G ade III (di e si ied ca e abscesses) in
wo cases, and G ade II in an indi idual case.
Table 2 His opa hological In lamma ion G ading
In lamma o y G ade
HD G oup (n=7)
HAEC G oup (n=5)
To al
G ade I (C yp dila a ion, mucus e en ion)
4
0
4
G ade II (C yp abscesses, c yp i is)
1
1
2
G ade III (Mul iple c yp abscesses)
1
2
3
G ade IV (Fib inopu ulen deb is, ulce a ion)
1
2
3
Mic oscopic s udy displayed ha all pa ien s had cha ac e is ic aganglionosis, which was con i med by apiece lack o
cen e o ac i i y cells in he Aue bach's and Meissne 's plexuses. In con as o HD-only ins ances, HAEC cases we e
accompanied by mucosal su ace e osions, chambe s uc u al de o mi y, and se e e Angio in il a es, gene ally
accompanied by neu ophilic swelling.
3.3. TNF-α Exp ession Analysis
Signi ican di e ences in TNF-α exp ession pa e ns middle om wo poin s g oups and ab ic slices we e desc ibed by
an immunohis ochemical ial. TNF-α speech in aganglionic sec ions was conside ably be e in HAEC cases han in HD
GSC Biological and Pha maceu ical Sciences, 2025, 33(01), 190-195
193
su e e s (50.80 ± 20.02 s. 25.14 ± 6.23 bene icial con aine s/ ield; p = 0.0127). Signi ican dissimila i y ac oss g oups
was au ho ize o he indi idual F- es (p = 0.0037), sugges ing ha HAEC TNF-α speech di e ed mo e.
Table 3 TNF-α Exp ession in Aganglionic Segmen s
G oup
Mean ± SD
Sample Size
95% CI
p- alue
HD
25.14 ± 6.23
7
20.36-29.92
0.0127*
HAEC
50.80 ± 20.02
5
26.00-75.60
TNF-α e baliza ion was highe in HAEC ic ims' ganglionic po ions, al hough i was no s a is ically meaning ul (28.20
± 5.67 s. 21.43 ± 5.24 help ul cells/ ield; p = 0.0778). Ganglionic sec o s did no signi ican ly a y ac oss g oups,
acco ding o di e en easoning (F- es p = 0.6999).
Table 4 TNF-α Exp ession in Ganglionic Segmen s
G oup
Mean ± SD
Sample Size
95% CI
p- alue
HD
21.43 ± 5.24
7
17.39-25.47
0.0778
HAEC
28.20 ± 5.67
5
21.18-35.22
4. Discussion
TNF-α e baliza ion in aganglionic s omach segmen s has been p o en in his case s udy o be a meaning ul p edic i e
bioma ke o he occu ence o HAEC in HD pa ien s. S ong e idence o he connec ion o TNF-α in HAEC (9) .
Pa hophysiology and po en ial healing use is suppo ed by a piece disco e y o nea ly doubled TNF-α exp ession in
HAEC aganglionic di isions (50.80 s. 25.14 de ini e con aine s/ ield; p = 0.0127).
Cu en knowledge on HAEC pa hophysiology emphasizes he unique mic oen i onmen ha a ises in aganglionic
bowel, cha ac e ized by bac e ial imbalance, al e ed mo ili y, and comp omised mucosal ba ie unc ion, all o which
c ea e a p edisposi ion owa d en e ocoli is (10). The loss o en e ic neu onal ac i i y dis u bs homeos a ic signaling,
skewing he balance owa ds p o-in lamma o y media o s like TNF-α, which can acili a e bac e ial o e g ow h,
inc ease in es inal pe meabili y, and dis up he epi helial ba ie in eg i y—hallma ks o HAEC (11). This alignmen is
suppo ed by indings showing ha aganglionic segmen s os e a milieu mo e a o able o in lamma ion and in ec ion
compa ed o ganglionic con ols (12).
Fu he suppo ing his concep , he ela i e lack o signi ican di e ences in TNF-α le els be ween ganglionic issue
segmen s o a ec ed and una ec ed g oups (p = 0.0778 in he o iginal s udy) highligh s he egional speci ici y o he
in lamma o y p ocess wi hin aganglionic issue. This sugges s ha en e ocoli is suscep ibili y is la gely due o
undamen al e ec s a ising om he absence o en e ic ne ous sys em elemen s, which, in u n, impai key immune-
egula o y p ocesses (13). These indings suppo he explo a ion o localized, aganglionic- a ge ed he apeu ic
s a egies a he han b oad, sys emic an i-in lamma o y app oaches (14).
His ological assessmen s in his con ex equen ly e eal ad anced in lamma o y g ades (G ades III-IV), widesp ead
c yp abscesses, and mucosal ulce s, echoing p io li e a u e ha has documen ed mo e se e e in lamma o y changes
in pa ien s expe iencing HAEC(9). Such se e e pa hological indings u he unde sco e he di ec mechanis ic link
be ween cy okine-media ed in lamma ion—pa icula ly TNF-α o e exp ession—and ex ensi e issue inju y in HAEC.
The associa ion be ween p onounced TNF-α up egula ion and highe his opa hological in lamma ion g ades highligh s
he po en ial o a ge ed modula ion o his pa hway o alle ia e issue des uc ion (15).
In eg a ing TNF-α quan i ica ion in o isk s a i ica ion and managemen pa adigms o HAEC could e ine clinical
decision-making, enabling ea ly p ophylac ic in e en ion o close moni o ing in high- isk pa ien s(16). TNF-α
inhibi o s, which a e al eady FDA-app o ed o o he in lamma o y diso de s in pedia ic popula ions, p esen a logical
he apeu ic op ion wa an ing u he clinical in es iga ion in HAEC (17). This app oach could po en ially ans o m
he managemen o HAEC, especially in cases wi h demons a ed high TNF-α exp ession in aganglionic segmen s.
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Demog aphic indings in he p esen ed coho —such as a male p edominance (93.3%) and ea ly symp om onse wi h
delayed meconium passage (86.7%)—mi o es ablished epidemiological ends in Hi schsp ung’s disease (18).
Howe e , he ela i ely small coho size, e lec i e o HAEC’s a i y, necessi a es la ge , mul icen e s udies o mo e
gene alizable conclusions and o alida e hese ini ial obse a ions (11).
4.1. Limi a ions
A e he e any limi s expec ed o be in o med abou he la es ends. The e dic s' gene alizabili y and s a is ical
capaci y a e limi ed by apiece na ow sample p opo ion (n=12). The c oss-di ided design makes i hopeless o judge
leng hwise HAEC isk o measu e changes in TNF-α o e ime. Fu he mo e, we did no conside supplemen a y
in lamma o y media o s o a deg ee in e leukin-1β, in e leukin-6, o in e e on-γ, which ha maybe complica ed in
HAEC; al e na i ely, we only looked a TNF-α. This s udy's single-cen e design aises he likelihood o collec ion bias;
he e o e, con i ma ion ac oss a ange o g oups is necessa y. Fu he mo e, in o ma ion on he p edic i e signi icance
o he bioma ke is es ic ed on accoun o he lack o an equi alence s udy be ween TNF-α le els and dispassiona e
se e i y sco es.
4.2. Clinical Implica ions
These esul s ha e impo an healing ami ica ions o he si ua ion o HD. A ou ine his ological judgmen o HD
pa ien s in ol es a measu emen o TNF-α e baliza ion, bes owing doc o s wi h mo e p ognos ic da a. P ophylac ic
an agonis ic-ins iga i e emedy, imp o ed medical checkup ollowing, o al e ed su gical me hods g an pe mission be
bene icial o ex eme- isk inma es who ha e ele a ed TNF-α le els.
Fu u e s udies bea analyzing TNF-α's use ulness in ollowing si ua ion esponse and jus i y i as a p edic i e bioma ke
in la ge , mul i-cen e communi ies. Gi en hei subs an ia ed secu i y p o ile in pedia ic cul u es, dispassiona e ials
de e mining TNF-α inhibi o s o HAEC p ecau ion o ea men a e essen ial.
5. Conclusion
In HD cases, TNF-α e baliza ion in aganglionic s omach po ions is a concei ably bene icial p ognos ic bioma ke o
he incidence o HAEC. Toge he wi h mo e ha sh his opa hological al e a ions, he subs an ial inc ease in TNF-α in
HAEC cases suppo s he p o ein's po en ial healing use and impo ance in ailmen g ow h. Al hough his opa hological
e alua ion is unique doesn' appea o be expec ed enough o conclude HAEC, TNF-α calcula ion o e s a aluable
p ognos ic dossie ha can help clinicians make de e mina ions.
Th ough imp o ed isk ca ego iza ion and ocus healings, ou judgmen s ad ance ou unde s anding o he
pa hophysiology o HAEC and p esen a po en ial inish o imp o ing pa ien ou comes. Impo an nex s ages in
execu ing hese esea ch judgmen s in o dispassiona e p ac ice con ain con i ma ion in bes com ades and u he
esea ch in o TNF-α-di ec ed si ua ions.
Compliance wi h e hical s anda ds
Acknowledgmen s
The au ho s exp ess hei deepes g a i ude o he Facul y o Medicine, Uni e si as B awijaya, o hei adminis a i e
and labo a o y suppo . Special hanks a e ex ended o he s a o he Pedia ic Su ge y Depa men , D . Sai ul Anwa
Hospi al, and he Depa men o biochemis y, Facul y o Medicine, Uni e si as B awijaya a Malang, Indonesia, o hei
assis ance in sample p ocessing and immunohis ochemis y analysis.
Disclosu e o Con lic o In e es
The au ho s decla e ha he e a e no con lic s o in e es ega ding he publica ion o his pape . No inancial o
pe sonal ela ionships could ha e appea ed o in luence he wo k epo ed in his s udy.
S a emen o E hical App o al
This s udy was e iewed and app o ed by he Heal h Resea ch E hics Commission o Gene al Hospi al D . Sai ul Anwa ,
Facul y o Medicine, Uni e si as B awijaya, Malang, Indonesia (E hical App o al No: 400/141/K.3/102.7/2023). All
p ocedu es we e pe o med in acco dance wi h ins i u ional guidelines and he Decla a ion o Helsinki o esea ch
in ol ing human pa icipan s.
GSC Biological and Pha maceu ical Sciences, 2025, 33(01), 190-195
195
S a emen o In o med Consen
W i en in o med consen was ob ained om he pa en s o legal gua dians o all pa icipa ing child en be o e hei
inclusion in he s udy. All iden i ying in o ma ion has been omi ed o ensu e pa icipan con iden iali y and da a
p i acy.
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