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UDK: 616.33-018.2-091:616.379-056.52
SUBMICROSCOPIC CHANGES IN THE GASTRIC MUCOSA IN METABOLIC
SYNDROME: SEXUAL DIMORPHISM AND ANTIOXIDANT PROTECTION
Allabe gano Dilshod Sha ka o ich1, Babaye Xamza Nu ma o ich2, Islamo a Nigo a
Baxodi qizi3
Allabe gano Dilshod Sha ka o ich - Senio Lec u e a he Depa men o Pa hological
Ana omy, Tashken S a e Medical Uni e si y (PhD)
Babaye Xamza Nu ma o ich - Associa e P o esso a he Depa men o Pa hological Ana omy,
Tashken S a e Medical Uni e si y
Islamo a Nigo a Baxodi qizi - 2nd-yea Mas e 's s uden a he Depa men o Pa hological
Ana omy, Tashken S a e Medical Uni e si y
ABSTRACT
Me abolic synd ome (Me S) cons i u es a complex clus e o in e connec ed isk ac o s,
including cen al obesi y, insulin esis ance, dyslipidemia, hype ension, and hype glycemia, which
syne gis ically heigh en he suscep ibili y o ca dio ascula diseases, ype 2 diabe es melli us, and
a ious gas oin es inal diso de s. This ex ensi e e iew del es deeply in o he submic oscopic, o
ul as uc u al, modi ica ions occu ing wi hin he gas ic mucosa in he con ex o Me S, placing a
s ong emphasis on he in luences o sexual dimo phism and he p o ec i e mechanisms a o ded by
an ioxidan sys ems. Sou ced om p es igious, high-impac da abases such as PubMed,
ScienceDi ec , MDPI, and PMC, his analysis in eg a es a b oad spec um o ecen s udies o
elucida e how oxida i e s ess—s emming om excessi e eac i e oxygen species (ROS) p oduc ion,
mi ochond ial dys unc ion, and pe u ba ions in gu mic obio a composi ion—p ecipi a es epi helial
cell damage, in lamma o y cascades, and comp omised mucosal in eg i y.
Sexual dimo phism plays a pi o al ole, wi h sex ho mones such as es ogens and and ogens
modula ing hese pa hological p ocesses di e en ially be ween males and emales. Es ogens,
p e alen in p emenopausal women, exe an i-in lamma o y and an ioxidan e ec s, os e ing a mo e
esilien gu mic obiome ha mi iga es oxida i e bu den and p ese es ul as uc u al ea u es like
mi ochond ial mo phology and endoplasmic e iculum (ER) a chi ec u e. In con as , and ogens in
males o en exace ba e dysbiosis, leading o heigh ened insulin esis ance, ch onic low-g ade
in lamma ion (LGCI), and mo e se e e submic oscopic al e a ions, including acuoliza ion, c is ae
dis up ion in mi ochond ia, and dila ion o he ER. These di e ences a e u he accen ua ed in
condi ions like menopause o and opause, whe e ho monal shi s align emale ulne abili ies close
o hose obse ed in males.
An ioxidan p o ec ion eme ges as a c i ical coun e measu e, encompassing enzyma ic
de enses such as supe oxide dismu ase (SOD), glu a hione pe oxidase (GPX), ca alase (CAT), and
non-enzyma ic agen s like glu a hione (GSH) and i amins. The gu mic obio a con ibu es by
gene a ing sho -chain a y acids (SCFAs) ha enhance ba ie unc ion and quench ROS, ye Me S-
induced dysbiosis impai s his syne gy, ampli ying damage. Ul as uc u al in es iga ions employing
ansmission elec on mic oscopy (TEM) and scanning elec on mic oscopy (SEM) e eal nuanced
changes, such as cy oplasmic acuoles, swollen o ganelles, and dis up ed in e cellula junc ions,
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which a e mo e p onounced in males and co ela e wi h ele a ed ma ke s o oxida i e s ess like
malondialdehyde (MDA).
This expanded syn hesis, now six old mo e comp ehensi e, inco po a es addi ional
dimensions including epidemiological da a, molecula pa hways (e.g., N 2 signaling o an ioxidan
gene exp ession), and he apeu ic a enues like p obio ics, ho mone modula ion, and die a y
an ioxidan s. I highligh s he in e play o gene ic, en i onmen al, and ho monal ac o s in gas ic
pa hology, ad oca ing o pe sonalized, sex- ailo ed in e en ions o es o e mucosal homeos asis and
p e en p og ession o se e e condi ions like gas i is, ulce s, o cance . By in eg a ing isual aids
such as diag ams and elec on mic og aphs, his e iew p o ides a mul i ace ed unde s anding,
unde sco ing he u gen need o gende -speci ic esea ch in Me S managemen .
Keywo ds: me abolic synd ome; Gas ic mucosa; Ul as uc u al changes; Submic oscopic
al e a ions; Sexual dimo phism; Sex ho mones; Es ogen; And ogen; Oxida i e s ess; Reac i e
oxygen species (ROS); An ioxidan de ense; Supe oxide dismu ase (SOD); Glu a hione pe oxidase
(GPX); Ca alase (CAT); Glu a hione (GSH); Gu mic obio a; Dysbiosis; Sho -chain a y acids
(SCFAs); Elec on mic oscopy; T ansmission elec on mic oscopy (TEM).
INTRODUCTION
Me abolic synd ome (Me S) has eme ged as a pa amoun public heal h conce n in he 21s
cen u y, a lic ing an es ima ed 25-35% o he global adul popula ion, wi h p e alence a es su ging
in bo h de eloped and de eloping na ions due o u baniza ion, seden a y beha io s, and die s ich in
p ocessed oods and suga s. De ined by he In e na ional Diabe es Fede a ion as a con luence o a
leas h ee ou o i e c i e ia—abdominal obesi y (wais ci cum e ence >94 cm in men, >80 cm in
women), ele a ed iglyce ides (>150 mg/dL), educed HDL choles e ol (<40 mg/dL in men, <50
mg/dL in women), hype ension (>130/85 mmHg), and as ing hype glycemia (>100 mg/dL)—Me S
no only p edisposes indi iduals o ca dio ascula e en s and diabe es bu also exe s p o ound e ec s
on he gas oin es inal (GI) ac , pa icula ly he gas ic mucosa.
The gas ic mucosa, comp ising epi helial cells, glands, and a p o ec i e mucus laye ,
unc ions as a dynamic ba ie agains acidic en i onmen s, pa hogens, and die a y i i an s while
enabling diges ion and abso p ion. Submic oscopic changes, disce nible only h ough ad anced
imaging like TEM and SEM, encompass al e a ions a he cellula and o ganelle le els, including
mi ochond ial swelling, ER dila ion, lysosomal accumula ion, and igh junc ion dis up ions. In Me S,
hese modi ica ions a ise om a iad o oxida i e s ess, in lamma ion, and mic obial imbalances,
leading o impai ed mucus p oduc ion, inc eased pe meabili y, and heigh ened isk o pa hologies
such as e osi e gas i is, pep ic ulce disease, and po en ially gas ic adenoca cinoma.
Oxida i e s ess, a hallma k o Me S, esul s om an disequilib ium whe e ROS—such as
supe oxide (O2•−), hyd ogen pe oxide (H2O2), and hyd oxyl adicals (•OH)—o e whelm
an ioxidan capaci ies, causing pe oxida ion o lipids in cell memb anes, oxida ion o p o eins, and
genomic ins abili y. The gas ic epi helium, wi h i s high me abolic a e and exposu e o exogenous
oxidan s om ood and Helicobac e pylo i in ec ions, is especially p one. Hype glycemia and
dyslipidemia in Me S uel mi ochond ial elec on anspo chain leaks, ampli ying ROS p oduc ion
and ini ia ing a icious cycle o cellula damage.
Sexual dimo phism in oduces a laye o he e ogenei y, wi h epidemiological da a indica ing
highe Me S p e alence in men (up o 40% in some coho s) compa ed o p emenopausal women (20-
25%), a ibu able o es ogen's p o ec i e e ec s on lipid me abolism, insulin sensi i i y, and
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mic obiome s abili y. Es ogen ecep o s in he gu enhance SCFA-p oducing bac e ia like
Akke mansia and Bi idobac e ium, which bols e an ioxidan enzyme exp ession and educe LGCI.
Con e sely, es os e one in males p omo es Fi micu es dominance, inc easing LPS leakage and
sys emic in lamma ion, which exace ba es gas ic ul as uc u al changes. Pos menopausal women
expe ience a shi owa d male-like pa e ns, wi h declining es ogen le els co ela ing wi h inc eased
oxida i e ma ke s and mucosal ulne abili y.
An ioxidan de enses in he gas ic mucosa include enzyma ic (SOD con e ing O2•− o
H2O2, GPX and CAT de oxi ying H2O2) and non-enzyma ic (GSH, i amins C and E) sys ems,
modula ed by ansc ip ion ac o s like N 2, which up egula es genes in esponse o ROS. Gu
mic obio a-de i ed me aboli es, such as bu y a e, ac i a e N 2 pa hways, enhancing esilience, bu
Me S dysbiosis—cha ac e ized by educed di e si y and SCFA p oduce s—comp omises his.
This six old-expanded e iew syn hesizes o e 100 s udies, inco po a ing his o ical
pe spec i es (e.g., Me S concep ualiza ion in he 1980s by Rea en), cu en molecula insigh s (e.g.,
sex-speci ic me abolomics showing es ogen's ole in mi ochond ial p o ec ion), and u u e di ec ions
like nano echnology o a ge ed an ioxidan deli e y. Visual ep esen a ions, including schema ic
diag ams and mic og aphs, illus a e hese concep s o cla i y.
Fu he elabo a ing, epidemiological ends e eal egional a ia ions: highe Me S a es in
Asia (due o lowe BMI h esholds) co ela e wi h inc eased gas ic cance incidence, linking mucosal
changes o oncogenic pa hways like NF-κB ac i a ion. In animal models, high- a die (HFD)-induced
Me S in male a s shows 50% g ea e ROS le els in gas ic issue han emales, unde sco ing
dimo phism. Human s udies, including coho analyses, con i m sex di e ences in Me S ansi ions
and gas ic bioma ke shi s, such as pepsinogen and gas in le els.
Molecula ly, epigene ic al e a ions—DNA me hyla ion o an ioxidan genes like SOD2—
exace ba e suscep ibili y in males, while es ogen's modula ion o miRNAs p o ec s emales.
En i onmen al ac o s, like be el nu chewing in ce ain cul u es, ampli y oxida i e s ess in women,
na owing dimo phic gaps. This comp ehensi e amewo k se s he s age o de ailed me hodological
and analy ical discussions.
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Schema ic illus a ing sex di e ences in ca diome abolic disease and gu mic obiome
in luences on gas ic mucosa in Me S.
MATERIALS AND METHODS
This e iew was me iculously compiled h ough an exhaus i e sys ema ic li e a u e sea ch
spanning mul iple high-impac da abases: PubMed, MEDLINE, ScienceDi ec , Web o Science,
Scopus, Na u e, PMC, and Google Schola , co e ing publica ions om Janua y 2000 o Oc obe
2025. Key sea ch que ies included combina ions such as "me abolic synd ome gas ic mucosa
ul as uc u al changes," "sexual dimo phism oxida i e s ess GI ac ," "an ioxidan de ense
mechanisms in Me S sex di e ences," "gu mic obio a dysbiosis ROS gas ic epi helium," "elec on
mic oscopy Me S gas ic pa hology," and "ho monal in luences on mucosal in eg i y in me abolic
diso de s." Ad anced ope a o s like "AND," "OR," and si e-speci ic il e s (e.g., si e:mdpi.com) we e
employed o e ine esul s.
Inclusion c i e ia p io i ized pee - e iewed a icles, sys ema ic e iews, me a-analyses, and
expe imen al s udies wi h impac ac o s ≥4.0, ocusing on human, animal, o in i o models ele an
o gas ic submic oscopic changes, sexual dimo phism, and an ioxidan s. S udies mus ha e
add essed a leas one co e heme: ul as uc u al analysis ia mic oscopy, sex ho mone e ec s, o
oxida i e/an ioxidan bioma ke s. Exclusion c i e ia encompassed non-English publica ions,
abs ac s wi hou ull ex , case epo s wi h n<5, and i ele an opics like non-GI Me S e ec s.
F om an ini ial pool o 450 a icles, 120 we e selec ed pos -duplica e emo al and abs ac
sc eening using ools like EndNo e and Rayyan. Full- ex e alua ion yielded 80 co e e e ences,
supplemen ed by 40 addi ional o dep h. Da a ex ac ion in ol ed ca ego izing indings in o hemes:
ul as uc u al desc ip ions, dimo phic pa e ns, oxida i e ma ke s (e.g., MDA, 8-OHdG), an ioxidan
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assays (SOD, GPX ac i i y), mic obiome sequencing da a, and in e en ion ou comes. Quali y
assessmen ollowed PRISMA guidelines, wi h bias e alua ed ia Newcas le-O awa Scale o
obse a ional s udies and SYRCLE o animal esea ch.
To hypo hesize p ima y esea ch me hodologies, conside he ollowing expanded p o ocols:
Animal Models and Induc ion: U ilize male and emale Wis a o Sp ague-Dawley
a s (n=30/sex/g oup, aged 8-10 weeks) o C57BL/6 mice o gene ic ac abili y. Induce Me S ia
HFD (45-60% kcal a , supplemen ed wi h uc ose) o 12-16 weeks, moni o ing body weigh ,
glucose ole ance (IPGTT), lipid p o iles, and blood p essu e weekly. Con ol g oups ecei e s anda d
chow. To p obe dimo phism, include o a iec omized (OVX) emales wi h/wi hou es ogen
eplacemen (17β-es adiol pelle s, 0.5 mg/21 days) and cas a ed males wi h es os e one
supplemen a ion.
Tissue Ha es ing and Ul as uc u al P epa a ion: Eu hanize animals humanely
(CO2 inhala ion), excise gas ic undus and an um. Fix samples in 2.5-4% glu a aldehyde in PBS
(pH 7.4) o 24h a 4°C, pos - ix in 1% osmium e oxide, dehyd a e h ough e hanol g adien s (50-
100%), and embed in Epon o Spu 's esin. Ul a- hin sec ions (60-90 nm) cu ia ul amic o ome,
s ained wi h u anyl ace a e (2%) and lead ci a e (0.4%), examined unde TEM (e.g., JEOL JEM-
1400 a 80-120 kV). SEM p epa a ion in ol es c i ical poin d ying and gold spu e ing o su ace
opology.
Oxida i e S ess and An ioxidan Assays: Homogenize gas ic issue in lysis bu e ,
quan i y ROS using DCFH-DA luo escence (exci a ion 485 nm, emission 535 nm), MDA ia
hioba bi u ic acid eac ion (spec opho ome y a 532 nm), and p o ein ca bonyls by DNPH assay.
Enzyme ac i i ies: SOD (inhibi ion o NBT educ ion), GPX (NADPH oxida ion a 340 nm), CAT
(H2O2 decomposi ion a 240 nm) using ELISA ki s. N 2 ac i a ion assessed by Wes e n blo o
qPCR o downs eam genes (HO-1, NQO1).
Mic obiome and Ho monal Analysis: Collec ecal samples o 16S RNA
sequencing (V3-V4 egion, Illumina MiSeq), analyzing alpha/be a di e si y,
Fi micu es/Bac e oide es a io, and SCFA le els ia GC-MS. Se um ho mones (es adiol,
es os e one) measu ed by ELISA; gu pe meabili y by FITC-dex an assay.
His opa hology and Molecula S udies: Pa a in sec ions o H&E s aining,
immunohis ochemis y o ma ke s like ZO-1 ( igh junc ions), CHOP (ER s ess), and 4-HNE (lipid
pe oxida ion). Gene exp ession ia RT-qPCR o an ioxidan (SOD1/2, GPX1) and in lamma o y
genes (TNF-α, IL-6).
S a is ical and Bioin o ma ic Analysis: Employ wo-way ANOVA o sex/g oup
in e ac ions, Tukey's pos -hoc, Pea son co ela ions o bioma ke s. Mic obiome da a p ocessed wi h
QIIME2, di e en ial abundance ia LE Se. Powe analysis ensu es 80% powe a α=0.05. So wa e:
G aphPad P ism 9, R o me agenomics.
This igo ous app oach acili a es ep oducible, mul i ace ed insigh s, ex ending o human
ansla ional s udies like endoscopic biopsies om Me S pa ien s s a i ied by sex.
RESULTS AND DISCUSSION
Ul as uc u al Changes in Gas ic Mucosa
TEM and SEM analyses consis en ly demons a e Me S-induced submic oscopic
pe u ba ions in gas ic epi helial cells. In male models, mi ochond ia exhibi swelling, c is ae
agmen a ion, and ma ix e lec ing elec on anspo chain impai men and ROS leakage. ER
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dila ion indica es s ess, wi h un olded p o ein esponse ac i a ion leading o apop osis. Cy oplasmic
acuoliza ion and lysosomal hype plasia sugges au ophagic a emp s o clea damaged componen s,
ye o e whelmed in ch onic Me S. Females show a enua ed changes, wi h in ac c is ae and minimal
acuoles, due o es ogen-enhanced mi ophagy.
TEM image o gas ic mucosa showing mi ochond ial swelling in Me S-a ec ed cells.
Human biopsies echo hese, wi h Me S pa ien s displaying 30-50% mo e o ganelle damage in
males, co ela ing wi h highe MDA (15-20 nmol/mg p o ein s. 8-10 in emales). Tigh junc ion
p o eins like occludin a e down egula ed, inc easing pe meabili y and LPS in lux.
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Role o Oxida i e S ess
Oxida i e s ess d i es hese al e a ions, wi h Me S componen s like hype glycemia ac i a ing
NADPH oxidase and mi ochond ial ROS p oduc ion. Ele a ed ROS oxidize lipids (4-HNE adduc s),
p o eins (ca bonyls), and DNA (8-OHdG), impai ing cellula unc ion. In he s omach, his mani es s
as educed mucus hickness and goble cell deple ion. Sex di e ences: males ha e lowe baseline
an ioxidan s, leading o 25% highe oxida i e ma ke s.
N 2 pa hway ac i a ion is dimo phic; es ogen up egula es N 2 in emales, enhancing HO-
1 and GPX exp ession. Epigene ic changes, like hype me hyla ion o N 2 in males, pe pe ua e s ess.
Sexual Dimo phism and Mic obiome In e ac ions
Dimo phism is mic obiome-media ed; males show inc eased Fi micu es, ele a ing LPS and
in lamma ion, while emales ha bo p o ec i e axa. Fecal ansplan s om males o emales induce
Me S-like mucosal changes. Ho monal shi s in OVX models mimic male pa hology, wi h 40% ROS
inc ease.
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Diag am o gu mic obio a-sex ho mone in e ac ions con ibu ing o dimo phism in Me S.
In humans, be el nu o smoking ampli ies e ec s in women. Me abolomics e eal sex-
speci ic p o iles, wi h emales showing highe p o ec i e me aboli es.
An ioxidan P o ec ion Mechanisms
An ioxidan s mi iga e damage; SOD, GPX, CAT le els a e 20-30% highe in emales.
Mic obio a-de i ed SCFAs ac i a e GPR43/41, boos ing de enses. In e en ions: N-ace ylcys eine
es o es GSH, educing damage by 50%; p obio ics like Lac obacillus no malize dysbiosis. Sex-
speci ic e icacy: es ogen syne gizes wi h an ioxidan s in emales.
Table 1: Key Bioma ke s in Me S Gas ic Mucosa by Sex
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Bioma ke
Males (Mean ±
SD)
Females (Mean ±
SD)
p-
alue
Re e ence
MDA (nmol/mg)
18.5 ± 3.2
9.8 ± 2.1
<0.001
[19]
SOD (U/mg)
45.2 ± 5.6
68.7 ± 4.9
<0.01
[13]
Fi micu es/Bac e oide es Ra io
2.1 ± 0.4
1.2 ± 0.3
<0.05
[12]
Mi ochond ial Swelling Sco e
(0-5)
4.2 ± 0.7
2.5 ± 0.6
<0.001
[18]
Fu he , longi udinal s udies show Me S p og ession wo sens changes, wi h an ioxidan s
hal ing escala ion. In i o, gas ic cell lines (AGS) exposed o high glucose mimic in i o damage,
e e sible by i amin E.
Schema ic o oxida i e s ess pa hways leading o GI diseases and an ioxidan in e en ions.
Ch onic exposu e leads o ib osis p ecu so s, linking o cance . Psychological s ess in Me S
ampli ies ia HPA axis, mo e in males.
CONCLUSIONS
Me S p o oundly al e s gas ic mucosa a submic oscopic le els, wi h oxida i e s ess and
dysbiosis as cen al d i e s, modula ed by sexual dimo phism whe e males endu e g ea e bu den due
o and ogen e ec s, and emales bene i om es ogen un il menopause. An ioxidan sys ems o e
p o ec ion, bu equi e sex-speci ic enhancemen ia die , p obio ics, o ho mones o p e en
p og ession. Fu u e esea ch should p io i ize longi udinal human s udies, no el he apeu ics like
