Neurochemical Research

https://doi.org/10.1007/s11064-023-04084-7

REVIEW

Gut‑Brain Axis Modulation of Metabolic Disorders: Exploring

the Intertwined Neurohumoral Pathways and Therapeutic Prospects
Diya Bhalla1 · Susha Dinesh2 · Sameer Sharma2 · Gonchigar Jayanna Sathisha3

Received: 29 August 2023 / Revised: 6 December 2023 / Accepted: 8 December 2023

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024

Abstract
A significant rise in metabolic disorders, frequently brought on by lifestyle choices, is alarming. A wide range of preliminary
studies indicates the significance of the gut-brain axis, which regulates bidirectional signaling between the gastrointestinal
tract and the cognitive system, and is crucial for regulating host metabolism and cognition. Intimate connections between
the brain and the gastrointestinal tract provide a network of neurohumoral transmission that can transmit in both directions.
The gut-brain axis successfully establishes that the wellness of the brain is always correlated with the extent to which the
gut operates. Research on the gut-brain axis has historically concentrated on how psychological health affects how well the
gastrointestinal system works. The latest studies, however, revealed that the gut microbiota interacts with the brain via the
gut-brain axis to control phenotypic changes in the brain and in behavior. This study addresses the significance of the gut
microbiota, the role of the gut-brain axis in management of various metabolic disorders, the hormonal and neural signal-
ing pathways and the therapeutic treatments available. Its objective is to establish the significance of the gut-brain axis
in metabolic disorders accurately and examine the link between the two while evaluating the therapeutic strategies to be
incorporated in the future.

* Sameer Sharma
sameer@bionome.in
1
Faculty of Life and Allied Health Sciences, MS Ramaiah
University of Applied Science, Bangalore 560048, India
2
Department of Bioinformatics, BioNome, Bangalore 560043,
India
3
Department of Post Graduate Studies and Research
in Biochemistry, Jnanasahyadri, Kuvempu University,
Shankaraghatta, Shimoga 577451, India

Vol.:(0123456789)
 Neurochemical Research

Graphical Abstract

Deciphering the intricate communication of the GBA reveals its pivotal role in regulating metabolic disorders and cogni-
tion. This exploration underscores the dynamic interplay between gut microbiota, neurohumoral signaling, and potential
therapeutic interventions, highlighting new avenues for holistic metabolic management.

Keywords Gut-brain axis · Metabolic disorders · Gut microbiota · Signaling pathways · GBA

Abbreviations GLP Glucagon-like peptide 1

ANS Autonomous nervous system GM Gut microbiota
BMI Body mass index HFD High-fat diet
CNS Central nervous system HM Humanized
ENS Enteric nervous system IBS Irritabe bowel syndrome
FMT Faecal microbiota transplantation MeS Metabolic syndrome
GBA Gut-brain axis PNS Peripheral nervous system
GF Germ-free PYY Peptide YY
GHS-R Growth hormone-secretagogue receptor SCFAs Short chain fatty acid
GI Gastrointestinal T2DM Type 2 diabetes
Neurochemical Research
Introduction
The 'gut-brain' or 'brain-gut axis', is a bidirectional commu-
nication system consisting of humoral pathways, including
cytokines, hormones, and neuropeptides as signalling mol-
ecules, along with neural networks like the vagus, sympa-
thetic, spinal nerves and the enteric nervous system (ENS)
[1]. The gut-brain axis (GBA), commonly referred to as the
central nervous system-gut microbiota (GM) interaction
pathway, has recently drawn a lot of focus. The intricate
community of GM contributes to preserving a dynamic met-
abolic biological equilibrium. An adult's body has approx-
imately 100 trillion bacteria, 80% of which reside in the
gut and are around ten times more prolific than all of the
body's cells [1]. More than 100 species of bacteria with over
150 times more genes than the human genome have been
identified in the gut microbiome. The microbiota typically
includes microorganisms that thrive in a particular habitat
whereas the microbiome is composed of genomes from the
microbes found in the surroundings. The human microbi-
ome has been reported to consist of about 5000 strains of
bacteria and over 1000 different types of microflora. Bac-
teroidetes and Firmicutes are the two bacterial phylotypes
that primarily constitute the microbiome; Proteobacteria,
Actinomyces, Fusobacterium, and Verrucomicrobia are
present in relatively modest levels. Except for the recogni-
tion that pathogenic microorganisms in the gut can cross
the blood–brain barrier and impact the brain, the effect of
GM on the brain was barely recognized by people initially.
On the other hand, a public health emergency brought to
light the potential connection between the brain and GM.
When a flood struck the Canadian municipality of Walker-
ton in 2000, E. coli and C. jejuni contaminated the drinking
water. Of the 4561 individuals who contracted the infection,
2451 underwent a follow-up evaluation eight years later, and
1166 received an Irritable Bowel Syndrome (IBS) diagnosis
[1, 2]. Both depression and anxiety were discovered to be
separate risk factors for ongoing IBS in these IBS patients.
The precise process by which the GM and the brain com-
municate is yet to be thoroughly elucidated. In general, the
neurological system (the gut-brain neuroanatomical path-
way) is not the only way that GM affects the brain; other
pathways include the endocrine, immunological, and meta-
bolic systems. The gut microbiota‑gut‑brain axis (henceforth
referred to as the gut microbiota‑brain axis) is the interaction
of GM with GBA. Emphasis is placed on the role of bac-
teria in the gut microbiota-brain axis with the capability to
actively alter GM content and so employ it as an independ-
ent variable.
Both the brain and the gut inhabit the identical neural
crest during development, extensively coordinating and
influencing one another. The GBA is involved in numerous
biochemical processes, such as satiation, dietary intake,
regulation of glucose, fat and lipid metabolism and insu-
lin secretion [1]. Although the hypothesis of GBA initially
focused pn the regulation of cholecystokinin secretion, it has
subsequently been expanded to encompass all interactions
between the central nervous system (CNS) and the gastroin-
testinal (GI) tract. CNS functioning has been correlated with
the healthy functioning of the gut. It has been determined
that neurotransmitters, hormones, and immune-regulating
substances secreted from the gut interact with the CNS via
direct contact or through the autonomous nervous system
(ANS) [1, 2]. The novel research conducted by Sudo and
colleagues who discovered the altered reaction to stress in
germ-free (GF) mice established evidence for the presence
of the GBA [2]. Besides establishing its existence, further
investigations involving GF mice further strengthened the
hypothesis that the GBA expands these two systems and
extends into the endocrine, neural, and immune systems [3].
A recent comprehensive analysis by Mayer et al. examined
the neurological components of GBA interactions as well as
the purpose of centrally-driven networks [3].
Both the CNS and the peripheral nervous system (PNS)
are impacted by the interactions between these endocrine
and neural networks. The hormones employ specialized
neural receptors for stimulation in order to converse with
the CNS about the functioning of the hormone's producing
organs. The ANS and ENS, the neuroendocrine system, the
metabolic system, and the immunological system are some
of the acknowledged avenues of gut-brain interaction [3].
In recent years, an increasing variety of scientific evidence
from research on the gut microbiome in animal models has
led to a reexamination of how the CNS and PNS interact.
Considering abundant current research demonstrating that
the inhabitants of gut bacteria are essential for CNS func-
tioning, neuroscientists are paying attention to such distinc-
tive findings which directly emphasize the "bottom-up"
impact of microorganisms [1].
Over the past few decades, metabolic disorders MDs)
have grown significantly in prevalence across the globe
(Table 1). According to statistics from the World Health
Organization, 300 million individuals globally are medically
obese, which is characterized by possessing a body mass index
(BMI) of at least 30 kg/m2 [4]. Particularly worrisome is the
similarly frightening increase in childhood obesity. Alarmingly
elevated incidences of type 2 diabetes (T2DM), atherosclero-
sis, resistance to insulin, and other illnesses prevail. Therefore,
it is essential to evaluate all potential causes of these MDs.
More and more data indicate the pivotal role of GM in regulat-
ing the GBA. The link between GBA and MDs cannot be dis-
regarded as evidenced by previous research studies. Therefore,
it is crucial to analyze the GBA and its role in MDs.
This review highlights the translational study areas that
are essential for assessing the function of the GBA in MDs,

strategically assessing existing preclinical literature and
investigating currently available data from such studies.
Gut Microbiota and Metabolic Disorders
Gut Microbiota's Influence on Metabolic Health
and Disease
The functioning of GM and its impact on human health have
attracted more attention in recent years, especially in relation
to metabolic diseases which boost the risk of cardiovascular
diseases and, as a result, the death rate. Hippocrates report-
edly stated that "all diseases originate in the gut [18]." There
have been abundant studies corroborating this hypothesis
over the last few decades. Although bacteria and fungi from
the phyla Firmicutes and Bacteriodetes predominate, the
human colon contains trillions of diverse microorganisms
[18]. Lately, studies have been centred on how the immune
system, brain development, and behaviour are impacted by
GM. It is plausible that intestinal microbes interact with the
immune system and gut epithelial cells and have a role in the
emergence of an array of metabolic diseases.
According to Zimmer, a normal human harbours 100
trillion microorganisms (referred to as microbiota or micro-
flora) in their body [18]. The word "microbiota" refers to
the population of microbes that inhabit the human body's
multiple biological systems, such as the GM and the skin.
The gut contains 1­ 014 bacteria, which is ten times more than
the entirety of human cells [18]. Additionally, the DNA
sequences of these microbes have 150 times more genes
than that of humans. The cellular makeup of the intesti-
nal mucosa has been guarded and fostered by commensal
gut microbes since the evolution of human existence. As
a result, GM is widely acknowledged as a crucial control-
ler of human physiology and pathophysiology and indis-
putably performs an active role in both health and illness.
MDs including obesity, diabetes, and eating disorders, in
addition to stress-associated neuropsychological disorders
such as depression and anxiety, are typically identified by
fluctuations in eating behaviour, all including variations in
the human gut flora. Obesity, described as a chronic buildup
of lipids in fatty tissues, is one of the current primary health
issues [19]. There are numerous causes that lead to obesity,
but the most common one is an imbalance between energy
intake from food and beverages and energy expenditure.
There is mounting data that indicates the dysregulated GM
may be the cause of the imbalance. The GM serves a sub-
stantial role in several mechanisms that are associated with
the development of obesity, involving nutrient digestion and
utilization, energetic homeostasis, retainment of the rigidity
of the epithelium of the intestine, carbohydrate, lipid, and
bile acid metabolism, and regulation of intestinal processes
Neurochemical Research
(Fig. 1). Animal model investigations served as a basis for
the initial studies on the effects of GM diversity and behav-
iour on metabolic diseases, particularly obesity. Despite
consuming 29% more food than conventional mice, it was
found that germ-free mice—especially those who were bred
without any microbes—have a lower quantity of fat [19,
20]. Furthermore, Bäckhed et al. discovered that adult GF
mice with lower food intake experienced a 60% spike rise
in body fat composition and insulin resistance over 14 days
of being colonized with GM from conventionally grown
animals. It has been observed that mice fed a high-fat diet
(HFD) with the obesity-resistance trait consume fewer calo-
ries and excrete more lipids than normal mice fed an HFD
[20]. Investigation into the basis of these events revealed
that the GM makeup of obese and lean mice is distinct. The
microbiota of obese mice differs from lean mice due to a
higher concentration of Firmicutes and a lower prevalence of
Bacterioidetes. As reported by Riva et al. obesity was linked
to higher concentrations of Firmicutes, including Rumino-
coccaceae, and lower concentrations of Bacteroidetes, like
Bacteroidaceae and Bacteroides [21]. As per a Danish study
consisting of 169 obese and 123 non-obese subjects, people
with lower microbial gene counts (LCG) have poorer inflam-
matory states, obesity, diabetes, insulin resistance, adiposity,
and dyslipidemia [22].
Dysbiosis and Its Association with Metabolic
Disorders
An alteration in the ratio of advantageous to harmful micro-
organisms, a shift in the distribution of intestinal bacteria,
and a surge in the number of small bowel microbes can all
be indicators of dysbiosis, a microbial imbalance in the gut.
Essentially, a number of factors, such as microbial metabo-
lites, microbial interactions, the immune response of the
host, host physiology, nutrition, and host environment, con-
tribute to the development of the disease. The human GI
tract reportedly comprises more than fifty distinct bacterial
phyla, and the GM composition and prevalence rates vary
among the diverse microbial habitats of the GI tract. In gen-
eral, distinct microbial comunities dwell in distinct GI tract
segments [23]. Strict anaerobes constitute about 95% of the
microbial species that live in the colon; this is influenced
by the nutrients present there. Intrinsic and extrinsic factors
considerably influence the development of bacterial growth
in the small intestine. The most prominent intrinsic factors
hindering this proliferation of bacteria are secretion of gas-
tric juice and bile acid, peristaltic movements, typical gut
defence mechanisms, mucin fabrication, gut peptides with
antimicrobial properties, and mitigation of pathogenic bacte-
ria retrograde translocation from the lower parts to the upper
parts of the intestine through the ileocecal valve. Diet, bac-
terial and viral infections, prokinetic pharmaceuticals that
Neurochemical Research

Table 1  Metabolic diseases: enzyme deficiency, symptoms and treatment

Metabolic disorders Enzyme deficiency Symptoms Treatments References

Carbohydrate metabolic disorders

T2DM Intestinal Alkaline Phosphatase Abdominal obesity Metformin tablets [5, 6]
Nocturia
Blurry Vision
Galactosemia Galactose 1 P uridyl transferase Jaundice Agalsidase injection [7]
Diarrhoea
Liver failure
Acid Mucopolysaccharides Glycosaminoglycans Hepatomegaly Enzyme replacement therapy and [8]
Mental Retardation Hematopoietic stem cell transplanta-
tion
Glycogen storage disorders Glycogen metabolism enzymes Liver failure Protein Supplementation and Corn- [9]
Heart failure starch
Schindler Disease Alpha-N-acetylgalactosaminidase Cardiomyopathy No specific therapy [10]
Hepatomegaly
Lipid metabolic disorders
Tay- Sachs Hexosaminidase-A Mental Retardation No specific treatment [11]
Muscle Stiffness
Gangliosidoses Beta-galactosidase-1 Visual Impairment Gene Therapy [11, 12]
Hepatosplenomegaly Enzyme Replacement Therapy
Gaucher Disease Glucocerebrosidase Anaemia Blood Transfusion [12]
Eye movement disorders Enzyme Replacement Therapy
Niemann—Pick Acid sphingomyelinase deficiency Neural degeneration No cure available [13]
Recurrent Pneumonia
Amino acid metabolic disorders
Hyperglycemia Glycine Cleavage enzyme Ochronosis Insulin therapy [14]
Frequent urination Fluid Replacement
Tyrosinemia Fumarylacetoacetate Hydrolase Liver failure Nitisinone tablets [14]
Photophobia
Maple syrup Urine Disease Alpha-keto acid dehydrogenase Delayed Development Low protein diet [15]
Abnormal movements
Urea cycle disorders
Citrullinemia Arginosuccinate Lyase Hyperactivity Liver Transplantation [16]
Arginosuccinate synthase
Ornithine Carbomyl transferase
Hyperammonemia Arginase Ataxia Dialysis and administration of Neo- [16, 17]
Behaviour Changes mycin and Metronidazole tablets

affect motility, and medications that affect the GM, such as
H2 blockers, pre-and probiotics, proton pump inhibitors, and
antibiotics, are examples of extrinsic variables. Commensal
and pathogenic GM colonize disproportionately and result
in dysbiosis if one or more external events upset the delicate
equilibrium that numerous protective mechanisms have been
designed to protect [23]. It is well established that dysbiosis
is linked to both obesity and reduced glucose level toler-
ance observed in individuals with diabetes and pre-diabetes.
According to certain studies, the microbiota of obese and
overweight people differs from that of lean people in terms
of the proportions of Bacteroidetes members and Firmicutes
[23]. However, there have also been contradictory or inde-
terminate results [23]. Among other characteristics, blood
glucose levels were positively linked with the Bacteroidetes
to Firmicutes ratio, and people with T2DM had lower ratios
of Firmicutes and Clostridia members than control partici-
pants) [22, 23]. Although earlier research has linked obe-
sity and metabolic disorders to alterations in the makeup
and variety of the GM, no reliable indicators of these det-
rimental health conditions are currently established in the
gut microbial communities. This could also be because the
implications sizes are smaller than in other conditions that
are more clearly linked to the GM, like bowel inflammation
[23]. However, in order to direct us towards more effective
methods of disease diagnosis, treatment, and prevention, a
better knowledge of the role played by GM in the onset and
progression of obesity and metabolic disorders is of para-
mount importance [23]. The gut microbiome shifts as people
age from adolescence to elderly years, becoming less diverse
and more variable among individuals.

Fig. 1  Metabolic disorders; causes, symptoms and treatment methods
Influence of Gut Microbiota on Energy Metabolism
and Nutrient Absorption
GM can obtain energy from food and regulate fat accumu-
lation in the body. The GM has a significant role in mul-
tiple physiological processes within the gut, including the
body's pathogen defence, intestinal microvilli growth, and
non-digestible polysaccharide breakdown. As a result, the
GM uses food components that the host swallows but can-
not digest to generate energy for the host. Several metabolic
disorders linked to the regulation of glucose levels and the
emergence of cardiovascular diseases are associated with
obesity. In spite of substantial immediate shifts in energy
expenditure, body mass and adiposity remain relatively sta-
ble, while the level of quality and quantity content of dietary
intake varies greatly from every meal every day. Most people
can accurately calculate their cumulative calorie consump-
tion and expenditure when tracking their dietary habits and
exercise over a period of time comprising at least several
meals. Energy homeostasis is a constantly evolving mech-
anism that maintains an equilibrium of metabolic energy
accumulated as fat [24]. Therefore, every system regulating
the intake of calories and their following harvesting ought
to be involved in maintaining an equilibrium of body mass.
Numerous recently published studies conducted by the J.
Gordon group have demonstrated the role that the genetic
makeup of the intestinal microbes serves in the administra-
tion of energy equilibrium [24]. Backhed et al. discovered
that while mice having a normal GM consumed 30% less
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food than GF mice, they still had roughly 40% lower total
body fat [24]. The GM could directly affect the CNS by
altering the GBA's endocrine signaling pathways, such as
glucagon-like peptide-1 (GLP-1) and peptide YY signaling,
or by triggering reward pathways [24, 25]. An optimally
functioning metabolism and homoeostasis are dependent
upon a healthy GM, which considerably assists the host in
recompense for dwelling and thriving in the gut ecosystem.
The association between GM and human physiology is not
solely commensal; but actually, a mutualistic relationship,
as evidenced by statistical analysis of the alterations in the
genetic makeup of GM and accompanying clinical investiga-
tions. It is now apparent that the host's GM notably impacts
the host's physiology and phenotypes such as intake of nutri-
ents and well-being, obesity, diabetes, metabolic syndrome
(MeS), behavior, and numerous neurological conditions
[26].
Gut‑Derived Signaling Molecules
Short Chain Fatty Acids (SCFAs) and Effects
on Metabolism and Appetite Regulation
The three most extensively studied SCFAs are butyrate,
propionate, and acetate. They are the primary fermenta-
tion metabolites of the gut microbial breakdown of dietary
fibre, contributing approximately 10% of the host's over-
all energy needs. Additionally, the GM produces butyrate,
Neurochemical Research
propionate, and acetate, capable of binding to G-protein-
coupled receptors such as GPR43 and GPR41, also referred
to as free fatty acid receptors 2 and 3 (FFAR2 and FFAR3,
respectively) [27]. When SCFAs bind to FFAR3, enteroen-
docrine L-cells produce the hormone peptide YY, which
is demonstrated to stabilize gastrointestinal motility and
boost the amount of accessible energy obtained from meals
in mice. The secretion of GLP-1 by L-cells is triggered by
the interactions of SCFAs to FFAR2 and FFAR3 in the
lining cells of the small intestinal tract and colon. This has
a profound impact on insulin release, overall pancreatic
function, and hormonal effects which regulate the sensa-
tion of hunger. Propionate and butyrate possess the ten-
dency to trigger the synthesis of intestinal gluconeogenic
enzymes, and propionate is capable of acting indepen-
dently as a precursor for intestinal gluconeogenesis [27].
SCFAs autonomously perform a wide range of metabolic
activities. In mouse white adipose tissue, all 3 primary
SCFAs have the potential to stimulate FFAR2, which sup-
presses insulin signaling, decreases the retention of fat, and
further increases the expenditure of energy in hepatocytes
and myocytes. In accordance with a study by Reigstad et al.
the stimulation of EC cells by SCFAs in the colon induces
the expression of the tryptophan hydroxylase 1 (Tph1)
gene and the synthesis of 5-HT [28]. In order to examine
the relationship between intestinal bacteria, gut contrac-
tions, and serotonergic gene expression, GF or humanized
(HM) mice were employed. Results indicated that when
contrasted to GF mice, the microbiota from traditionally
bred mice and HM mice markedly elevated the colonies in
mRNA levels of TPH1[28]. The findings indicate that GI
and metabolic equilibrium depend on SCFA synthesis by
the GM, which is essential for controlling GI motility and
metabolic activities.
Bile Acids and Their Role in Metabolic Homeostasis
The primary role of bile acids is in the equilibrium of
cholesterol and dietary lipid absorption. However, current
results from bile acid studies suggest bile acids as essential
signaling molecules involved in the regulation of glucose.
Multiple studies have revealed an improvement in the gly-
cemic index of type 2 diabetes patients medicated with
numerous bile acid-binding resins [29]. Bile acids influ-
ence the GM having a profound effect on the host metabo-
lism and the development of metabolic disorders. Specific
agonists that activate the FXR inhibit the production of bile
acids and fatty acids while boosting insulin and glucose
sensitivity in obese and diabetic rat models[29]. In gen-
eral, liver FXR signalling activation delays the advance-
ment of fibrosis and the development of primary biliary
cirrhosis and non-alcoholic steatohepatitis (NASH) [30].
It is uncertain how intestinal FXR signaling affects the
regulation of metabolism. In mice and human patients,
T-MCA has been demonstrated to lower intestinal FXR
activity and increase weight gain. Mice with intestinal FXR
inhibition have diminished ceramide production and altered
hepatic gluconeogenesis. The intestine-restricted FXR ago-
nist fexaramine, on the other hand, lowers body weight
and insulin resistance, which may be driven by FGF15-
mediated adipocyte browning [31]. Enhanced insulin sen-
sitivity is triggered by intestinal FXR and TGR5 crosstalk
being stimulated in intestinal L cells. It was found that
GW4064's activation of FXR in intestinal L cells affects
the expression of proglucagon via interfering with the
glucose-responsive carbohydrate-response element bind-
ing protein [32]. It is widely recognized that bile acids
increase GLP-1 release due to glucose. The observed con-
tradictory effects on glucose tolerance and insulin sensitiv-
ity could be addressed by the mice's housing conditions,
genetic makeup, and the varied effects of FXR agonists on
their gut flora [33]. Through regulation of the GM, host
metabolism, and diseases, bile acid signaling controls
hepatic metabolism by way of FXR signaling in the intes-
tinal tract and liver, as well as TGR5 in the intestine. Drug
therapy for liver diseases, NASH, diabetes, and obesity has
been designed as a result of recent advances in bile acid
metabolism and homeostasis studies. Although mice have
a substantially distinct bile acid composition and pool size
than humans, the majority of bile acid research is carried
out on them[34]. Bariatric procedures are successful in
helping obese individuals lose weight and improve their
insulin sensitivity, and FXR and TGR5 signaling has been
linked to an increase in serum bile acids and FGF19 after
bariatric procedures. To develop therapeutic approaches to
treat diabetes and NAFL, the fundamental mechanism of
bile acid signaling’s improvement of diabetes complying
with bariatric surgery must be elucidated [34].
Gut Peptides and Their Impact on Energy Imbalance
and Satiety
Peptide YY(PYY)
Peptide YY (PYY) is a gut hormone linked to neuropeptide
Y(NPY) [35]. Both peptides operate through members of
the Y family of receptors and possess the structural motif of
the PP fold. Similar levels of affinity are exhibited by all Y
receptors and full-length PYY. PYY3-36, which primarily
adheres to the Y2 receptor (Y2R), is the amino-terminally
abbreviated form of PYY that demonstrates the majority of
circulating PYY immunoreactivity.
Although it is more abundant in distal regions of the gut,
PYY exists in L cells along its length. Upon eating, PYY
is released into the bloodstream and is suppressed by fast-
ing [35, 36]. In both rodents and people, acute peripheral

administration of PYY3-36 cuts down food intake. These
results were initially debatable because several different labs
were unable to replicate certain components of the investi-
gation [36]. Stress can lower normal calorie intake, which
makes it more challenging for anorectic drugs to further
decrease hunger. In mice that have not been accustomed to
experimental methods or in rats that have been exposed to a
new environment, peripheral PYY3-36 administration does
not lower food intake [37]. Subsequent studies have veri-
fied that PYY3-36 acutely inhibits feeding in rodents and
primates. The anorectic effects of PYY3-36 are thought to
be mediated by Y2R, as they're attenuated by Y2R antago-
nists and eliminated in Y2R-knockout mice. Because of their
modified energy homeostasis, Pyy-knockout mice could
offer insight into how the PYY system regulates it. [38].
Glucagon‑Like Peptide 1(GLP‑1)
Preproglucagon is a big precursor protein that is synthe-
sized by the same type of gut endocrine cell that produces
PYY [39]. This is then processed to yield a wide range of
biologically relevant peptides, such as glucagon, oxynto-
modulin, GLP-1 and GLP-2 [40]. There are various distinct
variants of GLP-1, but glucagon-like peptide-1(GLP-1) is the
most extensively circulated one. GLP-1 is a powerful incretin
that penetrates the bloodstream after a meal and substantially
stimulates the release of insulin when administered centrally
or peripherally. Rodent food intake is substantially decreased
when GLP-1 is administered intracerebroventricularly, while
peripheral GLP-1 treatment minimises hunger in humans as
well as animals[39, 40]. A GLP-1 receptor agonist known as
exendin-4 is found in the saliva of the Gila monster lizard,
Heloderma suspectum [41]. Exendin, a condensed version of
this peptide, serves as an antagonist that competes with the
same receptor [41, 42]. Exendin enhances food intake when
administered acutely into the brain, and body weight when
administered continuously. Thus, it appears that endogenous
peripheral GLP-1 may be a component of the physiological
mechanism that reduces appetite and food intake. However,
GLP-1 receptor knockout mice had regular dietary habits and
body mass index. Exendin-4, sometimes referred to as exena-
tide and sold under the brand name Byetta, has been shown in
clinical studies to be effective in regulating glucose homeo-
stasis among type 2 diabetic patients [43]. It's crucial to note
that exenatide dramatically decreased body weight in treated
diabetics during phase III 30-week clinical trials. Similar to
PYY3-36, nausea is a relatively frequent adverse reaction to
therapy, but it does not appear to be indissociably associated
with changes in appetite [44]. These findings also imply that,
even though peripheral GLP-1 doesn't physiologically con-
trol appetite, it could still be possible to employ a medication
supplied peripherally to lower body weight by targeting the
GLP-1 system.
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Gut‑Brain Signaling Pathways
Vagus Nerve Signaling and Its Involvement
in Gut‑Brain Axis
The ENS, both sympathetic and parasympathetic nerves,
along with other ANS components are involved in the gut-
brain neural interaction networks. The sympathetic nerv-
ous system, which is linked to GBA, regulates the lamina
propria and Peyer's patches additionally, particularly in
T lymphocyte-rich areas. It also regulates the blood ves-
sels of the GI tract and the ENS. The sympathetic nervous
system regulates immune response stimulation, circula-
tion, the integrity of barriers, and movement within the
GBA [45]. A widely recognized conduit for gut-brain
signaling by the vagus nerve, a part of the PNS, is now
recognized as a vital microbiota for brain interaction path-
ways. The ENS is often described as "the second brain"
and is made up of intrinsic fundamental afferent neurons
and motor neurons. Recent study using germ-free (GF)
mice indicates that GM and ENS are interconnected [46]
(Fig. 2). The body's immune system is underdeveloped in
GF mice as they lack the commensal gut flora. Studies on
GF animal models have made considerable strides in the
previous years by advancing our knowledge of the way
the microbiota affect gut-brain function [47]. Postnatal
morphological and physiological disorders were detected
in GF mice by contrast with specific pathogen-free (SPF)
mice and mice inoculated with modified Schaedler flora,
which normalizes the immune response. In both the jeju-
num and ileum of GF mice, the plexus of myenteric nerves
had fewer ganglia and shorter fibres of the nerve [48].
When contrasted with SPF and mice with modified Schae-
dler flora colonization, intestinal movement in GF mice
declined both in the duration and frequency of spontane-
ous muscular contractions. Numerous studies have inves-
tigated GI nerve impulses and myoelectric contractions in
mature GF mice. During these investigations, it was deter-
mined that GF mice had impaired gut operation, which
was restored by standardization with typical microbiota.
Myenteric afterhyperpolarization (AH) nerves in adult
GF mice have been found to exhibit decreased excitability
of cells and a shorter duration of the suppressive slow
AH upon just one action response produced by a brief
electrical pulse [49]. The input conductance and relax-
ing membrane potential also proved different in GF mice
when contrasted with SPF animals. The colonization of
GF animals with SPF bacteria restored unresponsive mem-
brane functions and normalized excitability, indicating
the existence of GM mediates the neuronal activity of the
aforementioned ENS neurons. Although the ENS is able
to operate autonomously of the CNS, the microbiota-ENS
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Fig. 2  Gut-brain signaling: vagus nerve signaling
conjunction additionally influences CNS signaling mech-
anisms. ENS neurons' neural functions eventually come
to a stop in the gut's epithelial lining, so they can either
immediately react to the luminal surroundings or they
may indirectly react to neurological chemicals made by
luminal microbes or enteroendocrine cells [50]. The vagus
nerve is a potential route suggested for microbiota-ENS-
brain connection. It has been hypothesized recently that
ENS neurons could regulate the functioning of CNS via
stimulating the vagal afferents. Primary vagal afferents can
interact with the CNS concurrently in response to changes
in GI stimulants and regulatory peptides. Animal research
using subdiaphragmatic vagotomy surgery conveys con-
firmation regarding the significance of the vagus nerve
mediating microbiota-brain communication [51].
Specialized sensory terminal endings can more effec-
tively recognize a wide range of sensory signals. Along
the GI tract, vagal sensory neurons form various kinds of
mechano- and chemo-sensory terminals, such as intragan-
glionic laminar endings (IGLEs), which link to myenteric
neuron clusters located between the longitudinal and circu-
lar muscle layers, intramuscular array endings (IMAs) are
branches of parallel telodendria running parallel to smooth
muscle fibres more strategically situated near the sphinc-
ters, and mucosal endings arbour [52]. Additionally, intes-
tinal glands, antral glands, and the extreme posterior taste
buds in the throat and upper oesophagus are all innervated
by vagal afferents. Although it is believed that IGLEs and
IMAs sense mechanical changes, the underlying molecular
pathways by which gut distension is perceived by these
afferent terminals are yet unknown. Numerous physiologi-
cal mechanosensory functions, such as pulmonary stretch,
light touch, and blood pressure variation, are mediated by
mechanosensitive PIEZO channels [53]. Whether PIEZO
channels possess a part in gut mechanosensation is uncer-
tain. However, IGLEs' mechano-sensitivity is Gd3 + insen-
sitive while PIEZO channels are Gd3 + sensitive, point-
ing to the possibility of PIEZO-independent processes. A
thin layer of epithelial cells makes up the gastrointestinal
mucosal barrier that keeps luminal entities out of the GI
tissue underlying it. The principal sensors for intestinal
nutrients are enteroendocrine cells, which serve as a link
between afferent nerves and luminal contents. Cholecys-
tokinin (CCK), glucagon-like peptide-1 (GLP-1), peptide
YY (PYY), and serotonin are just some of the various
GI neurohormones that are derived from enteroendocrine
cells to modulate digestion, nutrient absorption, and food
intake [54]. This finding suggests that the programming
logic for intestinal nutrients in enteroendocrine cells is
possibly only partially understood. Traditionally, enter-
oendocrine cells were alphabetically categorized into 8
subpopulations based on the hormones they produce. The
intestinal villus shaft is the path taken by vagal afferents as
they arborize along the apical pole and develop varicosi-
ties and swellings close to the enteroendocrine cells [55].
Afferent nerves and enteroendocrine cells were anticipated
to not physically interact for a prolonged period. Instead,
they interact paracrinely by diffusing hormones that have

been produced to signal neighboring afferent terminals
[56]. Vagal sensory neurons express an array of gut hor-
mone receptors, such as CCKAR, GLP1R, NPY2R, and
HTR3A. The significance of this paracrine connection in
the GBA has been largely characterized and is generally
acknowledged, despite some gut peptide/receptor pairings,
such as GLP-1/GLP1R [57]. Utilizing immunostaining of
synaptic markers, monosynaptic rabies virus tracing, and
electron microscopy, recent studies have revealed that
about two-thirds of endocrine cells are capable of form-
ing synapses with adjacent neurons as a supplement to
this classic model. According to recent studies employing
electron microscopy, monosynaptic rabies virus tracing,
and immunostaining of synaptic indicators, about two-
thirds of enteroendocrine cells have the potential of form-
ing synapses with proximal nerves. A novel link between
vagal afferents and enteroendocrine cells including glu-
tamatergic synapses has been identified. When combined
with paracrine communication, these connections facilitate
ultrafast millisecond transmission from enteroendocrine
cells to vagal sensory neurons, providing gut-brain signal-
ing a continuous spectrum from fast to slow [58].
The vagus nerve is the neural pathway for the inter-
action between adipose tissue and the liver. Peroxisome
proliferative-activated receptor (PPAR)-c2 expression in
the liver of experimental mice induced acute hepatic stea-
tosis while drastically lowering peripheral adiposity that
is accompanied by a spike in energy expenditure and a
surge in systemic insulin sensitivity [59]. In addition to
experiencing greater hepatic PPAR-c2 expression, these
animals also showed significantly better insulin sensitivity
as indicated by significantly lower fasting plasma glucose,
insulin, leptin, and TNF-a levels, decreased glucose out-
put from the liver, and lower inflammatory response as
indicated by decreased TNF-a levels [60]. These animals
displayed high sympathetic nervous system tonus based
on the enhanced activity of UCP-1, PGC1a, and blood-
free fatty acid levels elevated. The afferent vagus nerve
regulates the implications of hepatic PPARc2 activity,
demonstrated by the complete inhibition of an upsurge
in serum fatty acid levels, and resting intake of oxygen,
with destruction of the Vagus Nerve. [61]. Therefore, it
seems that the electrical stimulation of the afferent vagal
nerve generated by the hepatocytes governs the far-off
ramifications of hepatic PPARc2 activation on peripheral
regions. [62]. Through humoral and neuronal pathways,
the CNS receives feedback from an array of tissues and
organs. These signals are subsequently integrated by the
CNS to generate appropriate feedback, such as parasympa-
thetic regulation or stimulation of the sympathetic nervous
system to ensure energy equilibrium.
Neurochemical Research
Hormonal Signaling Mechanisms Between Gut
and the Brain
The homeostatic system is the equilibrium of energy.
Although problems with this system can lead to obesity, a
relatively recent spike in the prevalence of the disease is
believed to be a consequence of a regulatory system that
cannot function in a certain environment of accessible,
energizing food increased transportation[62]. The greatest
opportunity for us to fight obesity could originate from
commanding aspects of this regulatory system.
The hypothalamus and brainstem are the primary neural
regions in charge of regulating energy homeostasis [63].
Numerous modern medications for obesity target central
neurotransmitters to assist patients lose weight. Rimon-
abant accomplishes a similar feat by opposing central
type-1 cannabinoid receptors, similar to how sibutramine
suppresses appetite by boosting noradrenaline and sero-
tonin transmission. In clinical trials, rimonabant and
sibutramine both led to a minor drop in BMI. However,
there is an elevated risk of adverse effects because the
the endocannabinoidsystems that these medicines affect
do not just control appetite [64]. For instance, sibutramine
has been linked to hypertension, while rimonabant has
been linked to potential reproductive and psychological
challenges.
The PNS transmits neurological and hormonal signals
to the hypothalamus and brainstem that are encoded with
information about the acute nutritional situation and obe-
sity [59]. Leptin, an adipose hormone that alerts the nerv-
ous system to the amount of fat that accumulates in the
body, isn't particularly effective in combating obesity [60].
The majority of obese people have elevated leptin levels in
their blood and are immune to their physiological effects.
There are currently no established techniques to overcome
this barrier.
Although the hunger experienced prior to a meal is con-
sidered to be mainly regulated by leptin, shorter-term sig-
nals may continue to influence the food intake. These neural
signals are subsequently coupled with hormones generated
from the gastrointestinal system and other structures to relay
information [65]. The vagal pathways that ascend from the
gut to the CNS are subsequently triggered by these gut hor-
mones, or these hormones directly affect the neurons in the
brain.
The primary regions of the CNS that regulate the equi-
librium of energy, the hypothalamus and brainstem, can be
activated by gut hormones [66]. The specific mechanisms of
central action for several gut hormones are obscure or debat-
able. It can be challenging to isolate the endocrine effects
of certain gut hormones such as ghrelin, PYY and GLP-1
because they also work as neurotransmitters in the brain,
where their roles might vary from those in the periphery.
Neurochemical Research
Leptin
Since its discovery in 1994, leptin has garnered a lot of inter-
est as one of the essential central and peripheral signals for
the preservation of energy homeostasis [67]. Adipose mass
and plasma leptin are often inversely correlated. Leptin's
main physiological function is to alert the CNS of the num-
ber of energy reserves that are readily accessible, to limit
dietary intake, and boost energy expenditure [68]. As a
result, leptin deficiency causes morbid obesity by increas-
ing appetite and food intake. Notably, leptin insufficiency
has only sometimes been linked to severe early childhood
obesity. Leptin levels among the obese population are usu-
ally high. Leptin resistance is hypothesized to be the cause
of the inability of leptin to promote weight reduction in such
instances [68].
A disruption of the hormone's characteristic behavior,
presumably at diverse locations in the circulation and/or
in the signaling cascade, is identified in conjunction with
hyperleptinemia, which is generally detected in people with
obesity and in animal models [69]. Obesity is caused by
the disturbance of leptin signaling in the hypothalamus,
demonstrating the critical role of this hormone in maintain-
ing energy equilibrium. In the CNS, leptin resistance may
be specific, as evidenced by the disruption of its impact on
central metabolic processes but the retention of its various
other effects like sympathetic stimulation of blood pressure
[69]. Leptin receptors (Ob-Rs) reside in several peripheral
tissues and regulate a range of systemic processes including
immunity, reproduction and cardiovascular operations, along
with its activities in the CNS. [69].
In lean individuals, leptin distributes at a level of 5–15 ng/
mL and is predominantly released by adipocytes [70]. Fast-
ing, testosterone, thyroid stimulating hormone, surplus glu-
cocorticoids and prolonged contact with cold temperatures
lower its expression while overeating, insulin, glucocorti-
coids, endotoxins, and cytokines boost it. Elevated leptin
expression is observed in the heart upon reperfusion after
ischemia, and endothelin (ET)-1 and angiotensin (Ang) II
therapy increases leptin levels in cardiomyocyte culture
serum, implicating synthesis of leptin in the heart [71].
The class I cytokine receptors comprise six isoforms of
the Ob-R (a to f) reported in a mouse model. The primary
isoforms in the heart are Ob-Ra and Ob-Rb, whereas the
expression of the remaining forms is at modest levels and is
poorly preserved across species [72]. Ob-Re is the released
variant of leptin that adheres to leptin in the blood and mod-
ulates the level of free leptin.
The Janus-activated kinase (JAK), signaling sensors
and transcription activators (STAT), and mitogen-acti-
vated protein kinase (MAPK) systems have all been dem-
onstrated to be induced by ob-Rs [73]. Ob-R undergoes
homo-oligomerization upon ligand engagement and
binds to JAK, especially JAK2. While weak connections
between Ob-Rb/JAK1 and Ob-Ra/JAK2 and leptin therapy
were documented in the context of transient transfection-
induced JAK overexpression, STAT-binding is specific
to Ob-Rb. However, The STAT-binding exists solely in
Ob-Rb [73].
Research conducted in vivo has revealed that STAT3
is primarily involved in signaling [74]. Tyr1138 is phos-
phorylated, which binds STAT proteins to the Ob-Rb/
JAK2 complex. To stimulate the transcription of targeted
genes, notably the one responsible for the suppression of
the cytokine signalling family (SOCS3), tyrosine-phos-
phorylated STAT3 molecules split and are delivered to
the nucleus [75]. The Ob-Rb/JAK2 complex's Tyr985
and other binding sites on SOCS3 serve as a conduit for
negative feedback related to leptin signaling. Tyr985 phos-
phorylation by JAK2 additionally activates the extracel-
lular signal-regulated kinase (ERK) signalling pathway by
phosphorylating the src homology 2 (SH2) domain of the
tyrosine phosphatase SHP-2 (src homology 2-containing
tyrosine phosphatase. Overexpression of SHP-2 has been
demonstrated to lower SOCS3-mediated inhibition, most
likely through interacting with Tyr985 competitively[75].
Numerous additional consequences result from JAK2
autophosphorylation that is not reliant on tyrosine phos-
phorylation sites on Ob-Rb [76]. One of these results is the
phosphorylation of receptors for insulin substrate proteins,
a prerequisite for the activation of downstream signaling
via the phosphatidylinositol 3′-kinase (PI3K). The leptin-
associated PI3K pathway in the heart appears to be essen-
tial to cardiomyocyte proliferation and shielding cardiac
cells from ischemia/reperfusion damage, along with ERK
cascades [77].
In the CNS, the hypothalamus is the region where the
majority of Ob-Rs reside. Leptin induces the production
of proopiomelanocortin, which then undergoes process-
ing to generate -melanocyte-stimulating hormone and
stimulate downstream melanocortin-3 and -4 receptors to
reduce appetite.. In the arcuate nucleus, leptin effectively
suppresses the hormone neuropeptide Y, which increases
appetite, as well as agouti-related peptide, inhibiting the
signaling of the melanocortin-3 and -4 receptors [78].
JAK2/STAT3 signaling induced by ob-Rb is essential
for leptin regulation of dietary intake and expenditure of
energy. Although JAK, an insulin receptor substrate, and
MAPK proteins may be triggered by short versions of the
leptin receptor, only Ob-Rb may activate STAT3 [79]. It
has been demonstrated that STAT3 is necessary for the
homologous replacement of Ob-Rb by a receptor mutant
for Tyr1138, which regulates the expression of proopi-
omelanocortin and NPY in the hypothalamus.

Ghrelin
Ghrelin is a peptide hormone that enters the bloodstream
from the stomach and was first indicated to be an endog-
enous receptor for the growth hormone-secretagogue recep-
tor (GHS-R). The addition of an octanoyl ring to the serine
residue in the third position is the single distinctive altera-
tion to the 28 amino acid molecule that makes up ghrelin.
[80]. For ghrelin to bind to the GHS-R and pass across
the blood–brain barrier, this acylation is necessary. Stud-
ies of increased appetite due to ghrelin were received with
enormous enthusiasm. Although the other circulating com-
pounds, such as the adipose hormone leptin and a number of
gut hormones, are linked to lower dietary intake, ghrelin is
the sole identified substance that stimulates appetite through
circulation. [81]. Fasting elevates circulating ghrelin levels,
causing them to reduce after eating. Acute stimulation of
acylated ghrelin, either centrally or peripherally, stimulates
dietary intake as well as growth hormone secretion in rats;
prolonged use leads to increased body weight. Humans who
acquire ghrelin intravenously or subcutaneously observe a
surge in both appetite and consumption of food. The term
"hunger hormone" is frequently utilized to describe ghrelin
[82].
According to studies, persistent central ghrelin infusion
enhances the production of enzymes which foster fat accu-
mulation in adipose tissue while peripheral ghrelin admin-
istration limits fat usage [82, 83]. Thus, ghrelin's effects on
metabolism may not be solely dependent on increased food
consumption.
Initial research revealed that ghrelin- and ghs-r-knockout
mice failed to show significant changes in their eating habits
or levels of fat in their bodies [84]. However, it has been
recently determined that ghrelin signaling disruption mod-
els can exhibit intricate phenotypes associated with energy
homeostasis. When administered a high-fat meal plan early
in life, ghs-r-knockout mice and male ghrelin-deficient mice
exhibit resilience to diet-induced obesity. When fed a high-
fat diet, ghrelin-deficient mice modified their metabolic
fuel preference, opting for fat as an energy source rather
than wild-type controls. Additional study has revealed that
reduction of ghrelin suppresses diabetes in the ob/ob obese
mouse while diabetic ghrelin-knockout mice exhibit reduced
hyperphagia [85].
It is enticing to contemplate employing GHS-R antago-
nists to regulate ghrelin signaling as a strategy for prevent-
ing obesity. A recent study has demonstrated that immu-
nizing rats against ghrelin can limit weight gain [85]. It
remains unclear whether inhibiting ghrelin signaling is
an effective long-term treatment for obesity in people,
and it might not be an appropriate decision to attempt an
Neurochemical Research
essentially irreversible approach there. Ghrelin agonists
could be beneficial in managing certain patient groups
experiencing anorexia. Acute ghrelin therapy has been
proven to promote digestion in diabetic individuals with
gastroparesis and appetite loss in cancer patients. It may
additionally boost appetite in dialysis patients who are
severely malnourished [86]. Thus, persistent ghrelin admin-
istration's orexigenic effects on anorexic individuals could
be advantageous, however, this has yet to be established.
Before ghrelin could be utilized as a therapeutic, the issue
of potential adverse effects must be thoroughly addressed.
It's essential to note that new research suggests peripheral
ghrelin treatment can alter the development of hippocam-
pal neurons and the flexibility of the hypothalamus[86].
Obestatin, an entirely distinct peptide, has been identi-
fied to be encoded by the same gene as ghrelin [86].
When delivered peripherally or intracerebroventricularly,
obestatin has been observed to lowe food intake and, when
administered peripherally, to decrease weight gain. It has
been proposed that the orphan G-protein-coupled recep-
tor GPR39 is responsible for these effects [86]. The reason
why the same gene could generate both an orexigenic and
an anorectic signal was the subject of much debate. The
initial findings, however, have not been corroborated by
subsequent investigations, which suggest obestatin may not
signal through GPR39 or have a function in the regulation
of calorie consumption [86].
The overview of the hormones and their effect on recep-
tors is summarized in Table 2.
Role of Gut‑Brain Axis in Metabolic
Disorders
Obesity and Its Relationship with Gut‑Brain Axis
Several facets of physiology, especially glucose homeosta-
sis, gut motility, and appetite, are greatly impacted by the
GBA. Therapeutics for several diseases like T2DM and obe-
sity, have been designed by studying the role of GBA.
Obesity is a severe health condition that is linked to
higher mortality and morbidity in addition to increased
personal, social, and economic repercussions. The brain
and gastrointestinal system interact together in a vast and
intricate system of neurons and hormones, and their recep-
tors influence appetite, dietary intake, and obesity. The
vagus nerve relays the complex hormonal and neurologi-
cal signaling caused by the existence of nutrients in the
GI Tract to the brain. Effector fibres carry data from the
gut to the NTS and the smooth muscle cells of the gut. It
obtains data from the NTS and employs it for regulating
Neurochemical Research

Table 2  Major hormones: site Hormones Site of release Receptor Effect on food References
of release, receptors and effects consumption
on food consumption
Peptide YY L cells of the GI tract Y2R ­(PYY3-36) Decreases [81]
Y1R, Y2R, Y4R
GLP-1 Distal L cells GLP-1R [82, 83]
Pancreatic Polypeptide F cells of the Pancreas PPY2 [84]
PPY4
Cholecystokinin L cells of the GI tract CCK1R [85]
CCK2R
Leptin S cells of the GI tract Ob-Rb [85, 86]
Leptin Receptor
Ghrelin Stomach GHSR Increases [86]
Oxyntomodulin L cells of the GI tract GLP-1R Decreases [87]
GCGR​
Amylin β cells of the Pancreas AMY1a [87]
AMY2a
AMY3a
Motilin Mo cells of the Small Intestine GPCR38 [88]

appetite, dietary intake, and energy levels in the neurons
of the arcuate nucleus (ARC). Cocaine and amphetamine-
regulated mRNA, agouti-related protein, orexigenic neu-
ropeptide Y, anorexigenic peptides (LEP), and pro-opi-
omelanocortin neurons comprise the ARC [86]. Research
has shown that vagotomy reduces the signaling of the ano-
rexigenic hormone, which causes animal models to con-
sume more food and gain more weight. [86]. The release
of several gut hormones, such as GLP-1, ghrelin, PYY, and
LEP, can be altered by certain gut bacteria. As a result,
hypothalamic neuroendocrine pathways influence satiety
and hunger. SCFAs from microbiota may bind to receptors
on EECs and modify how enteric hormones are released
into the bloodstream. Furthermore, ghrelin, GLP-1, and
cholecystokinin are secreted by EECs when different
taste receptors—such as those for bitter, fat, umami, and
sweet—are activated. The primary SCFA released by gut
bacteria, acetate, reduces hunger processes in the central
hypothalamic processes [87].
Notably, altered microbiota induces a spike in acetate
concentration, which upregulates the activity of the para-
sympathetic nervous system and elevates levels of ghrelin,
stimulating the release of insulin in response to glucose, as
well as obesity [88]. The gut bacteria generate neuroactive
metabolites that have an effect on the central regulation
of hunger, such as serotonin and GABA. Serotonin-regu-
lated common melanocortin neurons suppress appetite via
regulating body weight homoeostasis. The right control
of energy balance requires GABA, which is the primary
inhibitory neurotransmitter in the CNS.
The efficacy of calorie intake from consumed foods is
boosted by obesity-associated bacteria. Therefore, com-
pared to a lean-associated GM, an obesity-associated
microbiota offers the host more energy from additional
indigestible carbs and proteins by increasing the synthe-
sis of several primary fermentation enzymes and nutrient
carriers.
Non‑Alcoholic Fatty Liver Disease (NAFLD)
and the Influence of the Gut‑Brain Axis
NAFLD is a prevalent chronic liver condition that leads
to various kinds of damage to the liver, from steatosis to
steatohepatitis [89]. Hepatocellular carcinoma and other
problems, such as cirrhosis, may originate from fibrosis. In
terms of histology, NAFLD may split into non-alcoholic ste-
atohepatitis (NASH) and non-alcoholic fatty liver (NAFL).
Obesity, hypertension, hyperlipidemia, T2M, and metabolic
syndrome are all strongly associated with the development
of NAFLD. NAFLD is typically thought of to be meta-
bolic syndrome's hepatic manifestation [90]. Currently, the
cause of NAFLD remains to be unknown. The resistance to
insulin, oxidative stress, lipid metabolism shift, release of
inflammatory cytokines, endoplasmic reticulum stress, gut
dysbiosis or activation of the gut-liver axis, and genetic and
epigenetic factors have been suggested to be contributing
factors. Additionally, research has revealed links between
hyperammonemia, gut dysbiosis, metabolism, and functional
issues with particular brain regions and the neurobehavioral
condition known as NAFLD [91]. The key players in the
pathophysiology of NAFL/NASH are GM, its products of
bacteria, and the intestinal barrier. As a result, the microbi-
ota-gut-liver-brain axis serves a crucial regulatory function.
The colonization of the GM of NASH patients can worsen
hepatic steatosis and inflammation in sterile mice served a
high-fat diet (HFD), indicating that GM is crucial in the
emergence of NAFLD. Furthermore, studies conducted by
Boursier et al. revealed an association between gut dysbiosis

and modifications in GM's metabolic activity and the sever-
ity of NAFLD [92]. Intestinal permeability, low-grade
inflammation, dietary choline metabolism, bile acid metabo-
lism, and endogenous ethanol production are various ways
that modify GM, promoting hepatic fat deposition. Further-
more, it has been suggested by Ke Hu et al. that GM assists
in the neuroendocrine control of lipid metabolism [93].
Additional research is required in order to fully comprehend
the fundamental cause of functional modifications driven by
cognitive impairment in NASH, however, it is possible that
GM metabolites and ammonia can induce neurotoxic dam-
age, which contributes to the impairment of cognition in
NASH. According to the latest study by Mouries et al. the
breakdown of the gut vascular barrier (GVB) and intestinal
epithelial barrier (IEB) are preliminary occurrences in the
development of NASH, and HFD-mice will display dam-
aged GVB and transmit bacteria shortly after one week [94].
Therefore, the intestinal barrier is just as critical to NAFLD
as the GM and its end products are.
Comprehensive studies on the microbiota-gut-liver-
brain axis have rendered the GM an effective player in
NAFLD in recent times. Alteration in lifestyle, diet and
physical activity are first-line therapies for NAFLD. Studies
have demonstrated an important link between GM and the
management of NAFLD through diet and exercise [95]. The
makeup and variability of the GM are significantly influ-
enced by the mediterranean diet, which is more concentrated
in monounsaturated fatty acids. The high dietary fibre con-
tent and polyphenols that are present enhance bifidobacteria
while reducing firmicutes and elevating Bacteroides. Addi-
tionally, spinach consumption also has similar effects by
regulating the gut flora, which can alleviate the liver dys-
function associated with NAFLD[95]. It's also intriguing
that exercise successfully reverses the gut dysbiosis caused
by the HFD, minimizing the disruption of the gut-liver axis
and enhancing bile acid homeostasis, thereby helping to pre-
vent the development of NAFLD [96].
Gut‑Brain Axis and Neurological Disorders
Gut-brain interaction not only keeps the body in a state of
wellness, but it has also been associated with the emergence
of neurological and psychological disorders in the context
of gut-brain axis disruption. The host immune system, host
behavior, and neurological growth are all significantly influ-
enced by the gut flora. Elevated intestinal permeability, how-
ever, results in the translocation of gut microorganisms and
associated neuroactive metabolites and components, which
triggers a neuroinflammatory reaction in the brain [97].
Neurochemical Research
Alzheimer’s Disease
Alzheimer's disease (AD) is a prevalent neurological con-
dition characterized by cognitive decline in elderly people.
Dementia is a major symptom with this condition, which
affects activity, recall, cognition, language, and mental
functioning [98]. The excessive production and deposition
of amyloid-peptide (A) and the translocation of microbes
and their byproducts into the brain, where they can initiate
neurological inflammation and neurodegenerative alterna-
tion in AD, are the primary causes of these events. As a
result, AD is frequently linked to an increasing cerebral
A-peptide accumulation. The amyloid precursor protein
(APP) is cleaved by proteases to produce the 40–42 amino
acid peptide known as “A.” By starting the neuroinflam-
matory response in AD, it plays a significant part in the
pathogenesis of AD. In contrast to wild-type mice without
the APP gene, the APP transgenic mice exhibited an enor-
mous shift in the variety of their gut flora. Additionally,
GF APP transgenic (TG) mice showed a marked reduction
in the degree of cerebral A-amyloid pathology as com-
pared to control animals with GM [99]. It’s intriguing to
consider that TG mice colonized with microbiota from
wild-type mice demonstrated a lower impact on elevat-
ing the level of cerebral A, as opposed to TG mice that
got GM from standard APP transgenic mice [100]. Bauerl
et al. who stated that alterations to the GM's makeup were
noticed in the transgenic APP/PS1 mice model of AD,
provided similar outcomes [101]. When TG animals were
contrasted to wild-type control mice, it was observed that
the Erysipelotrichaceae family was more prevalent in TG
mice. Additionally, transgenic APP/PS1 mice displayed
less A pathology than regular mice, suggesting that the
GM may be associated with both the aetiology of A and
AD. In an additional in vivo investigation, TG APPswe/
PS1dE9 mice exhibited a decline in the expression of post-
synaptic density protein 95 (PSD-95) and synapsin I and
a boost in the brain deposition of the A-peptide, Tau pro-
tein, COX-2, and CD11b. In comparison to WT mice, TG
mice that received faecal microbiota transplants from WT
mice demonstrated superior amyloid peptide, p-tau protein
level, synaptic plasticity, and variation in GM composi-
tion[102]. Further evidence that AD patients' intestines
could mimic the nervous system and trigger inflamma-
tory and immunological changes related to APP and A
pathology with a higher intestinal A burden, observation
of APP, CD68, and p-Tau immunoreactivity has been
reported in both AD patients and APP/PS1 mice [103].
In addition, fructooligosaccharides alleviated cognitive
impairments and neurodegeneration in TG APP/PS1 mice
by stimulating the expression levels of PSD-95, synapsin
I, and GLP-1 and suppressing the levels of p-JNK and
GLP1R, based on research on the modulatory properties
Neurochemical Research
of prebiotics against AD[103]. Bacteria are not the only
factor in how the gut microbiome affects AD development;
viruses have additionally been linked to the disease [104].
However, further research is required to fully comprehend
the impact of the microbiome on the GBA in AD.
Parkinson’s Disease
Approximately seven to ten million people globally are
thought to be affected by Parkinson's disease (PD), the sec-
ond most prevalent neurodegenerative ailment [105]. The
primary characteristics of PD involve both motor and non-
motor abnormalities. The most apparent signs on the motor
side are inflexibility, delay in motion, and resting tremors.
Cognitive difficulties, depressive disorders, mood swings,
sensory disturbances, behavioral changes, and autonomic
dysfunctions all lead to serious handicaps on the non-motor
side [106]. Such a broad range of medical symptoms is the
result of alpha-synuclein buildup in the brain's central and
peripheral nervous systems. The vast majority of patients
with PD report GI problems. Individuals with PD have
been documented to suffer from a number of GI symptoms,
including hypersalivation, constipation, dysphagia, nausea,
modified bowel movements, and defecatory dysfunction
[107]. In the early stages of PD, higher intestinal permeation
has been reported. Increased intestinal permeability causes
the bacteria and microorganisms in the gut to migrate, caus-
ing oxidative stress and inflammation in the ENS, leading
to enteric-synucleinopathy in PD [108]. PD has been clini-
cally linked to gastric ulcers, caused by a Helicobacter pylori
(HP) infection, since the 1960s. Drug-induced HP infection
eradication reduces PD symptoms. Evidence gathered from
numerous studies indicates an association between PD and
the microbiota which inhabits the gut. The two most sig-
nificant co-factors in PD are inflammatory state and shifts
in GM [109]. Evaluation of faeces revealed that the cohort
of PD patients had a substantial change in the gut bacte-
rial composition, with lower levels of Prevotellaceae and
greater levels of Enterobacteriaceae. These alterations dem-
onstrated a positive association with greater postural insta-
bility and a unique gait. The levels of alpha-synuclein, a
presynaptic neuronal protein related to motor impairment
and a neuroinflammatory condition in mice, elevated in GF
mice given faecal microbiota from PD patients [109]. In an
experiment employing a mouse model of chemically induced
Parkinson's disease, it was additionally found that the overall
makeup of the GM had altered. According to a recent study,
PD patients and a human-synuclein overexpressing mice
model of PD (Thy-Syn) have larger relative abundances of
mucin-degrading Verrucomicrobiae and LPS-producing
Gammaproteobacteria than healthy and wild-type mice [108,
109]. It was discovered that faecal microbiota transplantation
(FMT) improved striatal DA and 5-HT in a rodent model
of PD and lowered microbial dysbiosis, faecal SCFAs, and
physical disability. The authors further claimed that FMT
suppressed TLR4/TNF- signalling in the gut and brain, as
well as the proliferation of microglial cells and astrocytes, in
PD mice [110, 111]. In accordance with a recent study, PD
patients had higher colonic expressions of TLR4, CD3 + T
cells, and cytokines and lower concentrations of bacteria-
producing SCFAs [111]. Researchers additionally demon-
strated that rotenone treatment may repair or lessen similar
gut and neurological conditions in TLR4-KO mice, indicat-
ing that TLR4-induced inflammatory signaling serves an
essential part in gut and neural inflammation in Parkinson's
disease. The LPS-induced PD animals exhibited a rise in
microglial cell activation, proinflammatory cytokines, heme
oxygenase-1 (HO-1) activity, and a drop in ferroportin (Fpn)
[111].
A role for fungi in PD should also be considered [112].
Epp and Mravic (2006) pointed to the Candida fungus
accompanying some cases of PD, whereas Pisa et al. (2020)
reported several fungal families, including Candida, in the
CNS of PD patients [113].
Gut‑Brain Axis and Mood Disorders
The brain and the gut are linked by the ANS, the HPA axis,
and nerves in the GI tract. This allows the cognitive sys-
tem to affect intestinal operations such as the functioning
of immune effector cells, and the gut to impact mental well-
being, mood, and cognition. Findings from clinical, scien-
tific, and epidemiological studies indicate that the gut-brain
relationship—that is, psychological state, behavioral control,
neuromuscular functioning, and HPA regulation—is greatly
and substantially influenced by GM [114].
Studies have revealed that variations in the microbiota
are connected to modifications in these neural networks, and
they are now striving to clarify the underlying mechanisms
of action that govern the physiological effects of bacteria on
the brain's emotional and cognitive processes, both directly
and indirectly. For instance, effective GI disruptions have
been linked to a number of mood disorders, including anxi-
ety and depression. Furthermore, studies have shown that
fetal and neonatal neural growth may be influenced by the
overall composition of the GM. It should come as no sur-
prise that nutrition has also been linked to the effects of
GM on cognition [114].
Anxiety
According to reports, the global incidence of anxiety dis-
orders was estimated to be 7.3% worldwide, with a range
of 5.3% in African cultures and 10.4% within Euro/Anglo
cultures [115]. The complexity and multifaceted nature
of anxiety and trauma-related diseases make it difficult to

distinguish between them and to treat them due to pheno-
typic variation. These diseases are hypothesized to occur as
a result of complex interactions between the environment,
the human genome, and the epigenome [115]. Animal mod-
els serving as practical model systems with greater influ-
ence on environmental and genetic variables affecting the
microbiome were the subject of most previous investigations
on the microbiome. The GF animal model is a potent instru-
ment for studying the impact of specific bacteria or dietary
interventions on the GBA axis, as well as for examining
the impact of GM on behaviour in an effort to demonstrate
causation.
The operation of the body's immune system and GI tract
may have substantial effects on behavioral and cognitive
functioning [116]. It should be highlighted, nonetheless, that
additional parameters, all of which are still unknown, such
as time, stress, sex, and species, are also part of such interc-
tions. The acceptory animal demonstrated the donor's behav-
ioral profile after FMT. The way that GF animals behave is
very different from how control animals behave. GF mice
showed an amplification of the HPA axis reaction when
exposed to stress, which was counteracted once a specific
type of Bifidobacterium was monocolonized [116]. Simi-
larly, GF rats displayed greater neuroendocrine responses
and anxiety-like behavior in contrast to SPF animals when
compared to stress-sensitive F344 rats that were free of
particular pathogens (SPF) [116]. However, the connection
between behavior and the microbiome is not one-way; stress
and emotions may alter the genetic makeup of the gut micro-
bial population by releasing sympathetic neurotransmitters
or stress hormones, which may modify the microbiota's
habitat and affect gut physiology [116, 117].
Human probiotic interventions suggest the gut micro-
biome may be directed to improve results associated with
stress, anxiety, and trauma [117]. Nevertheless, a number
of restrictions make it challenging to properly analyze these
results, such as small numbers of samples and confounding
factors like gender bias, demographic and ethnic differences,
and variations in probiotic strains and dosages as well as
treatment durations. More coordinated attempts to enlist
substantial cohorts and use standardized methodologies may
provide further understanding regarding how to focus on the
GM to mitigate the effects of stress and trauma or anxiety.
Depression
Over 350 million people worldwide suffer from depression,
a common neuropsychiatric condition with a high recurrence
rate that has a major detrimental effect on both public health
and economic growth [117]. Unfortunately, the majority
of antidepressants that are presently available on the mar-
ket, work by boosting monoamine neurotransmitter levels,
with incomplete therapeutic success; in fact, about 30% of
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patients experience a lacklustre response [117]. While keta-
mine's strong and immediate antidepressant effects have
altered the course of antidepressant advancements, its long-
term efficiency and side effects must additionally be con-
sidered [118, 119]. Therefore, it is important to investigate
the pathophysiology of depression extensively to determine
possible therapeutic targets. While the exact mechanism of
the microbiota-GBA’s effect on depression is unknown, an
expanding body of research shows that neuronal, endocrine,
immunological, and metabolic pathways play a significant
role in the interaction between intestinal microbes and the
brain.
The influence of gut bacteria on mood and depression
disorders can be attributed to their bidirectional contact with
the CNS through interacting pathways involving immuno-
logical, endocrine, and neurological system signaling sys-
tems. The liver’s anatomical location and circulatory supply
enable it to play a role in and coordinate crucial immune
functions [119]. Within the chemical signaling system, intes-
tinal flora controls the production of monoamine neurotrans-
mitters, specifically 5-HT, DA, and GABA, which in turn
controls the emergence and resilience of neural networks
related to behavior and mood [119]. It is possible to avoid
or normalize the hyperactive state of the HPA axis, which
is demonstrated by elevated cortisol, adrenocorticotropin
(ACTH), and corticotropin-releasing hormone (CRH), by
modifying the GM's role in the microbiota-GBA [120]. A
member of the neurotrophin family, the brain-derived neu-
rotrophic factor (BDNF) has been linked to a number of
activities, including cell division, neuronal survival, the con-
struction of synapses, and the development of neuroplasti-
city [119, 120]. A deficiency in BDNF increases the likeli-
hood of both decreased neuroplasticity and the emergence
of depression symptoms. Several studies have revealed that
when compared to healthy controls, depressive patients have
comparatively lower serum BDNF levels. Antidepressant
medications like ketamine may regulate cognitive and emo-
tional functioning in connection to depression by increasing
BDNF activation through mTOR signalling [120]. The onset
of depressive-like behaviour may be influenced by altera-
tions in the GM since they can elevate BDNF expression
levels.
Likewise, by altering the GM and BDNF expression, pro-
biotic therapy has a demonstrated potential as a therapeutic
or preventive strategy for reversing behavioral deficiencies.
According to Bercik et al. oral antimicrobial-treated SPF
mice exhibit a momentarily altered gut microbiome, that
raises hippocampus BDNF concentrations and minimizes
depression. Additionally, it was demonstrated that giving
stressed mice a two-week pretreatment with probiotics
(a blend of L. helveticus R0052 and B. longum R0175)
increased the hippocampal expression of BDNF, reversing
synaptic imbalances and eventually improving efficiency
Neurochemical Research
on memory and cognition tasks [120]. Furthermore, in the
rat model of persistent stress-induced depression, treatment
with L. helveticus NS8 could enhance hippocampus BDNF
mRNA expression as well as behaviour performance [120].
Thus, the onset of depressive-like behaviour may be influ-
enced by the GM through modulating the quantity of BDNF.
Gut Microbiota and Circadian Rhythms
Circadian rhythms (CRs) are 24-h cycles governing an
organism's habits, organs, and cells. In order to maximize
efficiency and well-being, these rhythms match biological
processes with periodic and systematic environmental pat-
terns [121]. A disturbance in these cycles may have nega-
tive consequences, such as MeS, tumours, or cardiovascular
diseases. More and more evidence is directed to the notion
that the host organism and intrinsic circadian clocks both
control the GM in response to time changes. Microbiota
rhythms are dictated by food and eating timing, which may
alter the overall makeup of the microbe communities and
their metabolic activity [121, 122]. These alterations can
have a substantial effect on the immunological and metabolic
systems of the host.
The gut microbial "organ" is completely integrated into
numerous fundamental life processes and its chemical
makeup and functioning are highly sensitive to dietary and
environmental variables [122]. Several studies indicate that
the GM is crucial to modulating host metabolism, especially
when it pertains to responding to and influencing host CRs.
For instance, research on rodents has demonstrated that alter-
ation of the biological circadian clock by genetic changes
in animals (i.e., disruptions in Bmal1, Clock, or Rev-erb)
is linked to characteristics associated with MeS, such as
hepatic steatosis, hyperglycemia, hypoinsulinemia and
abnormal lipid profiles [123]Host metabolism is eventu-
ally influenced by the interactive relationship between the
GM and CRs[124]. This intricate, bidirectional network con-
tains numerous bioactive chemicals from the host, for which
scientists have only recently begun to recognize and define
their modes of action. Anti-microbial peptides and glu-
cocorticoid hormones are host-derived regulators that are
demonstrated to modulate GM in a circadian setting. Sev-
eral antioxidants, tryptophan derivatives, and hydrogen sul-
phide are examples of microbially derived regulators that
are additionally believed to serve as circadian modulators.
There is presently minimal information available about
the underlying mechanisms that regulate these mediators,
despite the fact that they are probably significant parts of
the circadian-microbiome connection and require further
study. In mice, host CRs and GM have been demonstrated
to share extensive interactions in recent studies. Despite not
being subjected to sunlight, diurnal host indications cause
oscillations in the amount and functionality of GM. Several
microbial organisms, including essential microbially-derived
compounds, are shown to display diurnal oscillations in their
relative abundances over a 24-h duration. Microbial oscil-
lations are observed throughout all studies, even in spite
of potential covariates including variations in the initial
microbial communities of mice cohorts, variations in ani-
mal facilities, and distinctive research designs focused on
manipulating the CR. Additionally, GM is associated with
host cellular rhythms; in a dearth of gut microbes, GF mice
display completely distinctive suprachiasmatic nuclei (SCN)
and hepatic transcriptional patterns, especially in fundamen-
tal CR. In recent times, studies indicate that the timing of
a person's meal consumption is correlated with their oral
microbiome's diurnal dynamics. It's evident that GM and
CRs, particularly peripheral clocks, react to identical stimuli
such as feeding habits and nutrition[123].
There are still several obstructions and challenges to
the study of CR: determining human CR accurately neces-
sitate labor-intensive monitored conditions that are primarily
attainable in laboratories; participant-to-participant variation
is significant; and assessing the human GI tract's CR is tough.
Although evaluating human CR may seem relatively easy
(for example, using melatonin and temperature regulation),
study must be carried out in extremely monitored settings
that limits light exposure while regulating meal timing and
portion sizes—factors that have been associated with CR
[124]. Furthermore, humans vary greatly in terms of their
genetic makeup, gender, age, and food, all of which effect
CR making it difficult to identify strong signals in data. The
most significant challenge, though, is that assessing CR in the
GI system is not feasible under the experimental conditions.
While it is viable in rodents, continuous tissue sampling isn't
feasible in humans. Clinically targeting metabolic well-being
and nutritional condition has proven to difficult to date, but
this is mostly due to the synchronization of these mecha-
nisms to one another and to external stimuli. Studying certain
mechanisms employed by the two "organs" for controlling
metabolism will enable researchers to utilize that knowledge
and ultimately modify both of these systems for medicinal
interventions in metabolic disorders. Within this system, the
ex vivo assessment of CR using intestine organoids i.e. self-
organised three-dimensional structures that can partially rep-
licate the original tissue's characteristics, cell heterogeneity,
and behaviour in vitro, ay show some possibilities (Table 3).
Therapeutic Implications and Interventions
The intricate interplay between GBA and metabolic disor-
ders offers a promising avenue for therapeutic advancements.
This overview delves into the multifaceted therapeutic impli-
cations and interventions that harness the GBA's intricate

network to mitigate metabolic distrurbances. Among the
forefront strategies are probiotics, postbiotics, prebiotics,
fecal microbiota transplantation (FMT), and metabolic
therapy (Fig. 3).
Probiotics, live beneficial microorganisms, exhibit
potential in ameliorating metabolic disorders by modulat-
ing the gut microbiota composition (see sections below for
all details). Their administration can promote a balanced
microbial profile, fostering favorable metabolic outcomes.
Postbiotics, comprising bioactive compounds derived from
probiotics, exert direct effects on host physiology and
metabolism, demonstrating a novel avenue for intervention.
Prebiotics, on the other hand, provide substrate for beneficial
microorganisms, supporting their growth and activity. These
non-digestible compounds confer metabolic benefits by
influencing gut microbiota composition and function. FMT,
a pioneering approach, involves transferring fecal material
from a healthy donor to a recipient, effectively reestablish-
ing a healthier gut microbiome and potentially rectifying
metabolic imbalances. Metabolic therapy, encompassing
pharmacological and lifestyle interventions, capitalizes on
GBA-mediated pathways to regulate metabolic disorders.
This comprehensive overview accentuates the integration
of these interventions, rooted in the GBA, as a progressive
strategy for addressing metabolic disorders holistically. By
elucidating the intricate relationships between the GBA and
metabolic health, this exploration underscores the therapeu-
tic promise of harnessing this axis for innovative and effec-
tive interventions (Fig. 4).
Probiotics, Prebiotics and Postbiotics for Metabolic
Disorders
Probiotics have been scientifically demonstrated to improve
lactose tolerance, preventing diarrhoea, strengthening immu-
nity, lessening inflammation, and healing dysbiosis in the
gut-associated with obesity [125]. They are dietary supple-
ments containing living microbes that, which when ingested
in sufficient quantities, boost the host's health. Prebiotics are
food components that are fermentable but indigestible and
encourage the growth of intestinal microorganisms [126].
To improve the effectiveness of probiotics, prebiotics are
frequently combined with them. Through immediate altera-
tions of the GM and control of gastrointestinal inflamma-
tion and permeability, probiotics demonstrate their potential
therapeutic influence on the body.
According to recent human trials on the influence of
probiotics on metabolic diseases, implementing a probiotic
supplement for 8–12 weeks could have beneficial impacts
on blood pressure, weight, BMI, total and low-density lipo-
protein cholesterol, both systolic and diastolic blood pres-
sure A1c, and high-sensitivity levels of C-reactivity as well
as prohibit insulin resistance and body weight gain [127].
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These tests, which included a wide spectrum of human
individuals, used distinct probiotic strains. Probiotic ther-
apy proved to be inefficient for lowering weight and BMI
in a recent meta-analysis evaluating the impact of probiotic
supplements on body weight and BMI [128]. The authors
emphasized that the potential of the study to reach firm
conclusions was constrained by the overall number of rand-
omized controlled trials incorporated in the meta-analysis,
the relatively small sample size, and the heterogeneity of the
research. To establish which strains may be the most efficient
and most suitable prospects for probiotic therapy, additional
studies are required.
Postbiotics are an array of biologically active compo-
nents comprising inactivated microbes, cell substances and
any easily soluble substances or metabolites produced by
microorganisms [128, 129]. When consumed by people,
postbiotics can directly or indirectly regulate supportive bio-
logical reactions. Postbiotics are consequently suitable for
underdeveloped countries as they have been demonstrated
to imitate the behavior and properties of probiotics while
not necessitating strict manufacture or preservation require-
ments. Several kinds of postbiotic substances manufac-
tured by extrinsic and intrinsic probiotic bacteria are being
researched by experts. Therefore, postbiotics are believed
to provide therapeutic benefits by demonstrating local-
ized impacts on particular regions of the intestinal epithe-
lium. This is owing to highly predefined molecular makeup
and extended shelf life[128]. Besides being more resilient
and possessing extended storage stability, postbiotics seek
to imitate the curative effects of probiotics, minimizing
the potential hazards of administering live microbes with
modified gastrointestinal walls or weakened immunological
defences [130].The microbes can be through inactivation,
fermentation or extraction to produce microbes. The inacti-
vation can involve methods like heat treatment or chemical
preservation [130]. Postbiotics can also be produced during
the fermentation process where carbohydrates are broken by
microbes to produce various metabolic products like organic
acids, alcohols and carbon dioxide [128]. Postbiotics can
also be extracted from certain microorganisms, such as Bifi-
dobacterium and Lactobacillus, which produce compounds
like bacteriocins, exopolysaccharides, and conjugated lin-
oleic acid [128, 130]. These processes allow the generation
of non-living beneficial compounds that can be used to pro-
mote gut health and minimize potential hazards associated
with live microbes.. They could possess a broad spectrum
of prospective effects including anti-allergic and antimicro-
bial characteristics and anti-ageing actions. They may also
bolster the gastrointestinal barrier’s ability to operate while
exerting antibacterial responses. To investigate the wide
range of such postbiotic constituents’ potential biological
mechanisms and their exact therapeutic effects addressing
Neurochemical Research

Table 3  Types of disorders with Types of diseases Implicated microbiota References

the linked Gut Microbiota
Metabolic disorders
Obesity Firmicutes/Bacteriodetes ratio [19–21]
Eubacterium
Faecalibacterium
Proteobacteria
NAFLD Bacteroides [92, 94]
Veillonella
Ruminococcus
T2D Clostridium Hathewayi [21, 22]
Clostridium Symbiosum
Escherichia Coli
Neurological disorders
Alzheimer disease Collinsella [98, 99]
Bacteroides
Lachnospira
Veillonella
Parkinson disease Desulfovibrio [102, 108, 109]
Bifidobacterium
Lactobacillus
Mood disorders
Anxiety Bifidobacterium [115, 116]
Lactobacillus
Lactococcus
Depression Subdoligranulum [117–119]
Coprococcus
Eggerthella
Ruminococcaceae
Circadian rhythm disorders Selenomoadales [121–124]
Negativicutes
Odoribacter

specific illnesses, it’s essential to thoroughly purify them
first.
Fecal Microbiota Transplantation (FMT)
In contrast with a healthy lifestyle, fecal microbiota trans-
plantation (FMT) has gained significant attention in the
past few years. Randomized regulated studies indicate that
FMT works successfully in managing metabolic disorders
like obesity and irritable intestinal disorders such as ulcera-
tive colitis [131]. The absence of thorough donor screen-
ing parameters could be the reason why FMT in a short
pilot experiment on canine severe hemorrhagic diarrhoea
syndrome solely increased microbiome diversity and pro-
vided no therapeutic advantages[132]. Therefore, the method
necessitates standardization in the setting of the study as the
host's inappropriate details executed by the fecal microbiota
could hinder the equilibrium of the inner surroundings inside
the recipients; for instance, constipation-induced GM dys-
biosis exacerbates the controlled T cell (Treg)/T helper
cell 17 and Treg17/effector Th 17 imbalanceand disrupts
cytokines, subsequently contributing to encephalomyelitis
[133]. Further studies should focus on identifying donors
with favorable particular microbial profiles and a typical
dysbiosis index, as well as accurately identifying the most
appropriate treatment dosage for microbiota transplanta-
tion. Lately, an intriguing study demonstrated that FMT
can primarily exercise its therapeutic ability by reverting
the major miRNA alterations associated with the disease
[134]. Additionally, FMT regulates the CNS by interacting
not merely with the gut but also with the Microbiota Gut
Brain Axis, which manifests as encephalomyelitis, depres-
sion and nervousnes. Further studies should concentrate on
the potential impacts of FMT on the regulation of encephalic
areas associated with metabolism so as to promote the appli-
cation of FMT for the management of metabolic ailments.
It is noteworthy that FMT exhibits an extensive number of
indications in experiments with animals that can serve as
motivation for researchers [135]. Therefore, the most crucial
challenge to be addressed is turning fundamental research
discoveries into therapeutic applications.

Fig. 3  Regulation of dietary
intake by gut-brain axis
Fig. 4  Therapeutic treatment
methods for metabolic disorders
Metabolic Therapy
The physiological manifestations of obesity, includ-
ing hypertension, hyperglycemia and hyperglycemia are
capable of being addressed medically. While altering
nutritional consumption, gastric elimination, and gastric
acid production, metabolic therapy has an impact on the
gut flora and the molecular makeup of cholic acid [136].
Gut redirection, vagus nerve control, and regulation of
gut hormones comprise a few of the conventional meta-
bolic therapy procedures. Consequently, modifications in
Neurochemical Research
the GM and physiological metabolites (including endo-
toxins and digestive acids) can be additional side effects
of metabolic therapy.
In a research investigation by De Jonge et al. 17 obese
individuals with T2DM had a noninvasive duodenojeju-
nostomy bypass [136]. The individuals' body weight and
haemoglobin content rose six months into the regimen.
The amount of predominant small intestinal microbes also
varied differently in the excrement. Proteobacteria, Lac-
tobacillus and Veillonella spp were more prevalent in the
faeces than usual [137]A reduction in weight following
Neurochemical Research
metabolic therapy can be driven by nutritional limits or
dietary constraints, a smaller gastrointestinal amount, or
alterations to the levels of gut peptides [137]. Following
metabolic treatment, one of the potential pathways for
shedding pounds could involve the restoration of variation
in the gut flora. Research involving a substantial number
of participants remains crucial on this aspect of the GM's
function in outcome post metabolic treatment in order to
corroborate these presumptions.
Future Directions and Challenges
It has become widely recognized how the integrity
between the GM and cognitive health interacts symbioti-
cally and is crucial for maintaining homeostasis. Animals
and humans both exhibit physiological and behavioral
alterations as a result of alterations in the typical gut flora.
A novel, potential treatment approach for stress-related
ailments involves the therapeutic modification of the GM,
especially in the context of inflammatory GI diseases like
IBS. There is an imperative to investigate the possible ben-
efits of prebiotics and probiotics towards the administra-
tion of metabolic diseases like T2DM and obesity. Probi-
otics have demonstrated favorable outcomes with regard
to the treatment of mood disorders such as depression
and anxiety. Furthermore, targeted research is necessary
to investigate how herbal therapies interact with GBA.
Prospective studies should concentrate extensively on the
colony-derived impacts of GM on the host as well as itself.
The variation among individuals in the microbiome
constitutes one of the main obstacles and challenges faced
by this particular field of study. Future studies must incor-
porate the most recent developments in monitoring the
fluctuations of the microbiome and the metabolic changes.
In order to examine the metabolic consequences of the
GBA while developing tailored therapies for metabolic
disorders, extensive mapping of the human intestinal
microbiome is vital.
Conclusion
In conclusion, there is a medical imperative for the crea-
tion of new and stronger medications for metabolic disor-
ders. Experts can confirm that there tends to be a recip-
rocal connection between GM and metabolic disorder by
employing animal models in fecal transference investiga-
tions. The rapid alterations in the genetic makeup of GM and
their consequences on human metabolism should be inte-
grated into future research. It may be advisable to differ-
entiate the sequence of these events in humans by imaging
the gut microbiome, monitoring regular shifts within the
microbiome, and correlating those alterations to variations
in illness. Further research into the metabolic impacts of
GM with regard to the CNS and the mechanisms governing
energy consumption and expenditure, as well as additional
identification of the microbiome of human beings, are neces-
sary. Consequently, the GM may shed light on the intricate
relationship between mental and physical health, possibly
leading to new therapeutics for metabolic disorders.
Acknowledgements We thank Department of Scientific Research and
Education, BioNome for helping us with Scientific Writing
Author Contribution All the authors have equally contributed to the
manuscript.
Funding The present study is funded by the Department of Scien-
tific Research and Education, BioNome. (Funding ID: DSRE/BNM/
SR/2023/A0108).
Data Availability There are no data associated with this study.
Declarations
Conflict of interest The authors declare no conflict of interest.
Ethical Approval Not Applicable.
Consent for Publication Not applicable.
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