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Chapter

Serotonin: The Link between Gut

Microbiome and Brain
Mushtaq Margoob, Shazia Kouser and Neelofer Jan

Abstract

Serotonin, as a neurotransmitter plays a key role in regulating mood, sleep,

appetite, and various physiological processes. Serotonin is closely linked to the
microbiome-gut-brain axis, which is a bidirectional communication between the
gut and the brain facilitated by the gut microbiome which consists of trillions of
microorganisms that inhabit the digestive tract. This connection is a growing area
of research and serotonin produced in the gut is being investigated for its potential
impact on human personality, mood, and overall health. Microbiome influences
serotonin production, serotonin precursor metabolism, serotonin reuptake, and
immune system modulation. A balanced microbiome is crucial for regulating homeo-
stasis and stress response and altered gut microbiota composition has been linked
to depression, anxiety, bipolar, schizophrenia, stress-related, and autism spectrum
disorders. Microbiome-based interventions might help to regulate the immune
response, neuroprotection, and neuroplasticity to reduce neuroinflammation and
thus prove crucial to modifying the course of major depressive, bipolar, and related
disorders where inflammation is evidenced to lead to the progression of illnesses.
Microbiome-based interventions such as probiotic supplementation influence the
production of neuroactive compounds and have the potential to bridge the treatment
gap for Parkinson’s disease, multiple sclerosis, and Alzheimer’s disease and might
prove to be a turning point for the treatment of obesity-associated systemic low-
level inflammation, whether psychotropic medication related or otherwise. The gut
microbiome offers a novel possibility to employ manipulation of the gut microbiota
as a non-invasive measure in health and disease, especially at a time when the clinical
field of forthcoming psychotropics looks exhausted.

Keywords: serotonin, gut-brain axis, microbiome, probiotics, stress

1. Introduction

Serotonin is a biologically active amine that serves the dual functions of neu-
rotransmitters and hormones by exerting a wide range of physiological and patho-
logical effects through nearly a dozen receptors classified into seven families [1].
Serotonin also known as enteramine or 5-hydroxytryptamine (5-HT) was successfully
extracted and purified by Rapport and colleagues in 1948 [2].

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Serotonin – Neurotransmitter and Hormone of Brain, Bowels and Blood

1.1 Serotonin in the brain

1.1.1 Anatomy

The distribution of serotonin in CNS consists of the following:

1. Raphe Nuclei (Latin, meaning “midline”): Serotonin within the CNS is almost
exclusively produced in neurons originating in the raphe nuclei which are col-
lections of neurons, with poorly defined cytoarchitectonic limits localized to the
periaqueductal gray, also known as central gray, and the surrounding reticular
formation in the brain.

2. Long and extensively branched axonal processes called projections. Serotonergic

neurons from the raphe nuclei project widely throughout the CNS and form clas-
sical chemical synapses as well as such synapses that contribute to the so-called
paracrine or volume transmission, and this has led to the suggestion that sero-
tonin exerts a major modulatory role throughout the CNS.

3. Multiple cortical and limbic target regions: The raphe nuclei provide projections
to the cortex, and many forebrain limbic structures such as the hippocampus
and medulla. Projections to the dorsal, intermediate, and ventral columns in the
spinal cord regulate pain perception at the level of the dorsal horn. Serotonergic
terminals in the cortex are less organized than the noradrenergic cortical projec-
tions, however, the two systems are co-localized in most limbic areas of the brain
and this might explain the major involvement of these transmitters in the affec-
tive disorders [3–5].

1.1.2 Neurochemistry

Serotonin is synthesized from the essential amino acid L-tryptophan (Trp) which
is primarily obtained from dietary sources [6]. After absorption about 85% of trypto-
phan is bound to plasmatic albumin protein and only 10–20% is unbound and able to
cross blood–brain barrier (BBB) and hence available for 5-HT synthesis in the brain.
Tryptophan released from plasma proteins becomes available for incorporation into
proteins [7] as this is the principal role of tryptophan in the human body [8]. The
second most prevalent metabolic pathway of tryptophan, the kynurenine pathway,
accounts for the catabolism of approximately 99% of ingested tryptophan not used
for protein synthesis and has importance in generating cellular energy in the form of
nicotinamide adenine dinucleotide (NAD). The kynurenine pathway produces other
pro and antioxidant molecules of neurobiological importance namely, kynurenine,
kynurenic acid, and quinolinic acid (QUIN) [9, 10]. Synthesis of B6 and B12 vita-
mins, required as co-factors for kynurine pathway enzymes are dependent on gut
microbiome activity [11]. The third tryptophan metabolic pathway that leads to the
synthesis of 5-HT in the periphery (e.g. in blood platelets and the enterochromaffin
cells of the gastrointestinal tract) or in the nerve endings in brain is relatively minor.
It is estimated that 95% of mammalian serotonin is found within the gastrointestinal
tract and while 3% of dietary tryptophan is used for serotonin synthesis throughout
the body only 1% of dietary tryptophan is used for the synthesis of this broad-impact
neurotransmitter and neuromodulator in the brain. Melatonin and tryptamine
are other by-products of the tryptophan/serotonin pathway [12]. In serotonin
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synthesis from tryptophan, the first step is catalyzed by the enzyme tryptophan
hydroxylase which exists in two isoforms tryptophan hydroxylase 1 (Tph1) and
tryptophan hydroxylase 2 (Tph 2) and convert tryptophan to 5-hydroxytryptophan.
5-Hydroxytryptophan is then converted by the aromatic amino acid decarboxylase
to 5-hydroxytryptamine [13]. After synthesis serotonin (5HT) is transported into syn-
aptic vesicles using vesicular monoamine transporter 2 (VMAT2) to protect serotonin
from enzymatic breakdown. Once released from the presynaptic terminal serotonin
acts on various presynaptic and postsynaptic receptors which are also targets of
numerous drugs. The action of serotonin on its receptors at the synapses is terminated
mainly by an active reuptake process mediated by the serotonin transporter (SERT), a
sodium and chloride-dependent neurotransmitter transporter [14, 15].

1.2 Role of serotonin in mood regulation and emotional well-being

Speculations about the role of monoamines in affective states began with the
serendipitous discovery in the late 1950s that members of two structurally unrelated
classes of compounds monoamine oxidase inhibitors (MOAIs) and tricyclic anti-
depressants (TCAs) were effective in treating severe depression [16]. In the most
basic form, Monoamine Theories postulate that depression is related to decreased
levels of centrally available monoamines, typically either the catecholamine, nor-
adrenaline (norepinephrine in the United States), or the indoleamine, serotonin
[17]. Monoamine theories later evolved into monoamine receptor theories, which
associate depression with lesions at the level of monoamine receptors [18]. With the
advancement in neurosciences, even receptor theories have come under scrutiny, and
contemporary literature has expanded these theories to the non-mutually exclusive
neurotrophic and neurogenesis hypotheses which are closely related to a third entity
called neurotrophic hypothesis. These hypotheses were proposed as the monoamine
theory of depression was too simplistic to explain several conundrums which evi-
denced that monoamine deficiency cannot be the sole cause of depression [19]. The
Neuroplasticity hypothesis postulates that depression may result from environmental
contingencies like adverse life experiences that cause neuronal architectural changes
and resultant defects in brain processing, the pathophysiology of which is strongly
linked to impairments in serotonin (5-HT) neurotransmission [20]. Neurogenesis
research suggests that very sophisticated transport systems can allow freshly pro-
duced neurons (from lateral subventricular zone (SVZ) and the dentate gyrus (DG)
of the hippocampus and the olfactory bulb), called “neuroblasts,” to be migrated
long distances across the brain to help regenerate damaged areas or regions which are
experiencing neural dilapidation and thus neurogenesis is thought to be important
for maintaining brain health. Antidepressants might improve neurogenesis in the
hippocampus through activation of the 5-HT1A receptor [21, 22]. The neurotrophic
hypothesis of depression posits that major depressive disorder (MDD) is caused
partly by decreases in neurotrophic factors such as brain-derived neurotrophic factor
(BDNF) and their restoration is critical for the therapeutic efficacy of antidepressant
treatment [23]. Emotional and cognitive deficits in bipolar and related mood disor-
ders are linked to changes in neuroplasticity, cell resilience, and connectivity with
BDNF as an important contributor to the neuroplasticity changes described among
bipolar disorder patients. Thus, evidence from differential lines of research converges
to serotonin signaling and 5-HT receptors being involved in regulating the levels of
both neurotrophic factors and adult hippocampal neurogenesis thereby mediating
a pivotal role in neuroplasticity in both normal and neuropsychiatric conditions
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Serotonin – Neurotransmitter and Hormone of Brain, Bowels and Blood

[24–26]. Further, the neuroplasticity theory is not considered exclusive for MDD,
and the mechanisms of alterations in neuroplasticity accounting for the significantly
different symptomatology of schizophrenia [27] and bipolar disorders [28] are being
investigated.

1.3 Other roles of serotonin

1.3.1 Cognition

The role of serotonin in human cognition has been investigated, especially in the
context of the growing notion of memory deficits in neuropsychiatric disorders like
posttraumatic stress disorder, schizophrenia, depression, and Parkinson’s disease
[29]. 5-HT6 antagonists are expected to be effective against learning impairment from
anticholinergic and antiglutamatergic models of dementia. It is supposed that the
procognitive activity of some marketed antidepressants (Vortioxetine) and antipsy-
chotics (Lurasidone) is caused by potent 5-HT7R affinity, and both 5-HT6 and 5-HT7
receptors represent interesting targets in the search for innovative therapies of AD
[30]. Evidence is mounting for the role of 5-HT in human cognition and normalizing
5-HT activity in depression and Alzheimer’s disease (AD) may have specific beneficial
effects on cognition, independent of a general relief of mood symptoms, however, as
of now, data is not sufficient to comment on emergent use of 5-HT targeting drugs as
potential cognition enhancers [31].

1.3.2 Appetite

Brainstem-derived serotonin influences cognitive functions including eating

behaviors and regulates homeostatic functions of bone remodeling, appetite, and
energy expenditure. Gut-derived serotonin, on the other hand, plays a critical role
in feeding activity. Serotonin thus acts as a hormone when made in the gut and a
neurotransmitter when made in the brain [32, 33]. Although social and psychological
aspects of eating are powerful influences that are independent of or only partially
dependent on the physiologic control mechanisms, at the receptor level there is
evidence that the 5-HT1B and 5-HT2C receptors are involved in mediating the effects
of serotonergic drugs on food intake. Appetite suppression appears to be associated
with agonist action at 5-HT2C receptors in the central nervous system. 5-HT2C
agonist, lorcaserin, is approved by the FDA for use as a weight-loss medication in
monotherapy. While no available pharmacologic therapy has succeeded in maintain-
ing a weight loss of over 10% for 1 year, bariatric (weight-reducing) surgery readily
achieves a sustained weight loss of 10–40%, and surgery that bypasses the stomach
and upper small intestine rapidly reverses some aspects of the metabolic syndrome.
Gastrointestinal flora also influence energy expenditure, and research suggests that
altering the microbiome can lead to weight gain or loss [1, 34].

1.3.3 Sleep

Serotonin along with fast-acting non-monoaminergic neurotransmitters (gluta-

mate and GABA) and other monoaminergic neurotransmitters plays a crucial role in
regulating the sleep–wake cycle. Earlier it was thought that serotonin might help to
produce NREM and possibly REM sleep, however, more recent work indicates that
serotonin generally promotes wakefulness and suppresses REM sleep. The role of
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serotonin in sleep is, however, not straightforward. On one hand, serotonin inhibits
the wake-promoting cholinergic neurons and serves as a precursor of melatonin in the
pineal gland where 5-HT is Ο-methylated to form melatonin. In humans, melatonin
plays a significant role in both inducing and maintaining nocturnal sleep and drives
the circadian rhythm which in turn regulates the sleep–wake cycle, and endocrine,
immune and neurotransmitter rhythmicity [35]. On the other hand, the firing rates
of dorsal raphe neurons and extracellular 5-HT levels are highest during wakefulness,
much lower during NREM sleep, and lowest during REM sleep. This wake-promoting
role of serotonin is further evidenced by agonists of the 5-HT 1A, 5-HT 1B, 5-HT2,
or 5-HT3 receptors that increase wakefulness and 5-HT2 receptor blockers such as
ritanserin or agomelatine that promote NREM sleep [36].

1.3.4 Pain

Advances in basic sciences, clinical research and now neuroimaging have estab-
lished that central sensitization and alterations in neuroplasticity induced by the
enhancement of descending pain facilitation and/or the impairment of descending
pain inhibition underlie many chronic pain conditions. The descending serotonergic
neurons in the raphe nuclei target receptors along the descending pain circuits and
exert either pro- or antinociceptive effects, thus, serotonin has a definite role in the
pathogenesis of chronic pain conditions like chronic primary pain (CPP), inflamma-
tory bowel disease (IBD), Fibromyalgia syndrome (FMS), etc. [37]. Antidepressants
like TCAs, SNRIs, and SSRIs influence the descending pain modulation system by
increasing 5-HT at the synaptic junction [5, 38].

1.3.5 Neurological diseases

Migraine, epilepsy, Parkinson’s disease (PD), multiple sclerosis (MS), ALS, and
neuropsychiatric disorders (ADHD, ASD) are connected to abnormal 5-HT synthesis
and metabolism as the efficiency of 5-HT metabolism is changed in neurodegenera-
tion. Patients with amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS)
present with reduced plasma and CSF levels of tryptophan and subsequently a
decreased 5-HT synthesis. In MS, 5-HT synthesis is decreased because of the over-
activation of the kynurenine pathway, which drives Tryptophan away from 5-HT
synthesis [39]. Migraine is caused by a decreased level of platelet serotonin and its
metabolite N-acetylserotonin (NAS) that activate trigeminovascular system (TGVS)
and lead to cortical spreading depression (CSD) during an acute attack of migraine.
Triptans, acting via 5-HT 1B receptor and serotonin activity at the 5-HT1F receptor on
neuronal synapses inhibiting the release of calcitonin gene-related peptide (CGRP)
are disease-specific treatments of migraine. It has long been known that serotonin
inhibits epileptic activity and because of its crucial role in influencing seizures,
regulating sleep and wakefulness, arousal, circadian rhythms, breathing, and cardiac
activity, serotonin (5-HT) has been implicated in the pathophysiology of sudden
unexpected death in epilepsy (SUDEP) [40]. Apart from other actions, CBZ and
VPA release serotonin and LTG inhibits serotonin uptake, however, only a few AEDs,
such as the recently approved fenfluramine, act via 5-HT receptors [41]. Progressive
dopaminergic denervation is the cardinal pathology in Parkinson’s disease, however,
several lines of evidence suggest that a progressive and non-linear loss of serotonergic
terminals which is not related to disease duration, disability or dopamine replacement
therapy takes place in Parkinson’s disease though at a slower rate. Human PET studies
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Serotonin – Neurotransmitter and Hormone of Brain, Bowels and Blood

indicate that striatal serotonergic terminals contribute to Levodopa-induced dyski-

nesias (LIDs) via aberrant processing wherein serotonergic neurons take up, convert
exogenous Levodopa into dopamine, and release dopamine as a false neurotransmitter
in the denervated striatum of PD patients with LIDs. This study also speculates the
development of selective serotonin receptor type 1A agonists for use as antidyskinetic
agents in PD [42]. In clinical studies, the nonselective 5-HT 1A agonist buspirone
reduced LID without worsening parkinsonian disability. 5-HT 2C receptor antagonism
is a potential mechanism whereby clozapine and quetiapine can reduce LID [42, 43].
Abnormalities in SERT and MAO-A activity in various brain regions have been found
to be associated with impulsivity and aggressive tendencies in ADHD. 5-HT deficiency
leads to a failure of 5-HT-mediated inhibition of aggressive behavior in adults as well
as children and decreased levels of 5-HT and its metabolite 5-HIAA, in the blood,
urine, and CSF in individuals with ADHD compared with healthy controls. Although
precise pathomechanism of ASD has not been elucidated, hyperserotonemia is present
in approximately 30% of patients of ASD. One of the consequences of hyperserotone-
mia is increased catabolism of 5-HT [39].

2. Serotonin in the gut

Nearly 95% of the body’s content of serotonin is found in GIT and only 5% is found
in the brain. Within the gut, about 90% of serotonin is in EC cells and about 10% is
found in enteric neurons, pancreatic cells and mast cells. Enterochromaffin (EC) cells are
excitable, serotonergic neuroendocrine cells located throughout the length of the lining
of the gastrointestinal tract. EC cells synthesize 5-HT, in the presence of some cofac-
tors, such as vitamin B6, vitamin B3, and magnesium, from its precursor L-tryptophan
in a reaction catalyzed by the enzyme tryptophan hydroxylase, which exists in two
isoforms (Tph1 and Tph2). Tph1 is mainly present in EC whereas Tph2 is found in CNS
and enteric neurons [44]. EC cells release 5-HT in a regulated manner in response to
various mechanical and chemical stimuli. 5-HT thus released from EC cells reaches the
blood, surrounding tissues, and gut lumen. Once released, 5-HT is transported into
surrounding epithelial cells and platelets by the serotonin reuptake transporter (SERT)
and degraded to 5-hydroxyindoleacetic acid (5-HIAA). Platelets are a major source of
peripheral 5-HT as they store the 5-HT synthesized by EC cells in the gut and are always
present in the circulation. Five (5-HTR1, 5-HTR2, 5-HTR3, 5-HTR4, and 5-HTR7) of the
seven 5-HT receptor (5-HTR) families are expressed in the gut smooth muscle, enteric
neurons, enterocytes, and immune cells through which serotonin mediates various
secretomotor and sensory functions such as nausea, vomiting, intestinal fluid and mucus
secretion and peristaltic movement [45].

2.1 Functions of serotonin in the gastrointestinal tract

1. Serotonin as a regulator of gut motility: 5-HT plays a crucial role in the generation
of peristaltic reflexes, segmentation, and mucosal stimulation in response to food
intake, under normal circumstances and in disorders of GI tract associated with the
alteration of motility and sensation like the irritable bowel syndrome (IBS) [44].

2. Serotonin in fluid and mucus secretion: 5-HT inhibits gastric acidity by increas-
ing the gastric mucus and fluid secretion. Mucus in GIT acts as a physical barrier
for microorganisms, diffusion of toxins, and as an antioxidant [46].
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Serotonin: The Link between Gut Microbiome and Brain
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3. Pain and anxiety: EC cell activation produces persistent visceral hypersensitivity

in response to gut distension, even in the absence of inflammation.

4. Serotonin in immune cell function: Serotonin receptors are expressed by nearly

all innate immune cells, such as the Langerhans cells or the immature dendrite
cells (DCs) in the skin and other epithelial tissues lining the nose, lungs, stomach
and intestine, monocytes, mast cells and eosinophils. 5-HT, along with other
platelet-derived factors, plays a crucial role in the recruitment of these cells at
the site of acute inflammation [47].

5. Serotonin in inflammation: Serotonin evokes divergent pro as well as anti-

inflammatory actions and while 5-HTR4-mediated anti-inflammatory action
predominates in the basal or normal conditions, 5-HTR7-mediated pro-inflam-
matory signals predominate under pathological conditions. Inflammatory bowel
diseases (IBD) viz., Crohn’s disease (CD) and ulcerative colitis (UC) are believed
to result from an abnormal response to self-antigens or the gut resident micro-
biota and are characterized by activation of both innate and adaptive immune
systems in response to enhanced cytokine production in GIT [48].

6. Angiogenesis: 5-HT release from platelets stimulates angiogenesis in many physi-

ological processes, such as organ development, reproduction, wound healing
and pathological conditions like IBD, diabetic retinopathy, rheumatoid arthritis,
age-related macular degeneration, and tumor growth and metastasis [49].

3. The gut microbiome

Conventionally brain has been considered sealed from microbial influence unless
infection occurs, however, evidence in favor of gut microbiota interplays with differ-
ent systems ultimately impacting the brain has accumulated over the past few decades
to the extent that the gut microbiome has earned the name “second brain” from some
authors.

3.1 Composition and diversity of gut microbiome

The term microbiome pertains to the community of microorganisms, their

structure, activity, metabolites and mobile genetic elements while microbiota is a
collection of microbial communities associated with a habitat [11]. This collection
of bacteria, viruses, fungi, protozoans, and archaea found in an individual consti-
tutes about 1–3% of total human body mass. Majority of the human microbiome is
comprised of bacteria, about 100 trillion bacteria from 500 to 1000 different species,
with varying diversity adding over eight million genes to the human genome. The
microbiota colonize predominantly the human intestine and to a lesser extent the
airways and the skin surface. A simplified taxonomic composition of gut microbiota
is presented in Table 1. Most of these microorganisms belong to the phyla Firmicutes
and Bacteroidetes [51].

3.2 Factors influencing the composition of the microbiome

Gut microbiome is a dynamic with many variables influencing its composition.

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Serotonin – Neurotransmitter and Hormone of Brain, Bowels and Blood

Phylum Examples

1. Actinobacteria Bifidobacterum longum

Bifidobacterium bifidum

2. Firmicutes Faecalibacteruim prausnitzii

Clostridium spp.
Roseburia intestinalis
Runinococcus feacis
Dialister invisus
Lactobacillus renteri
Enterococcus faecium
Staphylococcus leei

3. Bacteriodetes Bacteriodes fragilis

Bacteriodes vulgaris
Bacteriodes uniformis
Parabacteriodes diastaoms
Alistipes finegoldii
Prevotella spp.

4. Proteobacteria Escherichia coli

Shigella flexineria
Desulforibrio intestinalis
Bilophila
Wadsworthia

5. Fusobacteria H. Pylori
Fusobacterium nucleatum

6. Verrucomicrobia Akkermansia muciniphila

Table 1.
Simplified taxonomic classification of gut microbial composition [50].

3.2.1 Genetics

Twin studies have revealed similar microbiome composition in monozygotic twins

and this similarity has been seen to be more in monozygotic twins and dizygotic twins
than in other family members [52]. Genetic animal models of 5-HTT deficiency have
revealed the presence of altered microbial composition in 5HTT knockout mice such
as they had predominance of pathobionts [53].

3.2.2 Early life factors

Microbes colonize the various sites from the first days of life, reach high numbers
immediately after birth, and gradually evolve and diversify with the growth of the
individual to outnumber somatic cells by a number of ten. Microbiota are shaped in
the first few years of life by gut maturation developing from enterotypes, which are
functionally harmonious clusters of bacteria that characterize individuals and are
regrouped by functions. The first 2 years of life including the intrauterine period
seem to represent the most critical time for microbiome modulation. Other factors
modulating this composition of microbiota in early life are birth gestational age, type
of delivery, methods of milk feeding, weaning period, maternal diet/weight, pro and
prebiotic use, early antibiotic exposure, timing and type of complementary feeding,
lifestyle, dietary and cultural habits [54–56].
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3.2.3 Gut permeability and inflammation

Gut epithelium serves a protective and structural role in the human body and
when this barrier is compromised, the so-called “leaky gut” is associated with patho-
logical conditions that activate gut pain sensory pathways and dysregulate the enteric
nervous system. The stress of varying types can impact the developmental trajectory
of intestinal barrier by causing significant perturbations in gut permeability as well as
gut microbiome [57, 58] and maternal separation has been shown to cause such a shift
in the microbial composition in a drastic way [59, 60].

3.2.4 Body mass index (BMI) classes and exercise frequency

Gut microbiota variations are correlated with obesity, anorexia nervosa and
exercise as a form of environmental enrichment has been shown to impact the gut
microbiome in a positive way [61, 62].

3.2.5 Aging

Microbial changes that occur with Aging have been grouped into two categories; those
associated with healthy aging and pathobionts associated with ill health in aging [63].

3.3 Gut-brain axis

It is a complex, firmly established, bidirectional network that connects the micro-

biota, enteric and central nervous system. The microbiome gut-brain axis (MGBA)
can be modulated by endocrine, neural and immune pathways in a bottom-up or top-
down approach with multiple feedback loops regulating this network. In top-down
approach, the brain uses these mechanisms to influence the composition of micro-
biota in gut. In the bottom-up approach microbiome signals brain through immune
regulation by the production of cytokines and through production of neurotransmit-
ters and neuroactive metabolites like short-chain fatty acids (SCFAs) [11, 64].

3.4 Pathways of the gut-brain axis

3.4.1 Neurologic pathway

The vagus nerve tonically transmits information from the viscera to the brain and
vice versa and is considered to be the fastest and most direct way for the microbiota to
influence the brain. Specific bacteria within the gut microbiota utilize the vagus nerve
to communicate with the brain to alter certain neurocircuits by affecting primary
afferent neuronal excitability. Ablation of gut-related vagal communication between
lower GI tract and brain, as evidenced by animal studies and surgical procedures like
gastrectomies, resulting in changes in adult neurogenesis, stress reactivity, cognition,
and increased occurrences of psychiatric-related disorders has been recognized for
long [65, 66].

3.4.2 Endocrine pathway

The hypothalamus pituitary adrenal (HPA) axis regulates cortisol secretion in

response to stress by directly affecting immune cells and release of cytokines systemi-
cally as well as locally in the gut. Cortisol affects gut permeability, its barrier function
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Serotonin – Neurotransmitter and Hormone of Brain, Bowels and Blood

as well as composition of gut microbiota. Gut microbiome, in a bottom-up fashion,

influences the release of cytokines and other immune mediators like interferon-
gamma. Serotonin plays a crucial role in recruitment of innate immune cells in
response to this cytokine release during time of dysbiosis. Gut microbiome also
influences the release of neuropeptides like galanin, leptin and neuropeptide Y (NPY)
from enteroendocrine cells which reach the systemic circulation and bind recep-
tors on immune cells and vagus nerve terminals thereby enabling indirect gut-brain
communication [67–69]. Another mechanism of microbiome-gut-brain crosstalk is
through tryptophan and its metabolites such as 5-hydroxyindoleacetic acid (5-HIAA).
The gut microbiota can alter concentrations of kynurine and disruption of this
metabolic pathway has been linked to both GI and brain disorders.

3.4.3 Metabolic/humoral pathway

Bacterial metabolites like short-chain fatty acids [SCFAs] and lipopolysaccharides,

which are produced by their fermentation of dietary carbohydrates are important
humoral influencers. These metabolites affect the nutrition of the enterocytes,
possess hormone-like activity, stimulate the sympathetic nerves of gut and also have
immunomodulatory properties. SCFAs also regulate microglial homeostasis which in
turn affects brain development, brain tissue homeostasis, and behavior [70].

3.5 Impact of the gut microbiota on serotonin levels in gut and brain

Serotonin is directly synthesized by commensal bacteria from the colonic luminal

tryptophan and serotonin biosynthesis is promoted in the colonic ECs by spore-forming
bacteria. Gut microbiota promotes enteric 5-HT production through SCFAs as well as
phenolic and indolic compounds derived from microbes. Microbiota affects the central
serotonin levels through many pathways. It influences availability of the peripheral
tryptophan by affecting the metabolism of the gut luminal tryptophan thereby alter-
ing the central tryptophan levels and hence the central serotonin levels. The microbial
metabolites e.g., SCFAs, especially butyrate have been reported to increase brain sero-
tonin concentration. In addition, inflammatory stimuli, such as LPS, the major compo-
nents of the outer membrane of Gram-negative bacteria, have been postulated to affect
the kynurenine pathway thereby diverting tryptophan away from serotonin synthesis.
In gut dysbiosis, as demonstrated by antibiotic studies, central levels of serotonin and
its precursor tryptophan has been seen to be reduced and these are posited to be due to
increased serotonin metabolism as reflected by increased SERT and MAO expression
in the hypothalami of piglets. The microbiome also regulates serotonin transporter
(SERT) expression by gut bacteria via posttranslational and transcriptional mechanisms,
alterations in SERT surface levels, and epigenetic or immune mechanisms. Gut microbi-
ome metabolites like SCFAs also affect serotonin signaling by regulating 5-HT receptor
expression by increasing the mRNA expression of 5-HTR1A, 2B, and 5-HT7. Bacterial
extracellular vesicles (EVs) that are hypothesized to permeate the blood–brain barrier
(BBB) cause an increase in colonic and hippocampal serotonin levels [71].

4. Influence of microbiome on brain function and behavior

Bacteria within the gut microbiome play crucial roles in the maintenance of
gut epithelium integrity, digestion, metabolism, synthesis of beneficial substances

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including vitamins, combating infection and inflammation and resisting coloniza-

tion by pathogenic bacteria during conditions of good health [72]. Gut microbiome
dysbiosis is being implicated in a myriad of conditions like stress, obesity, and inflam-
mation, however, elucidating the effects of the microbiome on behavior has been
especially fascinating. Such research highlights the importance of the complexity and
diversity of gut microbiome in both health and disease and underscores the need for
further exploration.

4.1 Human personality

Investigation of microbiome composition and diversity with respect to human

personality has analyzed bacterial genera linked to human behavior and has revealed
that sociability is associated with higher diversity and stress and anxiety are associ-
ated with reduced diversity. These results add a new dimension to the evidence that
gut microbiome can influence the central nervous system in humans with effects on
behavior and stresses the ways in which modern-day living with fewer social interac-
tions, less time spent with nature, processed diets, and oversanitized environments
might be contributing to gut dysbiosis [73].

4.2 Cognition

Microbiome mediates the plasticity of cognitive traits by altering protein expres-

sion, adult hippocampal neurogenesis and performance on cognitive tasks [74].

4.3 Physical activity

Evidence suggests that aerobic exercise improves the diversity and abundance
of genera from the Firmicutes phylum, which may be the link between the positive
effects of exercise on the gut and brain [75].

4.4 Autism spectrum disorder (ASD)

Numerous studies, stimulated by frequent gastrointestinal complaints and

immune dysregulation in ASD, have suggested microbial dysbiosis in clinical popula-
tions of ASD. Increased blood levels of lipopolysaccharides with a corresponding
increase in peripheral IL-6 levels have been found in ASD patients. Further, increased
intestinal permeability as reported in ASD subjects and their first-degree relatives
is posited to be a pathogenetic factor rather than a consequence of autistic behavior.
Probiotic supplementation, oral vancomycin treatment and a modified fecal micro-
biome transfer have been demonstrated to have therapeutic potential in children with
ASD [57].

4.5 Major depressive disorder

Serotonin in CNS is synthesized from tryptophan transported from blood

and hence, tryptophan availability is critical for serotonin synthesis in brain [76].
Normal gut microbiota buffer extreme fluctuations in serotonin levels by making
the serotonergic system less sensitive to variations in its precursor. Gut serotonin,
which is under the control of gut microbiota, through neural routes communicates

11
Serotonin – Neurotransmitter and Hormone of Brain, Bowels and Blood

to the brainstem neurons by stimulating serotonin receptors at the terminals of vagal

afferents [77]. It has been shown that vagotomy abolishes the antidepressant effects
of SSRIs thus implicating the role of peripheral serotonin and vagus nerve stimulation
in the regulation of depressive behavior [78] and leading to the postulation that gut
microbiome through stimulation of the vagus nerve influences depressive behavior
[79]. A few case–control studies have reported differences in the gut microbiome
between depressed patients, and healthy controls and preliminary evidence suggests
that probiotics might prove to be beneficial in patients with major depressive disorder
and in healthy populations as well [80].

4.6 Bipolar disorder

Extensive research has suggested an abnormal inflammatory response in bipolar

disorder and evidence is emerging for alterations in gut microbial composition of
patients with bipolar disorder suggesting that gut microbial dysbiosis contributes to
disease progression and cognitive impairment in bipolar disorder [81]. Gut microbial
profiling in bipolar disorder patients revealed some correlation between certain
genera and sleep and stress in these patients [82].

4.7 Schizophrenia

High rates of comorbidity reported in schizophrenia with autoimmune and

gastrointestinal conditions, systemic low-level inflammation, and increased
intestinal permeability suggest the involvement of gut microbiome. Studies
that need further investigation, have identified reduced phylum Proteobacteria
and Gammaproteobacteria as class-level biomarkers of schizophrenia [57].
Antipsychotic medications have been shown to alter gut microbiome and this
alteration is considered to play a crucial role in adverse effects like metabolic syn-
drome resulting from antipsychotic medication use [83]. A positive correlation was
seen between Lactobacillus bacterial group members and the severity of psychotic
symptoms in a study in which 70% of subjects showed remission on antipsychotic
treatment whereas only 28% subjects with “abnormal” microbiota experienced
remission indicating thereby that gut microbiome may moderate treatment
response in schizophrenia. The use of probiotics improved gastrointestinal distur-
bance in psychosis although improvement in symptoms of psychosis has not shown
promising results [57].

4.8 Attention deficit hyperactivity disorder (ADHD)

Altered and reduced diversity of gut microbiome in children with ADHD has been
reported in studies limited by sample size and concomitant methylphenidate intake
[84, 85].

4.9 Anxiety and related disorders

Anxiety and related disorders viz., obsessive-compulsive disorder (OCD) and

pediatric autoimmune neuropsychiatric disorder associated with streptococcal infec-
tion (PANDAS) are other areas wherein indirect evidence suggests that gut microbi-
ome has a potential causative role and therapeutic potential [57].
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5. Recent advances and potential therapeutic targets

Some of the key technologies used to investigate the complex interactions between
the gut microbiome and the central nervous system include:

5.1 Multi-omics

Metagenomic sequencing allows researchers to analyze the genetic material of

the entire microbial community in the gut, providing insights into the diversity and
functional potential of the microbiome. Metatranscriptomics technology focuses
on the RNA transcripts of the gut microbiome, revealing which genes are actively
expressed and providing information on microbial functions. Metabolomics is used to
study the small molecules produced by gut microbes, such as short-chain fatty acids
and neurotransmitters, which can influence brain function. Multi-omics integration
combining data from genomics, transcriptomics, and metabolomics can provide
a comprehensive understanding of the microbiome–gut–brain axis. In microbiota
profiling, 16S rRNA sequencing and shotgun metagenomic sequencing are used to
identify and characterize the composition of microbial communities in the gut [86].

5.2 Functional neuroimaging

Techniques like fMRI (functional magnetic resonance imaging) can be employed

to observe changes in brain activity in response to gut microbiome alterations.

5.3 Animal models

Animal studies, including germ-free and gnotobiotic models, are used to investi-
gate the effects of specific microbial communities on behavior and brain function.

5.4 Germ-free studies

Germ-free animals are the “microbiota free” control group for the animals whose
gut is conventionally colonized. They are maintained in gnobiotic units which are
sterile, eliminating the chances of postnatal colonization of their GI tracts [87].
Germ-free animals are studied for social, stereotypical, and anxiety-like behaviors
on exposure to novel and aversive environments (elevated plus maze, light/dark box,
open field), and non-spatial and working memory tasks (novel object recognition
and spontaneous alternation assessed in the T-maze) in labs. Germ-free mice have
been shown to have lower levels of molecular targets like the N-methyl-daspartate
receptors (NMDARs) in the hippocampus, or amygdala and decreased levels of brain-
derived neurotrophic factor (BDNF). Apart from other findings, the results have been
seen to be dependent on the time of colonization, be it in adolescence or adulthood,
positing that there is a critical time period that is neurodevelopmentally sensitive to
dysbiosis [88].

5.5 Antibiotics

Both in-vitro and in-vivo experiments [89] have documented the perturbation
of gut microbiota with antibiotic treatment that leads to an increase in sensitivity to
visceral pain, increase in gut motility and altered BDNF levels in the brain.
13
Serotonin – Neurotransmitter and Hormone of Brain, Bowels and Blood

5.6 Probiotics and prebiotics

Probiotics are defined as live organisms which when administered in adequate

amounts confer a health benefit on the host. Prebiotics are non-digestible food
ingredients that selectively stimulate the growth of Lactobacilli and Bifidobacteria
in the gut, hence indirectly affecting the brain function. The two main genera
which are used as probiotics are Lactobacillus and Bifidobacterium. Several pre-
and probiotic studies have demonstrated their beneficial effects on behavior of the
host and offer novel therapeutic potential for treating mood and anxiety disorders
[90]. Caution is warranted when translating and generalizing the evidence that
certain pre- and/or probiotic strains are able to modulate brain function and
behavior.

5.7 Microbiome manipulation

Researchers can manipulate the gut microbiome using techniques such as fecal
microbiota transplantation (FMT) to assess its impact on brain health and behav-
ior [91].

5.8 Brain-gut communication assays

These assays involve measuring biomarkers like cytokines and neuropeptides to

understand how the gut and brain communicate. Finally, researchers may employ
psychological tests and behavioral observations to assess the impact of the gut micro-
biome on mood, cognition, and other brain-related functions [92].

5.9 Potential therapeutic strategies targeting the microbiome gut-brain axis

Efforts are being put to target the vast ecosystem of the gut microbiome for a role
in neuropsychiatric disorders.

5.9.1 Psychobiotic

Dinan et al. coined the term “psychobiotic” and defined it as “live organism that,
when ingested in adequate amounts, produces a health benefit in patients suffering
from psychiatric illness.” This definition has been expanded since then to include “any
exogenous influence whose effect on the brain is bacterially-mediated.” Thus, psy-
chobiotics include a range of substances that have the potential to affect microbiota–
gut–brain axis signaling, including probiotics, prebiotics, symbiotics, and postbiotics.
These substances can be delivered through supplements, functional foods, and
improvements to dietary intake. Some microbial therapeutics have been engineered
to sense a range of biomarkers and respond accordingly and are currently in clinical
trials for the treatment of diabetes, inflammation, and cancers [71].

5.9.2 Probiotics

There is preliminary evidence from human studies wherein Probiotics have

demonstrated their efficacy in ameliorating anxiety and depression states [93]. These
findings have been supported by systematic reviews of therapeutic potential of
probiotics in MDD [94].
14
Serotonin: The Link between Gut Microbiome and Brain
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5.9.3 Prebiotics

Prebiotics consist of fibers such as resistant starch, fructo-oligosaccharides, galacto-

oligosaccharides (GOSs), and inulin which are unabsorbed in the small intestine and
are selectively fermented by gut microbes. Prebiotics are also found in human milk. One
study which was done in a cohort of patients suffering from IBS demonstrated a signifi-
cant decrease in anxiety scores with prebiotic administration [95].

5.9.4 Synbiotics

Synbiotics are a combination of both pre- and probiotics, whereby the prebiotics
improves the viability of the probiotic, providing a source of fermentable fiber as well
as acting as a general prebiotic. In a recent study, a symbiotic comprising galacto-
oligosaccharides (GOS) and a dual-strain probiotic (Lactobacillus helveticus and B.
longum) was successfully shown to decrease scores on depression scale and positively
impacted tryptophan signaling in mild to moderate MDD [96].

5.9.5 Postbiotics

Postbiotics are nonviable entities that are byproducts of bacterial fermentation

and include bioactive metabolites such as SCFAs. The use of gut peptides directly as
an intervention in gut–brain axis may not be feasible due to technical issues, however,
targeting specific microbiota in order to modulate specific gut peptides may be a
useful psychobiotic therapy. Para probiotics, or nonviable probiotics, e.g., heat-killed
probiotics, can also be included in the category of postbiotics in that they contain
structural components that may exert biological activity in the host. In preclinical
studies, several heat-killed probiotics have described antidepressant and anxiolytic
effects, with heat-killed Lactobacillus paracasei [97].

5.9.6 Fermented foods and diet

Fermented foods contain probiotics, prebiotics, and bacterially derived bioac-

tives. Two of the most common strains used in the fermentation process include
Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus. In dairy
products, lactic acid-producing Bifido-bacterium and Lactobacillus are commonly
used. Studies using fermented food interventions in humans are limited, however,
there is some evidence showing ameliorations in anxiety and mood scores. Fermented
milk drinks have been found to result in positive benefits in emotional processing.
Fermented milk containing Lactobacillus casei strain Shirota prevents the onset of
physical symptoms in medical students under academic stress by modulating the gut-
brain interaction [98]. Mediterranean diets have well-known mental health benefits.
One large-cohort, cross-sectional study in women found healthier dietary patterns
to be associated with better general health scores and decreased incidence of anxiety
and depression outcomes [99].

6. Ethical considerations and challenges

As with any medical intervention, ethical concerns arise regarding the use
of microbiome-based interventions for mental health and neurology. Balancing
15
Serotonin – Neurotransmitter and Hormone of Brain, Bowels and Blood

potential benefits with safety and long-term effects is crucial. It is important to

note that while there is promising research in this area, it is still relatively new and
complex. More studies are needed to fully understand the mechanisms at play and to
establish the effectiveness and safety of microbiome-based interventions for mental
health and neurology.
Ethical considerations in microbiome-based treatments include issues related to
informed consent, privacy and data security, equitable access, potential conflicts of
interest, and the long-term effects of manipulating the microbiome. These treatments
involve complex interactions with individual health and the broader ecosystem,
requiring careful consideration of both short-term benefits and potential unintended
consequences. One of the challenges in this field is the identification of neuroactive
compounds originating from the host rather than gut microbiome due to complex
communications between these two. Many of the dietary benefits on the microbiome
and brain health have been attributed to anti-inflammatory effects mediated by
the microbial metabolites of dietary fiber and polyphenols. Overall, it is clear that
although animal studies have shown much promise, more progress is necessary before
these findings can be translated for diagnostic and therapeutic benefit in patient
populations.

Author details

Mushtaq Margoob1,2*, Shazia Kouser2 and Neelofer Jan2

1 Advanced Institute for Management of Stress and Lifestyle-related Problems

(AIMS), Srinagar, Kashmir, India

2 Department of Psychiatry, Institute of Mental Health and Neurosciences-Kashmir,

Government Medical College, Srinagar, Kashmir, India

*Address all correspondence to: mushtaqmargoob2@[Link]

© 2024 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of
the Creative Commons Attribution License ([Link]
which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.
16
Serotonin: The Link between Gut Microbiome and Brain
DOI: [Link]

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