Arcle Citaon:

Esther Watson, De Susanna P, Sharmila Wesley, Renie Anthony, Jeya Sheela

Role of the Gut Microbiota in Anxiety and Mental Health Regulaon: A Comprehensive

Review.

Journal of Research in Biology (2026) 16(2): 1-29

Journal of Research in Biology

Role of the Gut Microbiota in Anxiety and Mental Health Regulation: A

Comprehensive Review

Keywords:

Gut microbiota; microbiota–gut–brain axis; anxiety; depression; psychobiocs;

dysbiosis; short-chain fay acids; tryptophan; HPA axis; neuroinammaon

ABSTRACT:

The gut microbiota has emerged as an important contributor to mental health

through its bidireconal communicaon with the central nervous system via the

microbiota gut brain axis. Dysbiosis has increasingly been associated with anxiety,

depression, and other neuropsychiatric disorders, although the causal nature of these

associaons remains under invesgaon. The MGB axis operates through mulple

interconnected pathways, including neural (vagus nerve, enteric nervous system),

endocrine (hypothalamic–pituitary–adrenal axis), immune (cytokine signaling), and

metabolic (short-chain fay acids, tryptophan metabolites, bile acids) mechanisms.

Emerging evidence from preclinical and clinical studies have reported composional

changes in the gut microbiota is characterized by reducons in Lactobacillus,

Bidobacterium, and butyrate-producing genera alongside elevaons in pro-

inammatory taxa are have frequently been associated with heightened anxiety and

depressive symptomatology. Therapeuc modulaon of the gut microbiota through

psychobiocs, prebiocs, synbiocs, dietary intervenons, and fecal microbiota

transplantaon (FMT) has emerged as a promising adjuncve approach, although

clinical evidence remains heterogeneous. This review systemacally synthesizes current

evidence on the mechanisc underpinnings of the gut–brain axis in anxiety and mental

health regulaon, evaluates the therapeuc landscape of microbiota-targeted

intervenons, and idenes crical gaps requiring further invesgaon in the context of

personalized psychiatry.

1-29| JRB | 2026 | Vol 16 | No 2

This article is governed by the Creative Commons Attribution License (http://creativecommons.org/

licenses/by/4.0), which gives permission for unrestricted use, non-commercial, distribution and

reproduction in all medium, provided the original work is properly cited.

www.jresearchbiology.com

Journal of Research in Biology

An International

Scientific Research Journal

Author:

a

Esther Watson,

b

De Susanna P,

c

Sharmila Wesley

d

Renie

Anthony,

e

Jeya Sheela P

Institution:

a

Assistant Professor, Department

of Botany, Bishop Cotton

Women’s Christian College,

Bangalore, Karnataka, India.

b,c

Assistant Professor,

Department of Biotechnology,

Bishop Cotton Women's

Christian College, Bengaluru,

Karnataka, India.

d

Assistant Professor, Department

of Psychology, Bishop Cotton

Women's Christian College,

Bengaluru, Karnataka, India.

e

Assistant Professor, Department

of Microbiology, Sadakathullah

Appa College (Autonomous),

Tirunelveli, Tamilnadu –

627011, India

Corresponding author:

Watson E

Web Address:

http://jresearchbiology.com/

documents/RA0900.pdf

Dates:

Received: 26 Dec. 2025 Accepted: 19 May, 2026 Published: 30 June, 2026

Journal of Research in Biology

An International Scientific Research Journal

ISSN No: Print: 2231 –6280; Online: 2231- 6299

Review

Watson et al., 2026

2 Journal of Research in Biology (2026) 16(2): 1-29

1. Introduction

Mental health disorders, particularly anxiety and

depression, represent a formidable global public health

challenge. According to the World Health Organization,

an estimated 280 million people worldwide suffer from

depression, and anxiety disorders rank among the most

prevalent psychiatric conditions globally (Głaz et al.,

2023). Despite significant advances in pharmacological

and psychotherapeutic interventions, remission rates

remain unsatisfactory, underscoring the urgent need for

novel therapeutic paradigms (Bautista, 2025). The

limitations of conventional antidepressant and anxiolytic

therapies including drug resistance, systemic side

effects, and poor blood–brain barrier permeability have

catalyzed interest in alternative and complementary

approaches (Jafari, 2025).

Over the past two decades, a paradigm shift has occurred

in our understanding of the biological substrates of

mental illness. The gut microbiota has increasingly been

recognized as a potential modulator of brain function

and behavior (Sasso et al., 2023). The human

gastrointestinal tract harbors up to 10¹⁴ microbial cells,

encompassing nearly 1,000–1,500 bacterial species

alongside diverse fungal and viral communities

(Luqman et al., 2024; Wilczek et al., 2023). This

complex ecosystem, collectively termed the gut

microbiota, engages in continuous bidirectional

communication with the CNS through what is now

designated the microbiota–gut–brain (MGB) axis

(Dziedzic et al., 2024; Dziedziak et al., 2025).

Dysbiosis may alter signaling along the microbiota gut

brain axis, leading to alterations in microbial

composition and function that influence neuronal

activity, immunity, and intestinal inflammation

(Dziedzic et al., 2024). Emerging evidence suggests an

connection between microbiota alterations and

neurological and psychiatric disorders, including

depression, anxiety, autism spectrum disorder (ASD),

schizophrenia, bipolar disorder, and neurodegenerative

diseases (Dziedziak et al., 2025). The MGB axis is

proposed to function not merely a passive conduit but an

active regulatory network through which microbial

communities modulate neurotransmitter synthesis,

neuroendocrine signaling, immune activation, and

metabolic homeostasis (Bautista, 2025; Singh et al.,

2022).

This review aims to provide a comprehensive,

systematic synthesis of the current evidence on the role

of the gut microbiota in anxiety and mental health

regulation. We examine the structural and functional

architecture of the MGB axis, delineate the key

mechanistic pathways through which gut microbiota

influence brain function, review the microbial signatures

associated with anxiety and depressive disorders, and

evaluate the therapeutic potential of microbiota-targeted

interventions. Special attention is given to quantitative

and statistical evidence from clinical and preclinical

studies, as well as emerging concepts such as circadian

regulation of the gut–brain axis and precision psychiatry.

2. The Microbiota–Gut–Brain Axis: Structural and

Functional Architecture

2.1 Overview and Bidirectionality

The MGB axis constitutes a complex, bidirectional

communication network linking the gut, its resident

microbiota, and the brain (Dziedzic et al., 2024). This

axis is thought to integrate neural, endocrine, immune,

and metabolic signals to maintain homeostasis across

multiple physiological systems (Dziedziak et al., 2025).

The bidirectional nature of this communication implies

Watson et al., 2026

3 Journal of Research in Biology (2026) 16(2): 1-29

that the state of the gut microbiota may influence brain

function and behavior, while the brain, through its neural

properties, reciprocally influences gut function, motility,

secretion, and microbial community structure (Sasso et

al., 2023; Wilczek et al., 2023).

The gut–brain axis (GBA) is mediated through multiple

direct and indirect pathways, including: (1) neural routes

involving the enteric nervous system (ENS), vagus

nerve, and spinal nerves; (2) neuroendocrine signaling,

primarily via the hypothalamic–pituitary–adrenal (HPA)

axis; (3) immune mechanisms involving cytokines such

as IL-1β, IL-6, and TNF-α; and (4) microbiota-derived

metabolites and neuroactive compounds, including

short-chain fatty acids (SCFAs), neurotransmitters,

vitamins, and tryptophan metabolites (Dziedziak et al.,

2025). The brain can influence the structure and function

of gut microbiota through the autonomic nervous system

by regulating gut motility, intestinal transit, secretion,

and gut permeability (Sasso et al., 2023). The principal

signaling pathways of the microbiota–gut–brain axis and

their respective roles in neuropsychiatric regulation are

summarized in Table 1.

The microbiota gut brain axis provides a useful

conceptual framework for understanding communication

between the gastrointestinal tract and the central nervous

system. However, many mechanistic pathways remain

incompletely understood, particularly in humans.

Most current knowledge is derived from experimental

animal models, whereas direct evidence demonstrating

equivalent mechanisms in clinical populations remains

limited. Future studies integrating microbiome profiling

with functional neuroimaging, metabolomics, and

longitudinal clinical assessment are needed to clarify the

relative contribution of each signaling pathway to

psychiatric disorders. As illustrated in Figure 1,

communication occurs through multiple interconnected

pathways rather than a single linear mechanism.

2.2 The Enteric Nervous System and Vagus Nerve

The ENS, often referred to as the "gut brain," comprises

an extensive network of neurons embedded within the

gastrointestinal wall and is considered important in

regulating stress and gastrointestinal activity. The ENS

interacts closely with the gut microbiota, which includes

neurotransmitter-producing bacteria capable of

synthesizing GABA, serotonin, dopamine, and

norepinephrine (Mosquera et al., 2024). The vagus

nerve is considered one of the principal communication

pathways between the gut and the brain, conveying

microbial-derived chemicals and influencing brain

function and behavior (Almahal et al., 2025).

Microbial metabolites are proposed to influence

neurotransmitter production such as serotonin, GABA,

and glutamate is influenced by the binding of microbial

metabolites to specific receptors in vagal sensory

neurons (Dziedzic et al., 2024). Increased vagal

activation occurs with probiotic supplementation; for

example, with Lactobacillus johnsonii La1 and

Bifidobacterium infantis and vagotomy has been shown

to prevent the restorative effect of probiotics on anxiety

in animal models. Specifically, vagotomy prevented the

anxiolytic effects of B. longum NCC3001 and L.

rhamnosus JB-1 in rodent studies, directly implicating

the vagus nerve as a key mediator in the gut–brain axis

(Bear et al., 2021).

Experimental evidence strongly supports the

involvement of vagal signaling in microbiota brain

communication. Nevertheless, direct assessment of

vagal activity in human psychiatric disorders remains

technically challenging. Consequently, the contribution

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4 Journal of Research in Biology (2026) 16(2): 1-29

of neural signaling relative to endocrine, immune, and

metabolic mechanisms remains uncertain. Future studies

combining electrophysiological measurements with

microbiome analyses may help clarify these

relationships. The neural pathways highlighted in Figure

1 emphasize the central role of vagal communication

within the microbiota gut brain axis.

2.3 The Hypothalamic–Pituitary–Adrenal Axis

The HPA axis is considered a major neuroendocrine

pathway through which the gut microbiota modulates

stress responses and emotional regulation.

Adrenocorticotropic hormone (ACTH) stimulates the

adrenal glands to synthesize gluco-corticosteroid

hormones (stress hormones), such as cortisol or

corticosterone (Chudzik et al., 2021). Acting

systemically, Stress hormones may increase intestinal

permeability of tight junctions and thus increase the

permeability of the intestinal barrier, leading to bacterial

translocation, which causes HPA axis response and

immune activation (Chudzik et al., 2021). Preclinical

studies demonstrate that germ-free or dysbiotic states

exaggerate HPA reactivity, remodel synaptic plasticity,

and induce anxiety- and depression-like behaviors

(Bautista, 2025).

Exaggerated waking cortisol is a biomarker of emotional

disturbances such as depression (Cerdó et al., 2017).

Psychobiotics have been reported to improve symptoms

in some studies by reducing inflammation, restoring gut

permeability, restoring blood–brain barrier (BBB)

integrity, modulating neurotransmitters, regulating the

HPA axis, and raising SCFA levels (Singh et al., 2022).

Some probiotics impair the HPA tension feedback,

which controls mood and emotion, resulting in reduced

corticosteroid levels (Ugwu, 2025). The integrated and

bidirectional nature of microbiota–gut–brain

communication across neural, endocrine, immune, and

metabolic domains is illustrated in Figure 1. The

intestinal microbiota communicates with the central

nervous system through interconnected neural,

endocrine, immune, and metabolic pathways while

intestinal barrier integrity regulates the systemic

exposure to microbial products. Disruptions in microbial

homeostasis may alter signaling to brain regions

involved in emotional regulation and cognition,

potentially contributing to anxiety, depression, stress

related disorders, and cognitive dysfunction.

Communication is bidirectional, with central nervous

system activity also influencing gut physiology and

microbial composition. The figure summarizes the

principal mechanisms discussed throughout this review

and serves as a conceptual framework rather than a

representation of a single biological pathway.

Although experimental models consistently demonstrate

interactions between the gut microbiota and the

hypothalamic pituitary adrenal axis, human evidence

remains less consistent. Variability in stress exposure,

lifestyle, medication use, and endocrine assessment

contributes to conflicting findings across studies. These

factors should be considered when interpreting the

relationship between microbial composition and stress

related disorders.

Table 1. Major signaling pathways of the microbiota–gut–brain axis with representative mechanisms and

supporting references.

Pathway Key

Components

Mechanisms Neuropsychiatric

Impact

Key References

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5 Journal of Research in Biology (2026) 16(2): 1-29

Neural Vagus nerve,

ENS

Microbial metabolites activate

vagal afferents; neurotransmitter

signaling (GABA, serotonin)

Anxiety modulation,

behavioral changes

Dziedzic et al.,

2024; Almahal

et al., 2025

Endocrine HPA axis (CRH,

ACTH, cortisol)

Stress-induced cortisol alters gut

permeability and microbiota

composition

Stress disorders,

depression

Chudzik et al.,

2021; Bautista,

2025

Immune Cytokines (IL-6,

TNF-α, IL-1β)

Peripheral inflammation → BBB

signaling → microglial

activation

Neuroinflammation,

mood dysregulation

Randeni & Xu,

2025; Dziedziak

et al., 2025

Metabolic SCFAs,

tryptophan

metabolites

SCFAs regulate epigenetics;

tryptophan metabolism affects

serotonin/kynurenine balance

Cognitive and

emotional regulation

Singh et al.,

2022; Zeppa et

al., 2022

Barrier

Integrity

Tight junctions,

intestinal

epithelium

Dysbiosis → increased

permeability (“leaky gut”) →

LPS translocation

Systemic

inflammation, anxiety

Dziedzic et al.,

2024; Mosquera

et al., 2024

Figure 1. Integrated overview of the microbiota gut brain axis and its proposed role in mental health.

Watson et al., 2026

6 Journal of Research in Biology (2026) 16(2): 1-29

2.4 Immune Pathways and Neuroinflammation

The gut microbiota may contribute to immune

regulation, shaping inflammatory responses within the

brain and orchestrating complex interactions that

modulate immune responses, promote tolerance to

commensal microorganisms, and contribute to the

maintenance of immune homeostasis. A resilient and

diverse gut microbiome is indispensable for robust

immune function and appropriate immunoregulatory

mechanisms (Dziedzic et al., 2024).

The gut–brain axis is mediated through immune

mechanisms involving cytokines such as IL-1β, IL-6,

and TNF-α (Dziedziak et al., 2025). Inflammatory

cytokines produced within the gut may cross the BBB or

signal through the vagus nerve to affect brain functions,

influencing the development of mood disorders such as

depression. Dysbiosis has been associated with

increased intestinal permeability known as "leaky gut,"

which allows bacterial endotoxins to enter the

bloodstream and induce systemic inflammation; this

inflammation can then impact brain function and

behavior. Dysbiosis also compromises intestinal barrier

integrity, allowing endotoxins like lipopolysaccharide

(LPS) to enter the bloodstream and trigger systemic

inflammation, which may promote microglial activation;

the brain's immune cells leading to neuroinflammation, a

hallmark of neuropsychiatric disorders (Randeni & Xu,

2025).

Immune signaling represents one of the most plausible

biological links between gut dysbiosis and psychiatric

disorders. However, inflammatory markers are

influenced by numerous environmental and clinical

factors, making it difficult to isolate microbiota specific

effects. Large prospective studies are required to

determine whether immune alterations precede or follow

changes in microbial composition.

3. Gut Microbiota Composition and Dysbiosis in

Anxiety and Depression

3.1 Microbial Diversity and Mental Health

The composition of the gut microbiota is influenced by

factors such as diet, age, lifestyle, and inflammatory

status. A stable and diverse microbiota plays a crucial

role in regulating metabolic and immune processes

within the human body. In recent years, scientists have

discovered a bidirectional communication between the

gut microbiota and the brain, termed the gut microbiota–

brain axis, and have demonstrated that disturbances in

this ecosystem are associated with psychiatric and

neurological diseases (Wilczek et al., 2023).

Multi-omics studies consistently demonstrate that

microbial signatures in anxiety and depression are

mirrored by metabolic shifts; reduced SCFAs, indoles,

and serotonin precursors alongside elevated kynurenine

pathway metabolites that converge to impair

neurotransmitter balance and promote chronic

neuroinflammation. Clinically, many patients with

depression and anxiety also present with gastrointestinal

comorbidities, highlighting the translational relevance of

the microbiota–gut–brain axis (Bautista, 2025).

3.2 Dysbiosis Patterns in Anxiety and Depressive

Disorders

Dysbiosis in major depressive disorder (MDD) is

frequently characterized by reductions in butyrate-

producing genera and elevations in pro-inflammatory

taxa, which have been linked to neuroinflammation,

impaired neurotransmitter synthesis, and HPA axis

dysregulation (Abidin et al., 2025). Changes in the

Watson et al., 2026

7 Journal of Research in Biology (2026) 16(2): 1-29

composition of the gut microbiota are associated with

conditions such as depression, schizophrenia, bipolar

disorder, ASD, attention deficit hyperactivity disorder

(ADHD), and neurodegenerative diseases such as

Parkinson's and Alzheimer's (Dziedziak et al., 2025).

A landmark study demonstrated that fecal microbiota

transplantation (FMT) from patients with major

depression into germ-free rats induced alterations in

tryptophan metabolism, anhedonia, and anxiety-like

behavior, supporting a potential mechanistic link, gut

microbiota composition to depressive-like symptoms

(Westfall & Pasinetti, 2019). Similarly, when fecal

samples from depressed people were transplanted into

mice, an increase in fecal acetate and total SCFA

concentrations was found along with increases in

depression-like behavior (Bear et al., 2021). These

findings provide experimental evidence supporting a

causal contribution in animal models for the role of the

gut microbiota in mental health regulation.

Several studies have reported that reduced abundance of

GABA-producing taxa is associated with heightened

amygdala reactivity and anxiety-like behavior, whereas

probiotic supplementation that increases microbial

GABA production correlates with decreased behavioral

despair and reduced physiological stress markers in

preclinical and clinical settings. In depressive

phenotypes, dysbiosis diverts tryptophan away from 5-

HT synthesis toward the kynurenine pathway,

contributing to anhedonia and low mood; restoration of

eubiotic communities or targeted psychobiotics

increases 5-HT–related signaling and tracks with

symptom improvement (Bautista, 2025). A consolidated

overview of microbial compositional changes and their

functional implications in anxiety and depressive

disorders is presented in Table 2.

Table 2: Major Gut Microbiota, Biological Functions, and Proposed Roles in Anxiety and Mental Health

Gut Microbial

Taxon

Principal

Biological

Function

Major

Bioactive

Metabolites

Proposed

Mechanism in

the Microbiota

Gut Brain Axis

Clinical Associations Representative

References

Lactobacillus

spp.

Carbohydrate

fermentation;

maintenance of

intestinal

homeostasis

GABA,

lactate

Modulation of

vagal signaling,

neurotransmitter

synthesis, and

stress responses

Frequently reduced in

anxiety and

depression;

commonly

investigated as

psychobiotics

Bravo et al.

(2011);

Cryan et al.

(2019);

Liu et al.

(2019)

Bifidobacterium

spp.

SCFA

production;

immune

regulation

Acetate Strengthens

intestinal barrier,

modulates

immune

responses,

regulates

emotional

behavior

Reduced abundance

reported in depressive

disorders; therapeutic

potential

demonstrated in

clinical trials

Kelly et al.

(2016);

Ng et al.

(2018);

Liu et al.

(2019)

Faecalibacterium

prausnitzii

Anti

inflammatory

activity

Butyrate Suppresses

inflammatory

signaling,

promotes

Frequently depleted

in major depressive

disorder

Jiang et al.

(2015);

Dalile et al.

(2019)

Watson et al., 2026

8 Journal of Research in Biology (2026) 16(2): 1-29

intestinal

integrity

Akkermansia

muciniphila

Mucin

degradation

Acetate,

propionate

Maintains mucus

layer and

epithelial

integrity

Reduced abundance

associated with

metabolic

dysfunction and some

psychiatric cohorts

Cryan et al.

(2019);

Mayer et al.

(2015)

Roseburia spp. Fermentation of

dietary fiber

Butyrate Anti

inflammatory and

neuroprotective

functions

Reduced abundance

associated with

dysbiosis

Dalile et al.

(2019);

Foster et al.

(2017)

Prevotella spp. Complex

carbohydrate

metabolism

SCFAs Influences host

metabolism and

immune

regulation

Variable findings

depending on dietary

pattern and

population

Foster et al.

(2017);

Cryan et al.

(2019)

3.3 Specific Microbial Taxa and Psychiatric

Outcomes

Among the most frequently studied psychobiotic

bacteria are genera such as Lactobacillus, Lactococcus,

Bifidobacterium, Streptococcus, and Enterococcus,

which influence the MGB axis through the production of

SCFAs, neurotransmitters, and other bioactive

metabolites. The predominant psychobiotic strains

identified in systematic reviews belong to Lactobacillus

(45.5%) and Bifidobacterium (29%) genera (Śliwka et

al., 2025). Lactobacillus and Bifidobacterium are known

to enhance serotonin synthesis and have been linked to

reduced depressive symptoms. Individuals with

depression have significantly altered gut microbiota

composition, indicating that tryptophan-derived

metabolites are impacted by gut microbiota diversity

(Abidin et al., 2025). Chojnacki et al. (2022) reported

altered tryptophan metabolism in depressive patients

with small intestinal bacterial overgrowth (SIBO),

showing increased urinary kynurenine and quinolinic

acid levels alongside decreased tryptophan and

kynurenic acid, suggesting enhanced activation of the

neurotoxic kynurenine pathway. Additionally, SIBO

patients scored higher on depression and anxiety scales

(Hamilton Depression Rating Scale and Hamilton

Anxiety Rating Scale) compared to controls (Dziedziak

et al., 2025). Clinical investigations consistently report

associations between microbial alterations and

psychiatric disorders. However, considerable

heterogeneity exists across cohorts with respect to

microbial composition, sequencing methodology, dietary

patterns, medication exposure, and geographic variation.

These methodological differences likely contribute to

inconsistent findings and limit reproducibility. Animal

studies provide strong mechanistic evidence supporting

a role for the gut microbiota in behavioral regulation.

Nevertheless, rodent models do not fully reproduce the

complexity of human psychiatric disorders, including

psychosocial influences, genetic diversity, and

environmental exposures. Consequently, caution is

warranted when extrapolating experimental findings

directly to clinical practice.

4. Mechanistic Pathways: How Gut Microbiota

Regulate Anxiety and Mental Health

4.1 Neurotransmitter Modulation

4.1.1 Serotonin and Tryptophan Metabolism

Watson et al., 2026

9 Journal of Research in Biology (2026) 16(2): 1-29

The gut microbiota is an abundant source of

differentiated metabolites that serve as a chemical

toolbox in the communication between the intestines and

CNS via GBA pathways. These include tryptophan, γ-

aminobutyric acid (GABA), histamine, serotonin,

SCFAs, 5-hydroxytryptamine (5-HT), dopamine, and

acetylcholine (ACh) (Dziedzic et al., 2024).

Approximately 90% of the body's serotonin is produced

in the gut, and the gut microbiota contributes to the

regulation in regulating this production (Zeppa et al.,

2022). Spore-forming bacteria have been shown to

enhance serotonin production by up-regulating

tryptophan hydroxylase 1 (TPH1) in enterochromaffin

cells (Abidin et al., 2025). Approximately 10–20% of

the tryptophan allocated toward serotonin development

will directly pass through the BBB, initiating serotonin

synthesis in the brain. The remaining tryptophan is

metabolized along the kynurenine pathway, which forms

several metabolites important for the pathophysiology of

depression (Westfall & Pasinetti, 2019).

The activation of the kynurenine pathway may reduce

tryptophan availability bioavailability for serotonin

production and modulates brain functions, influencing

neuropsychiatric disorders like depression (Zeppa et al.,

2022). Inflammatory pathways, particularly the

kynurenine pathway activated by cytokines like IL-6,

divert tryptophan from serotonin synthesis toward

neurotoxic metabolites contributing to depression

(Abidin et al., 2025). Pro-inflammatory cytokines can

affect serotonin concentration through activation of the

kynurenine pathway, reducing levels of tryptophan and

serotonin and exacerbating symptoms of affective

disorders (Mosquera et al., 2024).

In germ-free and antibiotic-induced microbiota-depleted

mice, despite increased circulating tryptophan levels,

serotonin and kynurenine availabilities were decreased,

suggesting that gut microbiota modulated kynurenine

metabolism (Cerdó et al., 2017). Dysregulation of

tryptophan metabolites due to dysbiosis has been

associated to psychiatric disorders, including depression.

Experimental evidence suggests that SCFAs, primarily

butyrate, influence the activity of the enzyme

indoleamine 2,3-dioxygenase (IDO), may reduce

kynurenine production and help to alleviate

neuroinflammation (Almahal et al., 2025). The main

metabolites of tryptophan produced by gut microbiota

are tryptamine and indolic compounds that can reach

distant organs, including the brain. Indole has been

proposed to contribute in the gut–brain axis; an

accumulation of this molecule in the brain led to mood

disorders and anxiety in animal models. Other microbial

indolic derivatives from tryptophan catabolism exert

anti-inflammatory action, suppressing CNS

inflammation (Zeppa et al., 2022). The divergence of

tryptophan metabolism under eubiotic and dysbiotic

conditions and its implications for neuropsychiatric

outcomes are depicted in Figure 3.

Figure 2. Divergent metabolic pathways of

tryptophan under eubiosis versus dysbiosis and their

implications for serotonin availability and

neurotoxicity.

Watson et al., 2026

10 Journal of Research in Biology (2026) 16(2): 1-29

Mathematically, the kynurenine-to-tryptophan ratio

(KTR) serves as a quantitative biomarker of IDO

enzyme activity and tryptophan catabolism:

 =



ℎ

 1000

Elevated KTR values are consistently observed in

patients with depression and anxiety, reflecting

enhanced IDO activation and reduced serotonin

precursor availability (Westfall & Pasinetti, 2019; Głaz

et al., 2023). A bolus dose of resveratrol (5 g) in humans

significantly reduced tryptophan levels 2.5 and 5 hours

after treatment in healthy volunteers, resulting in a 1.33-

and 1.30-fold increase in the kynurenine-to-tryptophan

ratio, respectively (Westfall & Pasinetti, 2019).

4.1.2 GABA and GABAergic Signaling

GABA is the primary inhibitory neurotransmitter in the

CNS, reducing neuronal excitability and playing a role

in stress responses and mood regulation. Certain gut

bacteria, including Lactobacillus and Bifidobacterium

species, can produce GABA by converting glutamate, an

excitatory neurotransmitter into GABA through the

action of glutamate decarboxylase. GABAergic

signaling in the brain is essential for regulating anxiety,

stress, and mood, and the dysregulation of GABA

production may contribute to psychiatric conditions such

as depression and anxiety disorders (Randeni & Xu,

2025).

Depression and anxiety disorders are associated with

decreased GABA levels in the brain. Among GABA-

regulating bacteria, food-derived Lactobacillus strains

such as L. plantarum, L. paracasei, L. rhamnosus, and L.

brevis have been identified. Yunes et al. (2020) screened

135 human-derived Bifidobacterium and Lactobacillus

strains for their ability to produce GABA, identifying

significant inter-strain variability in GABA-producing

capacity (Chudzik et al., 2021). Reduced abundance of

GABA-producing taxa is associated with heightened

amygdala reactivity and anxiety-like behavior (Bautista,

2025).

4.1.3 Dopamine and Other Neurotransmitters

Distinct gut microbial species affect host physiology by

producing diverse neuromolecules involved in mood

regulation. Lactobacillus and Bifidobacterium spp.

generate GABA, while other bacterial species contribute

to the synthesis of dopamine, norepinephrine, and

acetylcholine (Cerdó et al., 2017; Dziedziak et al.,

2025). Bacterial metabolites produced by gut microbiota

such as GABA, acetylcholine, serotonin, and

norepinephrine may influence synaptic signaling and

play a crucial role in mood and behavior regulation.

These neurotransmitters modulate signaling pathways of

the local ENS and then the gut–brain axis (Jach et al.,

2023).

4.2 Short-Chain Fatty Acids (SCFAs) and

Neuroactive Metabolites

SCFAs, including acetate, propionate, and butyrate, are

metabolites produced by a healthy gut microbiota during

the fermentation of dietary fibers and resistant starch.

These SCFAs play a crucial role in immune modulation.

Butyrate, in particular, is thought to influence the gut–

brain axis, potentially by enhancing colonic serotonin

production, a key neurotransmitter involved in mood and

behavior regulation (Abidin et al., 2025).

Experimental studies suggest that certain SCFAs may

influence blood brain barrier integrity, although their

direct penetration into the human brain remains

incompletely understood. (Singh et al., 2022). Butyrate

can cross the BBB and produce a dose-dependent

Watson et al., 2026

11 Journal of Research in Biology (2026) 16(2): 1-29

increase in neuronal and glial nuclear histone H3

acetylation in mice due to its potential to inhibit histone

deacetylation (Cerdó et al., 2017). Gut bacteria also

produce SCFAs such as butyrate, which contribute to

maintenance of intestinal barrier integrity, reduce

systemic inflammation, and promote proper serotonergic

signaling in the CNS (Dziedziak et al., 2025).

In male mice, daily oral supplementation of SCFAs

(67.5 mmol acetate, 25 mmol propionate, and 40 mmol

butyrate) decreased stress-related increases in anxiety-

like behaviors in the open field test, and increased

sucrose preference and decreased urine sniffing; both

markers of depression-like behavior. The SCFA

supplement was associated with changes in gene

expression in the brain related to dopamine receptors,

part of the mesolimbic reward pathway, which can be

altered in depression. Prebiotic supplementation in mice

increased SCFA concentrations, many of which were

negatively correlated with depression-like and anxiety-

like behaviors (Bear et al., 2021).

Metabolites produced by the gut microbiota can

significantly influence the brain–gut axis. For example,

SCFAs like butyrate, produced by the microbiota, inhibit

histone deacetylases, supporting memory and neural

plasticity. Butyrate may have mood-stabilizing effects in

rodent models, such as reducing depressive-like

behavior induced by chronic psychosocial stress and

reversing anhedonia and sociability impairments

(Dziedziak et al., 2025).

Short chain fatty acids represent one of the best

characterized classes of microbiota derived metabolites.

Despite compelling experimental evidence, the extent to

which circulating concentrations influence human brain

function remains uncertain. Standardized metabolomic

analyses may improve understanding of their clinical

relevance.

4.3 Brain-Derived Neurotrophic Factor (BDNF)

The microbiome may influence concentrations of brain-

derived neurotrophic factor (BDNF) in the brain. BDNF

is a widely expressed neurotrophin serving several

functions within the CNS, including neuronal

differentiation and survival, and regulation of BDNF

concentration is involved in depression and anxiety.

BDNF levels have been observed to be lower in the

cortex and hippocampus of germ-free (GF) mice

compared to controls, suggesting that the gut microbiota

appears to contribute to the elevation of brain BDNF and

may modulate behavior through changes in BDNF levels

(Chudzik et al., 2021).

Prebiotic administration has been shown to enhance

expression of BDNF and improve cognition in animal

studies (Jach et al., 2023). The probiotic reversed

anxiety as well as a number of biochemical changes

produced by stress, including reversal of decreased brain

levels of BDNF and serotonin and restoration of plasma

levels of tryptophan and several of its metabolites, the

Firmicutes-to-Bacteroidetes ratio, and fecal levels of

SCFAs (MacKay et al., 2024).

Although increased intestinal permeability has been

proposed as a mechanism linking gut dysbiosis with

neuroinflammation, evidence remains inconsistent

across clinical populations. Standardized biomarkers of

intestinal barrier integrity are required before this

hypothesis can be translated into routine clinical

practice.

4.4 Intestinal Permeability and the Leaky Gut

Syndrome

Watson et al., 2026

12 Journal of Research in Biology (2026) 16(2): 1-29

One of the proposed contributors of the systemic

inflammatory response is enhanced intestinal

permeability, a condition commonly known as leaky gut

syndrome (LGS). The mechanisms engaged for LGS

development are primarily gut microflora disturbances,

breakdown of the intestinal barrier, and damage of

enterocytes, leading to systemic inflammation, which is

critical for depression pathophysiology (Dziedzic et al.,

2024). Increased intestinal permeability, known as LGS,

plays a major role in the systemic inflammatory

response, caused by intestinal dysbiosis, damage to

enterocytes, and stress, contributing to the

pathophysiology of depression (Mosquera et al., 2024).

Glucocorticoids may impair the intestinal barrier

function, reduce epithelial integrity, move bacteria

outward, and provoke an inflammatory immune

response (Singh et al., 2022). Gut bacteria can also

influence the expression and function of tight junction

proteins that regulate intestinal permeability. Dysbiosis

compromises intestinal barrier integrity, resulting in a

"leaky gut," allowing endotoxins like LPS to enter the

bloodstream and trigger systemic inflammation

(Randeni & Xu, 2025). The sequential biological

cascade linking gut dysbiosis to neuroinflammation and

behavioral manifestations is conceptually illustrated in

Figure 2.

4.5 Circadian Rhythmicity and the Gut–Brain–

Circadian Axis

An underappreciated yet critical dimension of the MGB

axis model is circadian rhythmicity. Both host endocrine

cycles and microbial communities exhibit diurnal

oscillations that synchronize metabolism, immune

activity, and neural signaling. Disruption of these

rhythms through factors such as sleep disturbance,

irregular feeding, or shift work alters microbial diversity,

dampens metabolite oscillations, destabilizes HPA

regulation, and enhances neuroinflammation, thereby

amplifying vulnerability to psychiatric disorders

(Bautista, 2025).

Collectively, evidence supports a model in which

anxiety and depression are systemic conditions arising

from integrated neural, immune, endocrine, metabolic,

and circadian dysregulation, rather than isolated brain-

based pathologies. This reconceptualization positions

microbial taxa and metabolites as candidate biomarkers

and therapeutic targets (Bautista, 2025).

The influence of the gut microbiota on neurotransmitter

metabolism is biologically plausible and supported by

extensive experimental evidence. However, microbial

production of neurotransmitters does not necessarily

translate into direct central nervous system effects

because many neurotransmitters do not readily cross the

blood brain barrier. Indirect signaling through neural,

endocrine, and immune pathways is therefore considered

more likely.

Watson et al., 2026

13 Journal of Research in Biology (2026) 16(2): 1-29

Figure 3. Mechanistic Pathways Linking Gut MIcrobiota to Anxiety and Mental Health Regulation

Table 2: Mechanistic Pathways Linking Gut Microbiota to Anxiety and Mental Health: Biological Basis,

Evidence, and Translational Significance

Mechanistic

Pathway

Principal Mediators Biological

Consequences

Evidence

from

Animal

Studies

Evidence

from

Human

Studies

Overall

Strength

of

Evidence

Representative

References

Neural

signaling

Vagus nerve, enteric

nervous system

Modulation of stress

responses and

emotional regulation

Strong Moderate Moderate

to Strong

Bravo et al.

(2011); Cryan

& Dinan (2012)

Endocrine

regulation

Hypothalamic

pituitary adrenal

axis, cortisol

Stress adaptation and

neuroendocrine

regulation

Strong Moderate Moderate

Sudo et al.

(2004); Foster

et al. (2017)

Immune IL-6, TNF-α, IL-1β, Neuroinflammation, Strong Strong Strong

Dantzer et al.

Watson et al., 2026

14 Journal of Research in Biology (2026) 16(2): 1-29

modulation IL-10 microglial activation

(2008); Miller

& Raison

(2016)

Microbial

metabolites

SCFAs, indoles, bile

acids

Neuroprotection,

immune regulation,

barrier maintenance

Strong Moderate Moderate

Dalile et al.

(2019);

Kennedy et al.

(2017)

Tryptophan

metabolism

Serotonin,

kynurenine

metabolites

Neurotransmission

and stress regulation

Strong Moderate Moderate

Kennedy et al.

(2017); Cryan

et al. (2019)

Intestinal

barrier

dysfunction

Lipopolysaccharide,

tight junction

proteins

Systemic

inflammation and

altered gut

permeability

Moderate Emerging Emerging

Moloney et al.

(2016); Cryan

et al. (2019)

Neuroplasticity Brain derived

neurotrophic factor

Synaptic plasticity

and neuronal

survival

Moderate Limited Emerging

Bercik et al.

(2011); Cryan

et al. (2019)

Scale

 Strong = consistent mechanistic evidence with substantial supporting studies

 Moderate = biologically plausible with moderate clinical support

 Emerging = promising evidence but limited human validation

5. Gut Microbiota Signatures in Specific Anxiety-

Related Disorders

5.1 Generalized Anxiety Disorder and Social Anxiety

A large body of research supports the role of stress in

several psychiatric disorders in which anxiety is a

prominent symptom. The gut microbiome–immune

system–brain axis is involved in a large number of

disorders, and this axis is affected by various stressors

(MacKay et al., 2024). Preclinical studies demonstrate

that germ-free or dysbiotic states exaggerate HPA

reactivity, remodel synaptic plasticity, and induce

anxiety- and depression-like behaviors (Bautista, 2025).

Mice fed with prebiotics showed diminished stressor-

induced anxiety-like behavior. In a mouse model of

ASD, a maternal high-fat diet reduced the number of

oxytocin immunoreactive neurons in the hypothalamus

and induced dysbiosis that was restored by a commensal

Lactobacillus reuteri strain (Cerdó et al., 2017). These

findings underscore the role of specific microbial taxa in

modulating anxiety-related neural circuits.

5.2 Post-Traumatic Stress Disorder (PTSD) and

Obsessive-Compulsive Disorder (OCD)

The gut microbiome has been implicated in the

pathophysiology of PTSD and OCD, with dysbiosis

Watson et al., 2026

15 Journal of Research in Biology (2026) 16(2): 1-29

contributing to altered stress reactivity and immune

dysregulation. Matters to be considered in future

research include longer-term studies with factors such as

sex of the subjects, drug use, comorbidity, ethnicity/race,

environmental effects, diet, and exercise taken into

account. The translatability of studies on animal models

to clinical situations and the effects on the gut

microbiome of drugs currently used to treat these

disorders represent important research priorities

(MacKay et al., 2024).

5.3 Environmental Pollutants and Gut–Brain Axis

Disruption

Humans are exposed to a wide range of pollutants in

everyday life that impact intestinal microbiota and

manipulate the bidirectional communication between the

gut and the brain, resulting in predisposition to

psychiatric or neurological disorders. Acute

methylmercury (Me-Hg) exposure changed the structure

and function of the gut microbiota in rats, including

Desulfovibrionales, Peptococcaceae, and Helicobacter,

all of which are linked to particular neurometabolites

like glutamate and GABA. In the mature CNS,

glutamate and GABA are the primary excitatory and

inhibitory neurotransmitters, respectively (Singh et al.,

2022).

6. Dietary Influences on the Gut Microbiota and

Mental Health

6.1 Dietary Patterns and Microbial Diversity

The complex relationship between diet, the gut

microbiota, and mental health has become a focal point

of contemporary research. Specific dietary components

such as fiber, proteins, fats, vitamins, minerals, and

bioactive compounds shape the gut microbiome and

influence microbial metabolism to regulate depressive

outcomes. These dietary-induced changes in the gut

microbiota can modulate the production of microbial

metabolites, which play vital roles in gut–brain

communication (Randeni & Xu, 2025).

The resulting imbalance in the gut microbiome from

poor dietary patterns can enhance intestinal

permeability, promote systemic inflammation, and

adversely affect the gut–brain axis. In contrast, the

Mediterranean diet rich in fruits, vegetables, whole

grains, nuts, seeds, and olive oil, along with moderate

consumption of fish and poultry has been shown to

promote a healthy gut microbiome and support mental

health (Randeni & Xu, 2025). Trials have demonstrated

robust improvements in depression following structured

dietary modifications (Bautista, 2025).

6.2 Prebiotics and Dietary Fiber

Prebiotics are defined as nondigestible dietary fibers

(e.g., inulin, fructo-oligosaccharides, and galacto-

oligosaccharides) that stimulate the growth and/or

activity of certain gut bacteria such as Lactobacillus and

Bifidobacteria. This modulation of the gut environment

may offer new avenues for reducing depression-like

behavior and anxiety. Prebiotics may influence serotonin

production by providing SCFAs, which can stimulate

TPH1 gene expression in cells and through the gut–brain

axis, thereby exerting anxiolytic or antidepressant-like

effects (Tang et al., 2025).

In clinical trials, prebiotic supplementation enhanced the

levels of SCFAs, improved social behavior symptoms

and sleep patterns in ASD, and caused a reduction in

anxiety scores in irritable bowel syndrome (IBS). In

other clinical studies, administration of a diet high in

prebiotic fibers improved mood, anxiety, stress, and

Watson et al., 2026

16 Journal of Research in Biology (2026) 16(2): 1-29

sleep in adults with moderate mental stress and low

prebiotic intake. Metabolites formed after prebiotic

degradation influenced brain function, decreased BBB

permeability, and reduced neuroinflammation (Jach et

al., 2023).

When prebiotic galactooligosaccharide (GOS) was

tested in a clinical trial (ISRCTN54052375), it increased

the probiotic bacteria Bifidobacteria within the gut,

helping to alleviate symptoms of IBS (Sasso et al.

2023). B-GOS attenuated vigilance to negative stimuli; a

behavioral marker of anxiety and depression suggesting

a reduction in anxiety and depression (Cerdó et al.,

2017). Recommended prebiotic doses range from 5–15

g/day of fibers such as inulin, fructooligosaccharides,

and galactooligosaccharides, with a duration of at least 4

weeks (Tang et al., 2025).

Current microbiota based interventions demonstrate

encouraging but modest therapeutic effects.

Considerable heterogeneity in intervention protocols,

microbial strains, treatment duration, and outcome

measures limits direct comparison across studies. Future

randomized controlled trials should prioritize

standardized methodologies and mechanistic outcome

measures in addition to clinical endpoints.

6.3 Polyphenols and Synbiotics

The gut microbiota manages the bioaccessibility of

phenolic metabolites from dietary polyphenols, whose

multiple beneficial properties have known therapeutic

efficacy against depression. Synbiotics is a term

combining probiotics with dietary polyphenols may

provide a novel therapeutic strategy for depression.

Synbiotics have the potential to alleviate

neuroinflammation by modulating microglial and

inflammasome activation, reduce oxidative stress, and

balance serotonin metabolism, thereby simultaneously

targeting several of the major pathological risk factors of

depression (Westfall & Pasinetti, 2019).

Polyphenols, through their probiotic effects on the gut

microbiota such as Bacteroidetes and Firmicutes, induce

the formation of SCFAs. Chlorogenic acid, caffeic acid,

rutin, and quercetin have all been shown to promote the

formation of SCFAs such as propionate, butyrate, and

acetate (Zeppa et al., 2022). Quercetin (60 mg/kg)

alleviated anxiety and depressive behaviors while

attenuating brain oxidative stress and suppressing

excessive corticosterone induction in rats treated with

adriamycin (Westfall & Pasinetti, 2019).

7. Therapeutic Interventions Targeting the Gut

Microbiota

7.1 Probiotics and Psychobiotics

7.1.1 Definition and Classification

Psychobiotics are defined as live organisms that, when

ingested in adequate amounts, produce beneficial health

effects in patients suffering from psychiatric illness

(Cerdó et al., 2017). Unlike conventional probiotics,

psychobiotics have the potential to positively affect

mental health by influencing the production of

neurotransmitters, SCFAs, and enteroendocrine

hormones (Mosquera et al., 2024). The definition has

been expanded in recent years to include prebiotics

whose effect on the brain is bacteria-mediated, and a

wider definition encompasses any substance that exerts a

microbiome-mediated psychological effect, including

probiotics, prebiotics, synbiotics, and postbiotics (Sasso

et al., 2023).

Psychobiotic mechanisms of action include

neurotransmitter regulation (27.1%), modulation of the

gut microbiota (27.1%), SCFA production (16.9%), and

Watson et al., 2026

17 Journal of Research in Biology (2026) 16(2): 1-29

control of inflammatory responses (15.3%).

Psychobiotic microorganisms can be found in fermented

foods such as yogurt, sauerkraut, and kimchi. Healthy

dietary patterns rich in pro- and prebiotics play a crucial

role in mood regulation through their impact on the gut

microbiome (Śliwka et al., 2025).

7.1.2 Preclinical Evidence

Several probiotic strains have been reported as

psychobiotics from animal studies, having psychotropic

effects on depression, anxiety, and stress, due to their

ability to produce and deliver neuroactive substances

such as GABA and serotonin, which act on the brain–gut

axis (Zeppa et al., 2022). Supplementation with the

probiotic Lactobacillus reuteri ATCC 23272 decreased

depression-like behavior, seemingly via the production

of H₂O₂, which inhibits the enzyme IDO1 and restores

the balance of serotonin/kynurenine pathways. IDO1 is

activated by inflammation and LPS (Bear et al., 2021).

A probiotic (L. rhamnosus GG), prebiotic mix

(polydextrose and galacto-oligosaccharide), or combined

synbiotic mix, following maternal separation stress in

male and female Sprague Dawley rats, reduced stress-

induced increases in anxiety-like behavior. The synbiotic

had the greatest effect and was also able to ameliorate

stress-induced memory changes. Increases in cortisol,

gut permeability, and bacterial adherence/penetration

were prevented by probiotic supplementation (Bear et

al., 2021).

Lactobacillus plantarum, Bifidobacterium breve, and

Akkermansia muciniphila demonstrated particularly

promising effects in systematic reviews of psychobiotic

interventions. Psychobiotics such as B. breve

CCFM1025 also modulate tryptophan metabolism by

influencing the kynurenine and indole pathways, which

translates into the regulation of serotonin levels (Śliwka

et al., 2025).

7.1.3 Clinical Evidence

In a study by Dinan and Cryan (2013), 124 healthy

volunteers (mean age 62 years), those who consumed a

mix of psychobiotics (L. helveticus and B. longum)

exhibited less anxiety and depression than controls

(Westfall & Pasinetti, 2019). A probiotic combination

of L. helveticus R0052 plus B. longum R0175 reduced

anxiety and depression in healthy subjects compared

with control ones (Zeppa et al., 2022). Messaoudi et al.

(2011) showed that consumption of these probiotics

reduced anxiety and depression scores in subjects with

reduced urinary free cortisol (Sasso et al., 2023).

Akkasheh et al. (2016) showed that the consumption of

a probiotics were associated with reduced Beck

Depression Inventory (BDI) scores, indicating overall

improved symptoms including mood, in 40 patients

diagnosed with depression. Marcos et al. (2004)

reported that probiotics decreased levels of stress and

anxiety assessed using the state-trait anxiety inventory

(STAI) that remained unchanged in subjects under

academic examination stress (Cerdó et al., 2017). In a

large cohort of pregnant women, supplementation with

L. rhamnosus HN001 led to less postpartum depression

and anxiety compared to placebo controls (Westfall &

Pasinetti, 2019). In a randomized controlled trial

evaluating the effect of probiotic and synbiotic

supplementation on reducing symptoms of depression

and anxiety in 75 hemodialysis patients aged 30–65

years, results showed a significant reduction in

depression severity according to the Hospital Depression

and Anxiety Scale (HADS) in the synbiotic supplement

group compared to controls (Głaz et al., 2023).

Watson et al., 2026

18 Journal of Research in Biology (2026) 16(2): 1-29

A systematic review by Liu et al. (2019) analyzed 34

controlled clinical trials in which the effects of pre- and

probiotics on depression and anxiety were studied; they

concluded that prebiotics showed no significant

differences from placebo for depression or anxiety, but

probiotics showed small significant effects for both

depression and anxiety. Chao et al. (2020) in a meta-

analysis of 10 randomized controlled trials, found that

probiotics reduced depressive symptoms in patients with

anxiety and depression and in healthy people under

stress, but there was no reduction in anxiety scores.

Smith et al. (2021) conducted a systematic review of 12

studies in which participants consumed probiotics,

prebiotics, or synbiotics and were evaluated for mood or

stress levels; 6 reported reduced depression with

probiotics and 2 reported reduced anxiety with

probiotics (MacKay et al., 2024). Results from recent

randomized controlled trials suggest that daily probiotic

supplementation significantly reduces the severity of

depression compared to placebo (p < 0.05). Additionally,

this effect may be enhanced by the combined use of a

probiotic with a prebiotic (Głaz et al., 2023).

For the effectiveness of antidepressant therapy,

psychobiotics should be administered at a dose higher

than 1 billion CFU/day (10⁹ CFU/day) for at least 8

weeks (Jach et al., 2023). Recommended doses for

psychobiotics in clinical studies range from 10⁹ to 10¹⁰

CFU/day, with a duration of at least 4 weeks (Tang et

al., 2025).

7.1.4 Strain-Specific Effects and Mechanisms

Probiotic supplementation, particularly with strains of

Lactobacillus and Bifidobacterium, has shown beneficial

effects in some clinical trials; however, findings

regarding anxiety are more variable, likely due to

differences in study design, probiotic strains, and sample

sizes. Emerging evidence suggests that personalized

biomarkers could help predict who will benefit most

from probiotic interventions. Baseline microbiota

diversity, higher levels of Lactobacillus and

Bifidobacterium, and lower abundance of pro-

inflammatory taxa appear linked to better outcomes in

neurological and psychiatric disorders. Reductions in

inflammatory markers such as IL-6, TNF-α, IL-17, and

CRP, along with favorable metabolomic profiles like

elevated SCFAs and balanced tryptophan metabolism,

correlate with improved cognition and mood (Jafari,

2025). Through modulation of the kynurenine pathway,

probiotics may promote the synthesis of neuroprotective

kynurenic acid (KYNA) over neurotoxic quinolinic acid

(QUIN). A multi-strain probiotic formulation

significantly reduced circulating IL-6 and TNF-α levels

in patients with Parkinson's disease, suggesting a

decrease in neuroinflammation relevant to conditions

such as depression, Alzheimer's disease, Parkinson's

disease, MS, and ASD (Jafari, 2025).

7.2 Prebiotics

Several studies have demonstrated the potential of

prebiotics to influence stress, anxiety, and depression,

possibly through a reduction in perceived stress

associated with changes in Bifidobacterium spp. or other

gut microbiota taxa (Abidin et al., 2025). Prebiotic

supplementation in mice increased SCFA concentrations,

many of which were negatively correlated with

depression-like and anxiety-like behaviors (Bear et al.,

2021). Animal studies have demonstrated that prebiotic

administration reduces stress responsiveness, anxiety,

and depressive-like behavior, enhances expression of

BDNF, and improves cognition (Jach et al., 2023).

Watson et al., 2026

19 Journal of Research in Biology (2026) 16(2): 1-29

Nurturing a beneficial gut microbiome with prebiotics

such as fructo-oligosaccharides (FOS) and galacto-

oligosaccharides (GOS) is an appealing but under-

investigated microbiota manipulation (Zeppa et al.,

2022). Prebiotic fibers, probiotics, and fermented foods

increase SCFAs with alterations in tryptophan

metabolism toward TPH1-dependent serotonin

production, linking nutrition-driven gut microbiota shifts

to symptoms across mood disorders and metabolic

disease along the microbiota–gut–brain axis (Tang et

al., 2025).

7.3 Synbiotics and Postbiotics

A synergic combination of probiotics and prebiotics is

referred to as a synbiotic, and prebiotics specifically

have a role in promoting probiotic colonization of the

gut (Luqman et al., 2024). Synbiotics synergistically

combine probiotics and prebiotics. The synbiotic had the

greatest effect in reducing stress-induced anxiety-like

behavior and was also able to ameliorate stress-induced

memory changes in animal models (Bear et al., 2021).

Postbiotics deliberately inactivated whole cells or their

components offer health advantages mediated by

changes in the microbiota, improved intestinal barrier

function, modulation of metabolic or immunological

responses, or nervous system signaling. Several studies

on humans and animal models have shown the anti-

depressive and anxiolytic effects of postbiotics (Singh et

al., 2022). Postbiotics have therapeutic benefits

comparable to those of probiotics in that they maintain

the integrity of the epithelial barrier function, restore the

variety and composition of the microbiota, manage

immune reactions, and modulate signaling along the

gut–brain axis (Luqman et al., 2024).

According to studies, regulating the gut–brain axis

protected mice against Salmonella-induced depressive-

like behavior by pretreatment with heat-killed probiotic

L. plantarum-derived postbiotics, notably their

metabolites. Some bacterial metabolites, including

SCFAs and bile acids, have postbiotic properties

(Luqman et al., 2024). When examining clinical trials

utilizing postbiotics for the treatment of mental

disorders, anxiety is the only disorder studied in current

clinical trial registries (Sasso et al. (2023). The

mechanisms, evidence base, and clinical implications of

microbiota-targeted therapeutic strategies are

comparatively summarized in Table 3.

Table 3: Clinical Evidence, Therapeutic Strategies, Current Limitations, and Future Research Priorities

Intervention /

Research Area

Mechanism of

Action

Current

Clinical

Evidence

Major

Limitations

Clinical

Readiness

Future

Research

Priorities

Representative

References

Probiotics

(Psychobiotics)

Modulation of

microbial

composition,

immune

signaling,

neurotransmission

Small to

moderate

improvements

in depressive

symptoms;

inconsistent

Strain

heterogeneity,

dosage

variability,

short follow

up

Adjunctive

therapy

Large

multicenter

randomized

trials and

standardized

formulations

Ng et al.

(2018); Liu et

al. (2019)

Watson et al., 2026

20 Journal of Research in Biology (2026) 16(2): 1-29

findings for

anxiety

Prebiotics Increased SCFA

production and

beneficial

bacterial growth

Limited but

encouraging

evidence

Small sample

sizes and

inconsistent

outcomes

Experimental Identification

of optimal

substrates

and dosing

strategies

Schmidt et al.

(2015); Liu et

al. (2019)

Synbiotics Combined

probiotic and

prebiotic activity

Emerging

evidence

Few high

quality

clinical trials

Experimental Comparative

effectiveness

studies

Liu et al.

(2019)

Dietary

interventions

Global

modulation of

microbial

diversity and

metabolism

Moderate

evidence for

improvement

in depressive

symptoms

Dietary

adherence and

confounding

lifestyle

factors

High Longitudinal

mechanistic

studies

integrating

microbiome

and

metabolomics

Jacka et al.

(2017); Cryan

et al. (2019)

Fecal

microbiota

transplantation

Restoration of

microbial

community

structure

Strong

preclinical

evidence;

limited

clinical

evidence in

psychiatry

Safety

concerns,

donor

variability,

lack of

standardized

protocols

Research

only

Well

controlled

clinical trials

in psychiatric

populations

Kelly et al.

(2016); Zheng

et al. (2016)

Precision

microbiome

therapeutics

Personalized

microbial

interventions

Preliminary Biomarker

validation and

reproducibility

Future

application

Multiomics

integration,

artificial

intelligence

assisted

prediction,

precision

psychiatry

Cryan et al.

(2019); Foster

et al. (2017)

Clinical readiness categories

 High: Supported by multiple clinical studies and suitable as an adjunct to standard care.

Watson et al., 2026

21 Journal of Research in Biology (2026) 16(2): 1-29

 Adjunctive: May complement established treatments but is not recommended as monotherapy.

 Experimental: Requires additional clinical validation before routine use.

 Research only: Currently limited to experimental or investigational settings.

7.4 Fecal Microbiota Transplantation (FMT)

Animal FMT studies support a causal contribution of the

gut microbiota to behavioural phenotypes (Bautista,

2025). FMT may provide antidepressant microbiota to

depressed people, and anxiety is transmissible via FMT

in mice. By using FMT, one may supplement harmful

gut bacteria with healthy ones (Luqman et al., 2024).

Therapeutic strategies aimed at the gut microbiota, such

as probiotics, dietary modifications, prebiotics, and

FMT, may offer future therapeutic opportunities (Ugwu,

2025).

Initial studies suggest that the microbiome may be

utilized to predict treatment outcomes and diagnose

psychological problems. Clinical study outcomes

support the use of probiotics as an adjunct in MDD

treatment and determine the efficacy of psychobiotic

therapy in populations with psychiatric conditions.

However, there have been no clinical trials on the use of

FMT to treat depression specifically, representing a

significant gap in the literature (Luqman et al., 2024).

7.5 Physical Exercise as a Microbiota-Modulating

Intervention

Physical exercise may exert a role in alleviating

depression-like symptoms by inducing changes in the

gut microbiota composition. These modifications have

an impact on the microbiota–gut–brain axis through

different mechanisms, such as activation of the vagus

nerve, modulation of neurotransmitter metabolism (i.e.,

tryptophan, which is converted and produces over 90%

of the serotonin in the gut), regulation of the HPA axis,

an increase in SCFA production (and thus inflammation

reduction), and gut hormones (i.e., GABA, neuropeptide

Y, and dopamine, that act locally on the ENS). A

possible mechanism through which exercise might be

beneficial in the control and treatment of depression is

the ability of the gut microbiota to regulate tryptophan

metabolism via the kynurenine pathway, which is

strongly associated with depression (Zeppa et al.,

2022).

8. Quantitative and Statistical Perspectives

8.1 Epidemiological Burden

Almost 4% of people in the world suffer from

depressive disorders, and the forecasts of further

increase in incidence are alarming (Wilczek et al.,

2023). According to current data from the World Health

Organization, an estimated 280 million people

worldwide suffer from depression (Głaz et al. (2023).

The prevalence of schizophrenia, affecting

approximately 1% of the global population, underscores

the urgency for innovative therapeutic strategies

(Mosquera et al., 2024). Anxiety and depressive

disorders rank among the most prevalent psychiatric

conditions worldwide, yet remission rates remain

unsatisfactory despite advances in pharmacological and

psychotherapeutic interventions (Bautista, 2025).

8.2 Clinical Trial Metrics

When examining clinical trials utilizing probiotics for

the treatment of mental disorders, there are currently a

total of 52 clinical trials covering all stages between

Watson et al., 2026

22 Journal of Research in Biology (2026) 16(2): 1-29

2004 and 2022 listed on the US NIH clinical trials

website. The most studied mental health disorders are

stress, followed by depression, anxiety, cognition

impairment, and sleep disorders. Postbiotic and FMT are

the least researched among all clinical trial categories

explored (Sasso et al., 2023).

A systematic review following PRISMA guidelines

identified 369 articles, of which 45 met inclusion criteria

for psychobiotic interventions in depression. The

predominant psychobiotic strains belonged to

Lactobacillus (45.5%) and Bifidobacterium (29%)

genera. Strain sources included commercial preparations

(24%), human-derived (16%), and food-derived (16%)

strains (Śliwka et al., 2025). In a meta-analysis by Liu

et al. (2019), 34 controlled clinical trials, probiotics

showed small but significant effects for both depression

and anxiety, while prebiotics showed no significant

differences from placebo. A meta-analysis by Chao et

al. (2020) consisting of 10 randomized controlled trials

found that probiotics reduced depressive symptoms in

patients with anxiety and depression and in healthy

people under stress, but there was no reduction in

anxiety scores (MacKay et al., 2024).

8.3 Dose–Response Relationships

For the effectiveness of antidepressant therapy,

psychobiotics should be administered at a dose higher

than 1 billion CFU/day (10⁹ CFU/day) for at least 8

weeks (Jach et al., 2023). Recommended doses for

psychobiotics in clinical studies range from 10⁹ to 10¹⁰

CFU/day, with a duration of at least 4 weeks. Prebiotic

doses range from 5–15 g/day of fibers such as inulin,

fructo-oligosaccharides, and galacto-oligosaccharides,

with a duration of at least 4 weeks (Tang et al., 2025).

The dose–response relationship for psychobiotics can be

conceptualized as follows.

 =





∙ 





+ 

Where:

  = clinical effect

 

max

= maximum achievable effect

  = dose (CFU/day)

 



= dose producing 50% of the maximum

effect

where ED₅₀ is the dose producing 50% of the maximum

effect. Current evidence suggests that doses below 10⁹

CFU/day are generally insufficient to produce clinically

meaningful effects, while doses of 10⁹–10¹⁰ CFU/day

over 4–8 weeks represent the therapeutic window for

most psychobiotic strains (Tang et al., 2025; Jach et al.,

2023).

9. Gut Microbiota in Neurodevelopmental and

Neurodegenerative Disorders

9.1 Autism Spectrum Disorder

In a mouse model of ASD, a maternal high-fat diet

reduced the number of oxytocin immunoreactive

neurons in the hypothalamus and induced dysbiosis that

was restored by a commensal Lactobacillus reuteri

strain. In humans, evidence of microbiome–gut–brain

axis interactions have been obtained from the

association of shifts in gut microbiota composition with

central nervous disorders including ASD and anxiety

and depressive behaviors (Cerdó et al., 2017). In

clinical trials, prebiotic supplementation improved social

behavior symptoms and sleep patterns in ASD (Jach et

al., 2023).

9.2 Alzheimer's Disease and Parkinson's Disease

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23 Journal of Research in Biology (2026) 16(2): 1-29

The microbiota–gut–brain axis has emerged as a

potential focus for the enhancement of cognitive abilities

and the improvement of Alzheimer's disease (AD).

Probiotics and prebiotics can improve the imbalance

associated with AD. SLAB51 and Lab4b, two mixed

probiotic formulations, have respectively shown

potential in in vitro models of Parkinson's disease and

neuronal protection. Although these "psychobiotics" are

effective in reducing neuronal damage and inhibiting

brain inflammation, direct clinical evidence for AD

patients is still lacking.

In the domain of mental and brain health, psychobiotics

such as Lactobacillus rhamnosus, Lactobacillus lactis,

and Lactobacillus casei differ in their effects on

improving cognitive function and all reduce the response

to stress. This form of treatment not only rectifies the

imbalance of intestinal flora but is also closely

associated with the restoration of the intestinal barrier

(Zhang et al., 2025).

9.3 Schizophrenia

The prevalence of schizophrenia, affecting

approximately 1% of the global population, underscores

the urgency for innovative therapeutic strategies. Recent

insights into the role of neuroinflammation, the gut–

brain axis, and the microbiota in schizophrenia

pathogenesis have paved the way for the exploration of

psychobiotics as a novel treatment avenue. These

interventions, targeting the gut microbiome, offer a

promising approach to ameliorating psychiatric

symptoms. Probiotics and psychobiotics, including

specific strains of Lactobacillus and Bifidobacterium,

have shown promising effects in reducing depressive

and anxiety symptoms in both animal models and

human trials (Mosquera et al., 2024).

10. Methodological Considerations and Limitations

10.1 Heterogeneity in Study Design

The results of MGB axis studies do not always agree,

and the results from animal studies do not always

translate well to human research. This has been a

concern with MGB axis research (Bear et al., 2021).

Heterogeneity in study design, small sample sizes, and

limited causal evidence underscore the need for

rigorous, large-scale trials (Abidin et al., 2025).

Findings remain heterogeneous due to strain specificity,

individual microbiome diversity, and methodological

differences across studies (Jafari, 2025).

10.2 Translational Challenges

Matters to be considered in future research include

longer-term studies with factors such as sex of the

subjects, drug use, comorbidity, ethnicity/race,

environmental effects, diet, and exercise taken into

account. The translatability of studies on animal models

to clinical situations and the effects on the gut

microbiome of drugs currently used to treat these

disorders represent important research priorities. Based

on animal work, supplementation with SCFAs looks

promising for improving anxiety-like and depression-

like symptoms, but more information about

translatability to humans, particularly across the

lifespan, must be obtained (MacKay et al., 2024).

10.3 Nuance and Disagreement in the Literature

It is important to note that not all studies report

consistent findings. In a study by Romijn et al. (2017)

with a cohort of 79 participants with self-reported mood

measures, a probiotic preparation containing L.

helveticus and B. longum did not significantly alter the

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24 Journal of Research in Biology (2026) 16(2): 1-29

mood or depression scores compared to the placebo

group; however, this could be from the heterogeneity,

severity, or chronicity of the treatment cohort (Westfall

& Pasinetti, 2019). Some researchers indicate that

probiotics may lead to significant improvements in

cognitive function in patients suffering from depressive

disorders, while others find no significant effect (Głaz et

al., 2023). The exact mechanisms of action and the

specific roles of psychobiotic microorganisms in

modulating the microbiota–gut–brain axis are still not

fully understood (Śliwka et al., 2025).

11. Future Directions and Precision Psychiatry

11.1 Personalized Microbiome-Based Therapies

Precision interventions ranging from diet and

psychobiotics to FMT, chrononutrition, and immune-

modulatory strategies offer promising avenues for

personalized psychiatry (Bautista, 2025). Future

directions should prioritize identification of microbial

biomarkers, optimization of strain-specific and dose–

response data, and integration of gut-targeted

approaches into personalized mental healthcare (Abidin

et al., 2025). The understanding of the gut microbiota

and its activities is essential for the generation of future

personalized healthcare strategies (Cerdó et al., 2017).

Innovative drug carriers, such as microbially-derived

nanoparticles and probiotics that target particular parts

of the gut or microbial communities, may improve

pharmaceutical treatment efficacy and specificity

(Ugwu, 2025). Advancements in artificial intelligence

and nanotechnology are set to revolutionize psychobiotic

development and application, promising to enhance their

production, precision, and effectiveness (Mosquera et

al., 2024).

11.2 Biomarker Development

Initial studies suggest that the microbiome may be

utilized to predict treatment outcomes and diagnose

psychological problems (Luqman et al., 2024).

Emerging evidence suggests that personalized

biomarkers could help predict who will benefit most

from probiotic interventions. Baseline microbiota

diversity, higher levels of Lactobacillus and

Bifidobacterium, and lower abundance of pro-

inflammatory taxa appear linked to better outcomes in

neurological and psychiatric disorders. Reductions in

inflammatory markers such as IL-6, TNF-α, IL-17, and

CRP, along with favorable metabolomic profiles like

elevated SCFAs and balanced tryptophan metabolism,

correlate with improved cognition and mood (Jafari,

2025).

11.3 Integration with Conventional Therapies

Administration of probiotics labeled as psychobiotics

and their metabolites as metabiotics, especially as an

adjuvant to antidepressants, improves mental disorders

(Jach et al., 2023). Microbial modulation offers a novel

adjunctive strategy for depression management,

particularly in treatment-resistant cases or to reduce the

side effects of conventional drugs (Abidin et al., 2025).

Nutritional interventions should be used cautiously for

the medical management of significant depressive

disorders; they ought to be paired with other therapies

such as behavioral therapy, medication for depression,

and habitual modifications (Luqman et al., 2024).

Studies suggest that probiotics may serve as an adjunct

therapy for depression, especially in treatment-resistant

cases. The increasing acceptance of the expanded

concept of the MGB axis underscores the importance of

microorganisms in mental well-being. As our

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25 Journal of Research in Biology (2026) 16(2): 1-29

understanding of the microbiome's role in health and

disease grows, probiotics emerge as promising agents

for addressing mental health issues, providing new

avenues for therapeutic interventions in depressive

disorders (Dziedzic et al., 2024).

Despite substantial progress during the past decade, the

field remains in an early stage of clinical translation.

Future advances will depend not only on identifying

disease associated microbial signatures but also on

establishing reproducible mechanistic pathways and

clinically meaningful therapeutic targets.

12. Conclusion

The gut microbiota plays a multifaceted and increasingly

recognized role in the regulation of anxiety and mental

health through its complex bidirectional interactions

with the CNS via the MGB axis. The mechanistic

underpinnings of this relationship encompass neural

(vagus nerve, ENS), endocrine (HPA axis), immune

(cytokine signaling, neuroinflammation), and metabolic

(SCFAs, tryptophan metabolites, GABA, BDNF)

pathways that collectively modulate neurotransmitter

synthesis, stress reactivity, intestinal permeability, and

neuroplasticity.

Dysbiosis has frequently been characterized by

reductions in Lactobacillus, Bifidobacterium, and

butyrate-producing genera alongside elevations in pro-

inflammatory taxa are consistently associated with

heightened anxiety and depressive symptomatology

across preclinical and clinical studies. Potential causal

role supported by animal studies of the gut microbiota in

mental health is supported by FMT experiments

demonstrating the transmissibility of depressive and

anxiety-like phenotypes through microbial communities.

Therapeutic modulation of the gut microbiota through

psychobiotics (10⁹–10¹⁰ CFU/day for ≥4–8 weeks),

prebiotics (5–15 g/day), synbiotics, postbiotics, dietary

interventions, and FMT represents a promising area for

future therapeutic development. Meta-analyses of

randomized controlled trials demonstrate small but

significant effects of probiotics on both depression and

anxiety, with strain-specific effects being a critical

determinant of therapeutic efficacy. Lactobacillus

plantarum, Bifidobacterium breve, and Akkermansia

muciniphila have demonstrated particularly promising

effects.

Despite these advances, significant challenges remain,

including heterogeneity in study design, small sample

sizes, limited causal evidence in humans, and the

complexity of individual microbiome variability. Future

research must prioritize large-scale, well-designed

randomized controlled trials; identification of microbial

biomarkers for treatment response prediction;

optimization of strain-specific and dose–response data;

and integration of gut-targeted approaches into

personalized mental healthcare frameworks. The

reconceptualization of anxiety and depression as

systemic conditions arising from integrated neural,

immune, endocrine, metabolic, and circadian

dysregulation rather than isolated brain-based

pathologies positions the gut microbiota as a central

therapeutic target in the evolving field of precision

psychiatry.

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