Article

ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 6, pp. 867-892 © Pleiades Publishing, Ltd., 2026.

867

REVIEW

Effects of Metabolites of Lactic Acid Bacteria

on Nerve Cells of the Microbiota–Gut–Brain Axis

Konstantin V. Sobol

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences,

194223 St. Petersburg, Russia

e-mail: peep9@yandex.ru

Received February 11, 2026

Revised May 20, 2026

Accepted May 21, 2026

Abstract— This review examines the key pathways of bidirectional communication between the gut and

brain along the microbiota–gut–brain axis, with particular emphasis on the effects of metabolites of lactic

acid bacteria (metLABs) on neurons of the enteric and central nervous systems. Special attention is given

to the role of metLABs in intracellular signaling. The review further explores the direct effects of metLABs

on mitochondrial function in nervous tissue, neuronal plasticity, and neuritogenesis. Potential mechanisms

for the release of neurotrophic factors in both cells and host organism following exposure to metLABs

or probiotic products are analyzed. Although clinical evidence remains limited, existing studies suggest

that regular consumption of metLAB-containing fermented foods may positively influence brain functions

through modulation of the microbiota–gut–brain axis. At least two ongoing clinical trials currently investi-

gate whether normalization of the gut microbiota through probiotic interventions can slow the progression

of Alzheimer’s disease. As this field continues to advance rapidly, further studies are expected to provide

important insights into the therapeutic potential of microbiota-targeted strategies for neurological health.

DOI: 10.1134/S0006297926600377

Keywords: gut–brain, microbiota, microbiota metabolites, lactic acid bacteria, neurons, central nervous system,

enteric nervous system, mitochondria, oxidative stress, neurotrophic factors, neuroplasticity

INTRODUCTION

A constant, bidirectional, and dynamic commu-

nication network existing between the gastrointesti-

nal (GI) tract and the nervous system is commonly

referred to as the gut–brain axis  [1-3]. Because the

gut microbiota and its metabolites are central com-

ponents of this system, the concept can be more ac-

curately described as the microbiota–gut–brain (MGB)

axis [1-7]. The microbiota of a host is often regarded

as a metabolically active “organ” that produces mol-

ecules involved in communication between bacterial

cells, as well as hormones and substances structural-

ly identical to human and plant hormones, microbi-

al neurometabolites, short-chain fatty acids (SCFAs),

growth factors, gaseous molecules, and other bio-

logically active compounds [1, 3, 6, 8-11]. Although

the microbiota functions relatively autonomously, it

significantly affects the host’s nervous system [1,  5,

8, 10, 12-15]. In general, pathogens and pathobionts

negatively influence the nervous system, while sym-

biotic microbiota has a beneficial effect on the host

and its organ systems [3, 8, 9, 15-17]. Live bacteria,

such as probiotics and psychobiotics, are commonly

used to restore intestinal imbalance and maintain

healthy intestinal homeostasis [1, 8, 18, 19]. Among

these, lactic acid bacteria (LAB) deserve particular at-

tention, since they dominate in the female birth canal

and play a significant role in the initial colonization

of the neonatal gut [1, 17]. Since beneficial effects of

LAB are mediated largely through their metabolites

(metLABs) [1, 5, 8-12, 20-24], investigating the action

of these compounds at the cellular level is of par-

ticular importance. Accumulating evidence suggests

that metLABs function as important signaling mole-

cules during early development by modulating neu-

rodevelopment, which also has implications for long-

term health, including prevention and treatment of

inflammatory and neurodegenerative diseases [3, 22,

25]. Therefore, this review focuses primarily on the

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effects of metLABs on the biochemical and intracellu-

lar signaling pathways in neurons of the enteric and

central nervous systems. Before discussing the direct

effects of metLABs on nerve cells, however, it is nec-

essary to briefly describe the main pathways, through

which the gut microbiota and the central nervous

system (CNS) communicate.

MICROBIOTA–GUT–BRAIN AXIS

The gut is closely connected to the emotional and

cognitive centers of the brain via neural, endocrine,

immune, and humoral pathways (Fig.  1) [1,  26-29].

This communication forms the MGB axis, a bidirec-

tional system linking the gut and its residential mi-

crobial community (microbiota) to the brain (Fig.  1)

[1, 3, 16, 30]. Through this complex communication,

gut microorganisms can influence cognitive function,

emotions, and brain health, while the brain regulates

intestinal motility, permeability, and secretion, as well

as the microbiota composition. The main pathways

through which such interactions occur are: 1)  neural

signaling mediated by the autonomic nervous system

and neurons of the enteric nervous system (ENS);

2)  the hypothalamic–pituitary–adrenal (HPA) axis;

3)  humoral and neuroendocrine mechanisms; 4)  in-

volvement of the immune system; and 5)  the micro-

biota and its microbial metabolites (Fig.  1).

The sympathetic and parasympathetic branch-

es of the autonomic nervous system and the ENS

participate in the MGB axis. The ENS, often referred

to as the “second brain,” functions autonomously but

also interacts bidirectionally with the CNS via the

gut–brain axis. This bidirectional signaling controls

digestion, mood, and cognitive function. The vagus

nerve (cranial nerve X) serves as the primary neural

conduit, transmitting approximately 80% of afferent

signals from the ENS to the CNS  [31], thus providing

information about the intestinal state, and 20% of ef-

ferent signals from the brain to the gut to regulate

intestinal motility [2, 3, 26, 32].

The vagus nerve is a major element of the para-

sympathetic nervous system, which controls a broad

range of essential body functions, including mood

control, immune response, digestion, and heart rate.

Fig.  1. The MGB axis. The bidirectional communication between the microbiota and the CNS occurs through neural con-

nections  (1), the HPA axis (2), humoral and neuroendocrine interactions  (3), and immune system-mediated signaling (4).

TheCNS modulates intestinal physiology, as well as controls the composition and some functions of gut microbiota via the

HPA axis, neuroendocrine signaling, and peripheral efferent nerves innervating the intestine (5). At the same time, microbial

metabolites influence the development and functioning of the CNS through neuro-immuno-endocrine pathways, establishing

a dynamic communication along the MGB axis. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone;

Nts, neurotransmitters, Nps, neuropeptides, Cytk, cytokines; GALT, gut-associated lymphoid tissue; GLP-1, glucagon-like pep-

tide  1, PYY, peptide tyrosine–tyrosine, EN, enteric neuron; vagus, vagus nerve. The figure was created using graphic elements

from Servier Medical Art (https://smart.servier.com) and BioRender (https://www.biorender.com).

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

Afferent vagal and spinal sensory neurons convey

information from the gut to the brainstem, which

integrates these signals and engages the hypothala-

mus and the limbic system, thereby influencing au-

tonomic, emotional, and cognitive functions. Spinal

afferent nerves (e.g., via the dorsal root ganglia)

transmit nociceptive and pain signals from the ENS

to the spinal cord  [26]. Descending projections from

the limbic system influence autonomic output to the

gut. Beyond various neurotransmitter receptors, the

vagus nerve expresses receptors for cytokines, leukot-

rienes, sphingolipids, and prostaglandins, as well as

purinergic receptors, and various G  protein-coupled

receptors (GPCRs)  [33,  34]. Among these, the alpha-7

nicotinic acetylcholine receptor (α7-nAChR) is par-

ticularly important due to its role in regulating in-

flammation and mediating communications between

the immune system and the CNS  [34]. Together, these

receptors enable the vagus nerve to act as a bidirec-

tional “highway”, constantly monitoring the internal

state of the body (inflammation, satiety, blood sugar

levels) and adjusting the organ functions accordingly.

However, the number of receptors located on the va-

gus nerve and capable of detecting GI hormones and

microbiota metabolites is limited, with only a small

fraction of SCFA receptors  [33]. Therefore, most mi-

crobial metabolites are unlikely to act directly on va-

gal afferent fibers. Instead, they may influence them

via enteroendocrine cells (EECs)  [33].

The ENS is an extensive neuronal structure em-

bedded in the GI tract (Fig.  2). Enteric neurons are

organized into ganglionic networks that surround the

intestine and are primarily arranged into two major

plexuses: the Auerbach’s (external) plexus, located

between the longitudinal and circular muscle layers,

and the Meissner’s (internal) plexus, located in the

submucosa (Fig.  2). The two plexuses are closely con-

nected via a network of interneurons, motor neurons,

and enteric glial cells. Through reflexes and coordi-

nated action, they enable regulation of GI activity:

the Auerbach’s plexus primarily controls peristalsis,

whereas the Meissner’s plexus regulates secretory

functions of the GI tract. The ENS is responsible for

maintaining digestive processes and has been impli-

cated in a variety of neurological disorders, including

those associated with the MGB axis [1, 3, 4, 7, 26].

The ENS provides intrinsic and extrinsic innervation

of the GI tract. The intrinsic innervation consists of

neurons localized in the GI tract, and the extrinsic

innervation is formed by neurons outside the GI tract

(Fig.  2). The intrinsic ENS network includes sensory

neurons, interneurons, and motor neurons that form

Fig. 2. Simplified diagram of the ENS. The GI tract has its own nervous system, the ENS, which is located in the intestinal

wall along its entire length. Enteric neurons are directly regulated by luminal stimuli, including nutrients, chemical com-

pounds, and mechanical signals, and also receive input from EECs. Although the ENS is capable of autonomous function,

it integrates signals from extrinsic sensory, parasympathetic, and sympathetic neurons to coordinate GI tract physiology.

Sympathetic neurons are involved in initiating stress responses and generally suppress intestinal activity, whereas para-

sympathetic neurons promote digestion and stimulate intestinal peristalsis  [36]. Nitric oxide (NO) and vasoactive intestinal

peptide (VIP) promote relaxation, while acetylcholine (ACh) and substance P (SP) stimulate contraction of GI smooth muscle

cells; SN, sensory neuron. Graphic elements were adapted from Servier Medical Art (https://smart.servier.com).

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Fig.  3. Effect of metLABs and pathogens/pathobionts on the nervous system. SCFAs and lactate diffuse across the intestinal

epithelium or enter cells via specific transporters and serve as important energy sources for colonocytes and nervous

tissue [40-42]. By activating GPCRs, SCFAs stimulate EECs to release intestinal hormones, such as PYY and GLP-1  [40].

MetLABs attenuate inflammation (Infl) (blue arrows) by reducing the levels of proinflammatory cytokines (Cytk) [40]. SCFAs

can also directly activate ENS neurons via cognate receptors and, after penetrating the blood-brain barrier (BBB), exert a

neuroprotective effect in CNS cells  [40]. External stressors and other adverse factors can cause dysbiosis and increase in-

testinal permeability to neurotoxic factors (NTx). For example, toxic aggregates of α-synuclein (α-syn) can spread from the

intestine to the CNS via the vagus nerve  [43]. NTx, such as lipopolysaccharide (LPS), amyloids, and trimethylamine N-oxide,

and proinflammatory factors can disrupt the BBB permeability and exert a negative impact on the nervous tissue. Chronic

negative impact on the cardiovascular system (CVS) may increase the risk of atherosclerosis, heart attack, and stroke  [44].

MetLABs may also stimulate intestinal motility  [45]. During stress, enteric neurons (EN) and immune cells (Im) release gut

neuropeptides (GNps), which can exhibit direct antimicrobial activity  [38]. The vagus nerve can stimulate the release of

ACh and VIP, which promote production of immunoglobulin  A (IgA) by immune and intestinal cells, thereby contributing

to pathogen suppression [8, 21, 30, 40, 46, 47]. Left panel illustrates the effects of metLABs; right panel depicts the detri-

mental effects of pathogens and pathobionts on the CNS and cardiovascular system. Proinflammatory cytokines (TNF-α,

IL-1β, IL-6, IL-8) are shown in red; anti-inflammatory cytokines (IL-4, IL-10) are shown in blue. NE, norepinephrine; UR,

unknown receptor; NF, neurotrophic factors; OS, oxidative stress; ROS, reactive oxygen species; Trp, tryptophan; EEC-L,

enteroendocrine cells type  L; EC, enterochromaffin cell; ΔΨm, mitochondrial membrane potential. Graphic elements from

Servier Medical Art (https://smart.servier.com) were used in creating the figure.

complex circuits within Auerbach’s and Meissner’s

plexuses [29, 35, 36]. It regulates such important func-

tions as muscle contraction, enzyme and hormone

secretion, local blood flow, and nutrient absorption.

The ENS actively interacts with intestinal immune

cells [1, 4, 35, 37]. Although the ENS is capable of

functioning autonomously, it interacts with the CNS.

The ENS shares structural and function similarities

with the brain, can influence mood and learning, and

is likewise susceptible to neurodegenerative changes

[1, 35, 36]. EECs of the GI tract, immune cells, and

neurons of the ENS, especially sensory neurons, can

recognize and differentiate between commensal and

pathogenic bacteria and release antimicrobial factors,

including intestinal hormones and neuropeptides

such as calcitonin gene-related peptide, vasoactive

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intestinal peptide (VIP), adrenomedullin, substance P,

neuropeptide  Y, glucagon-like peptide-1 (GLP-1), pep-

tide tyrosine–tyrosine (PYY), etc. [1, 38]. These antimi-

crobial factors can directly inactivate pathogenic bac-

teria, as well as attract immune cells and modulate

immune responses (Fig. 3) [30, 39].

The HPA axis is the body’s primary stress re-

sponse system, linking the brain (hypothalamus and

pituitary gland) with the endocrine system (adrenal

glands). In response to stress, it releases stress hor-

mones, e.g., cortisol, which regulate metabolism, im-

mune function, and mood (Fig.  1). Microbiota-derived

metabolites can enter the bloodstream and reach the

CNS, thus modulating the HPA axis activity (Fig.  1).

Conversely, stress and subsequent release of corti-

sol can alter the composition of the gut microbiota

(Fig.  1)  [4]. Thus, chronic activation of the HPA axis

can lead to adverse psychoemotional and physiologi-

cal outcomes, such as anxiety, fatigue, and metabolic

disorders  [4,  48].

Humoral and neuroendocrine interactions.

In response to external stimuli, including microbio-

ta-derived metabolites, EECs secrete a wide range of

hormones and neuropeptides, such as PYY, neuro-

peptide  Y, cholecystokinin, GLP-1 and GLP-2, ghrelin,

etc. These molecules enter the circulation and/or act

on nearby ENS neurons (Fig.  3) [1, 8, 14, 49]. Intes-

tinal hormones regulate digestion, appetite, metab-

olism, and intestinal growth, acting through local

(paracrine/autocrine) or systemic (endocrine) mech-

anisms  [1,  14]. Dysregulation of intestinal peptides,

such as EEC-derived GLP-1, has been associated with

neuroinflammation and the development of neuro-

degenerative diseases  [50]. Serotonin is synthesized

from tryptophan by gastrointestinal enterochromaffin

cells (Fig.  3) [14, 51]. More than 90% of the body’s

serotonin is produced in the GI tract. Serotonin re-

lease is predominantly triggered by mechanical and

chemical stimuli  [14,  52]. Locally, serotonin binds

to receptors expressed on enteric neurons, smooth

muscle cells, and epithelial cells, thereby regulating

gastrointestinal motility and secretion [14, 52]. It also

promotes epithelial proliferation and neurogenesis in

the ENS [14,  53]. Serotonin interacts with the brain

by binding to serotonin receptors of the vagus nerve

(Fig. 3)  [54].

Involvement of the immune system. Gut-associ-

ated lymphoid tissue (GALT) comprises approximately

70% of the body’s immune system (Fig. 1) and, there-

fore, can be considered as the largest immune organ

in human body. From birth, GALT immune cells con-

tribute to the CNS development [25, 55]. On the oth-

er hand, the brain regulates the immune system and

intestinal integrity through the autonomic nervous

system (ANS), particularly via the vagus nerve [30,

39]. After contact with microorganisms, innate im-

mune cells in the intestine release cytokines, chemok-

ines, and lipid mediators, which enter the circulation

and reach the brain endothelium (Fig.  3) [30, 55-57].

Immune cells also express receptors for numerous

neurotransmitters, neuropeptides, and hormones,

enabling their direct regulation by the nervous sys-

tem  [56]. Under physiological conditions, only a lim-

ited number of peripheral immune cells, such as pa-

trolling monocytes and certain T  cell subpopulations,

can access the CNS. However, in neurodegenerative

disorders, such as Alzheimer’s disease, disruption of

the BBB facilitates the infiltration of peripheral im-

mune cells into the brain tissue  [57]. While some of

these cells contribute to beta-amyloid (Aβ) clearance,

others exacerbate neuroinflammation by releasing

proinflammatory mediators  [57]. Microglia and res-

ident macrophages in the brain parenchyma detect

signals from peripheral cytokines, hormones, and mi-

crobiota-derived metabolites. These signals can regu-

late synaptic signaling, inflammatory responses, and

phagocytic functions  [58]. Communication between

the GALT and the brain occurs primarily through two

interconnected pathways: the circulation of signaling

molecules and immune cells via the bloodstream and

activation of afferent ANS fibers, particularly the va-

gus nerve, which detects cytokine signals and relays

this information to the brainstem nuclei (Fig.  3)  [30].

In response, efferent fibers of the vagus nerve re-

lease acetylcholine (ACh), which suppresses cytokine

release through activation of α7-nAChR expressed on

macrophages. Thus, the brain can control inflamma-

tion by weakening the immune response  [34]. In neu-

rodegenerative diseases, excessive activation of the

intestinal immune system and dysbiosis can aggra-

vate pathology by increasing the levels of circulating

proinflammatory cytokines, disrupting integrity of the

intestinal barrier and the BBB, and shifting microglial

activity towards pro-inflammatory phenotypes (Fig.3).

These processes lead to a decrease in serotonin levels

in the hippocampus, a region critical for regulating

mood and memory, as well as downregulate expres-

sion of brain-derived neurotrophic factor (BDNF) that

supports the growth and survival of neurons. Restor-

ing eubiosis and regulatory immune responses may

contribute to the restoration of the neuroprotective

phenotype (Fig.  3) [34, 56, 59]. In fact, immune sys-

tem cells act as a peripheral neuroendocrine organ,

receiving and integrating signals from the nervous

and endocrine systems through the corresponding re-

ceptors. This communication enables complex coordi-

nated responses, both under physiological conditions

and during stress, infection, and other pathological

states. These neuroimmune interactions represent a

key regulatory mechanism for maintaining homeosta-

sis, with the nervous system acting as a modulator of

immune responses.

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Microbiota and its metabolites. Gut microbio-

ta synthesizes a wide range of bioactive compounds,

including hormones, microbial neurometabolites,

SCFAs, growth factors, gaseous molecules, etc. [1, 3,

8-11, 60-62]. Microbial metabolites produced in the GI

tract provide the main mechanism of communication

between the host organism and its microbial commu-

nity [1, 8-11]. Through its metabolites, microbiota af-

fects neurogenesis  [21, 63-66], neurodevelopment  [25],

synaptic plasticity  [21, 66-68], neurodegeneration [3,

15, 16, 32], as well as mood and behavior  [1] of the

host. The microbiota directly modulates the activity

of ENS neurons  [1, 14, 49], altering their excitability

and electrophysiological properties  [13] and activat-

ing neuronal signaling through Toll-like receptors  [1].

Furthermore, gut microbiota sends signals to muco-

sal glial cells, which influence intestinal nerve cells

and release essential neurotrophic and structural

proteins, such as the glial cell line-derived neuro-

trophic factor and glial fibrillary acidic protein. These

molecules are essential for maintaining the health

and function of the intestinal mucosa and its neu-

ral network. In the absence of adequate interaction

with the microbiota, glial cells produce insufficient

quantities of these protective factors, resulting in im-

paired intestinal motility and compromised intestinal

barrier integrity  [55]. As mentioned above, neurons

of the ENS release antimicrobial factors in response

to certain bacteria, thereby suppressing the growth of

pathogenic microorganisms (Fig. 3). Some microbial

metabolites can penetrate the intestinal barrier and,

to a much lesser extent, the BBB [1, 5]. At the same

time, certain microorganisms of the gut microbiota

produce toxic metabolites that can also disrupt the

integrity of the intestinal barrier and the BBB and

promote neurodegeneration via induction of system-

ic inflammation (Fig. 3) [15, 32]. Recent studies have

demonstrated that microbiota-derived metabolites

can activate colonic motility  [45] both directly and

indirectly by stimulating serotonin synthesis in endo-

thelial cells, which, in turn, modulates intestinal mo-

tility and innervation (Fig.3) [14]. There is a growing

body of evidence suggesting that gut microbiota can

alter the redox balance in the CNS  [17].

Importantly, all these pathways are highly inter-

connected and do not exist in isolation. For example,

during inflammation, the host’s immune system pro-

duces excessive amounts of proinflammatory factors,

such as cytokines, which can affect ENS neurons and

afferent pathways, as well as the secretion of gut

hormones by EECs (Fig.  1). Commensal gut bacteria

also affect both the endocrine system and the CNS

through neural, endocrine, and immune pathways of

the MGB axis, modulating neurotransmitter produc-

tion and brain function (Fig.  3). For example, probi-

otics containing bifidobacteria and lactobacilli have

been shown to increase BDNF levels, supporting

neuronal growth and brain plasticity  [67]. Although

the overall relationship between the gut microbiota

and host organism has been well established, eluci-

dation of precise mechanisms, concentrations, and

long-term effects of specific microbial metabolites on

the normal host physiology and disease development

remains an important area of ongoing research.

METABOLITES OF LAB

AND THEIR EFFECT ON NERVE CELLS

Fermentation of foods by LAB has been practiced

by humans for thousands of years  [69,  70]. Louis

Pasteur was the first to demonstrate the role of mi-

croorganisms in lactic acid fermentation  [71]. Cur-

rently, LAB used in food industry and as probiotics

are generally recognized as safe (GRAS). During cul-

tivation and especially during fermentation, LAB syn-

thesize a wide range of biologically active compounds

(Table  1), most of which have a beneficial effect on

human and animal health [1, 9, 17, 70]. MetLABs do

not exhibit significant toxicity  [72,  73]. LAB and their

metabolites promote the stability of the gut microbi-

ota by modulating its composition, suppressing colo-

nization of the GI tract by pathogens, and protecting

the intestinal epithelial barrier [38]. In addition, met-

LABs are involved in the modulation and regulation

of the host’s immune system  [34,  56]. Finally, emerg-

ing evidence suggests that metLABs may influence

behavior, as well as mental and emotional health of

the host  [1,  17,  25]. Lactobacilli are also known to

dominate in the vaginal microbiome of healthy repro-

ductive-age women, where they lower pH and protect

against pathogenic microorganisms, thereby support-

ing the overall woman health and favorable course of

pregnancy [17, 74]. LABs are among the first bacteria,

which seed a fetus during passage through the birth

canal. This vertical transmission of bacteria supports

neonatal immunity and reduces the risk of infection

[17,  25]. Furthermore, maternal microbiota has been

shown to promote axonogenesis and fetal neurode-

velopment in mice  [75], while impaired colonization

of the fetus with lactobacilli increased neurodevelop-

mental risks  [76,  77]. The mechanisms by which met-

LABs influence nervous system cells, both invivo and

in  vitro, are discussed below.

SCFAs activate cognate receptors in nerve

cells and in neuronal cell lines. SCFAs are among

key metabolites of LAB (Table  1). Table  2 shows the

concentrations of various SCFAs in the intestine and

brain tissue. In the colon, the total content of SCFAs

ranges from ~80 to 131  μmol/g tissue, with the high-

est concentrations observed in the cecum (131  ± 

9  μmol/g tissue) and the lowest in the descending

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Table 1. Metabolites synthesized by LAB and substances involved in their metabolism/release in the host*

Class of substance Examples References

Neurotransmitters norepinephrine [60-62, 78]

dopamine [60-62]

histamine [60, 62, 78]

GABA [61, 78-81]

acetylcholine [60, 78, 82]

serotonin [60, 62, 78]

glutamate [60-62]

Precursors of neuroactive

substances

tryptophan [60, 61, 83]

L-DOPA (levodopa) [62]

Organic acids lactate, acetate, butyrate, propionate, valerate, succinate [71, 78, 84-86]

Amino acids alanine, arginine, serine, histidine, threonine, valine,

isoleucine, leucine, tyrosine, tryptophan

[60, 87, 88]

Hormones** PYY, ghrelin, leptin, GLP, insulin, calcitonin [86, 89-91]

oxytocin [92]

Peptides** β-endorphin, neurotrophic and growth factors [93, 94]

bacteriocins (lantibiotics, plantaricins, nisin) [95]

Lipids conjugated linoleic acids [78, 96, 97]

LAB may reduce cholesterol and triglyceride levels [98]

Inorganic compounds CO

, H

, NO [99-101]

Vitamins group B vitamins, vitaminK [102, 103]

Note. *  See also [1, 5, 8-11]. The table presents the most well-characterized metabolites produced by lactobacilli. Ramos

et  al.  [24] provide a complete list of esters, alcohols, phenolic compounds, barbiturates, and autoinducers identified in the

culture medium of Lactiplantibacillus plantarum ATCC 10241. **LAB and their metabolites, such as SCFAs, can stimulate the

release of various hormones and peptides from host’s EECs (Fig.  3) [91, 104-106]. Listed metabolites may also be produced

by other members of the host’s microbiota [104-106].

colon (80  ±  11μmol/g tissue)  [107]. Inhealthy individ-

uals, fecal SCFA levels are ~34  μmol/g tissue, serving

as an indicator of colonic metabolism. The GI tract

produces estimated 500-600  mmol of SCFAs per day,

with a molar ratio of acetate : propionate : butyr-

ate of 60  :  20  :  20  [91, 108-110]. Reduced content of

SCFAs, particularly butyrate, in the plasma or feces

can be used as a biomarker of various neurological

disorders [91, 110].

SCFAs activate receptors and ion channels asso-

ciated with neuronal signaling via the MGB axis, ei-

ther stimulating or inhibiting the neuronal activity.

SCFAs can act through GPCRs, primarily free fatty

acid receptor  2 (FFAR2/GPR43) and free fatty acid re-

ceptor  3 (FFAR3/GPR41) [40, 104, 106, 110, 114]. Acti-

vation of FFAR2 may triggers two different signaling

pathways depending on G  protein subunit. Coupling

to Gαi/o inhibits adenylate cyclase, whereas activation

of Gαq/11 stimulates phospholipase  C (PLC), leading

to the intracellular calcium ([Ca

]

) elevation and ac-

tivation of protein kinase  C [115]. FFAR2 is expressed

in the spleen, bone marrow, lungs, EECs, adipose

tissue, mammary glands, heart, immune cells, and

throughout the GI tract [105, 115]. FFAR3 receptor is

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Table 2. Normal SCFA concentrations in the GI tract and brain tissue of adults over 18 years of age

SCFA concentration in tissues Acetate Propionate Butyrate

GI tract 35-37 µmol/g [111] 6-12 µmol/g [111, 112] 4-12 µmol/g [112]

Brain – 18.8 pmol/g [113] 17.0 pmol/g [113]

Note. Beside addition to LAB, other genera of microorganisms can synthesize SCFAs [91].

found in intestinal EECs, enteric nerve plexuses, pan-

creatic cells, vascular endothelial cells, adipose tissue,

antigen-presenting cells, gastric mucosal cells, and in

the sympathetic nervous system  [105,  116]. In ner-

vous system, FFAR3 is expressed in a subset of sym-

pathetic neurons and in the CNS  [105,  116], whereas

FFAR2 is found primarily in immune and glial cells,

with very low expression in neurons. However, FFAR2

was identified in neurons of the cerebral cortex, pitu-

itary gland, and hypothalamus  [105,  115]. Activation

of FFAR3 in the proximal colon promotes stimulation

of vagal afferent fibers [40, 110, 117]. Both FFAR2 and

FFAR3 are expressed in dorsal root ganglia. In cells

isolated from these ganglia, activation of FFAR2 and

FFAR3 resulted in the elevated [Ca

]

  [117]. FFAR2 ac-

tivation in the colon triggers PYY release (Fig.  3)  [40,

110, 117]. Collectively, activation of FFAR2 and FFAR3

in the intestinal lumen stimulates spinal cord activ-

ity, whereas FFAR3 directly modulates the activity

of sensory afferent neurons [110, 117]. By acting

through FFAR2 and FFAR3, butyrate increased [Ca

]

in cultured rat pituitary cells, resulting in the stim-

ulation of synthesis and release of human growth

hormone[118]. Another study showed that activation

of FFAR2 by SCFAs in SH-SY5Y neuronal cells had a

neuroprotective effect. The authors suggested that

triggering signaling pathways through FFAR2 in nerve

cells may be a potential target for in the treatment

of neurodegenerative diseases [119]. SCFAs also act as

histone deacetylase (HDAC) inhibitors, thus promoting

histone acetylation in dopaminergic neurons and pro-

tecting them from toxic α-synuclein aggregates [40,

110]. However, some studies have shown that SCFAs

induced an increase in Aβ levels in the brain of germ-

free mice [120], while inhibition of signaling through

FFAR2 promoted Aβ-induced neurotoxicity  [121].

It should be emphasized that effects of SCFAs may

depend on studied concentrations. Thus, at particular

(usually high) concentrations, SCFAs exhibit neuro-

toxic effects, with each acid characterized by its own

toxicity threshold. SCFAs at concentrations observed

in human systemic circulation can negatively affect

lipid composition of the brain and neuronal func-

tion. The most noticeable changes are disruption of

lipid metabolism, altered mitochondrial function, de-

creased cellular respiration in neurons, and reduced

ATP production, eventually leading to increased cell

death  [122]. Effects of SCFAs may be cell type-specific.

Thus, acetate exhibited toxicity toward dopaminergic

PC12 cells  [123] but reduced inflammation in microg-

lial cells  [124]. Also, SCFAs exert distinct effects on dif-

ferent neuronal populations. SCFAs not only stimulate

an increase in [Ca

]

in neurons, but also suppress

influx into the cells. FFAR3 activation by SCFAs in

sympathetic neurons inhibits N-type calcium channels

(CaV2.2), thereby reducing Ca

influx and neuronal

excitability  [116]. By activating FFAR3, propionate in-

hibits voltage-dependent calcium channels in neurons

involved in trigeminal nociceptive pathways, suggest-

ing potential analgesic properties of SCFAs  [125]. The

same authors demonstrated that butyrate reduces

the inflammation-induced hyperexcitability of prima-

ry nociceptive neurons  [126]. Overall, SCFAs exhibit

bidirectional, dose-dependent, and organ- and cell

type-specific effects in host organism, which may also

depend on the presence of diseases in the body  [105].

Microbial metabolites influence calcium sig-

naling in host’s nerve cells. Calcium is a universal

messenger involved in intracellular signaling. In most

cell types, [Ca

]

increase represents a general cellu-

lar response to external stimuli. Microorganisms, in-

cluding pathogenic species, as well as their products

(cellular components, metabolites, secreted products,

etc.) can trigger [Ca

]

increase in host’s cells. While

transient elevation of [Ca

]

initiates most intracel-

lular signaling cascades, sustained or chronic [Ca

]

increase above the basal level can become cytotoxic.

For example, exposure of microglia to bacterial com-

ponents, such as lipopolysaccharide (LPS), has been

associated with the increase in basal [Ca

]

and

suppression of receptor-triggered [Ca

]

signaling in

these cells  [127]. LPS can induce low-grade systemic

inflammation, which may influence the onset and se-

verity of age-related neurological disorders such as

Alzheimer’s disease  [128]. Microbial metabolites can

also influence cell–cell signaling. Thus, cell-free cul-

ture medium of Akkermansia muciniphila (mucin-free

fraction) caused a significant elevation of [Ca

]

EECs  [129]. Similarly, SCFAs can modulate calcium

signaling in neuron-like cells. For example, acetate

caused a dose-dependent increase in [Ca

]

, in do-

paminergic PC12 cells and exhibited some toxicity

mainly due to the activation of ionotropic glutamate

NMDA receptors  [123].

EFFECTS OF LAB METABOLITES ON NERVE CELLS OF MGB AXIS 875

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

Direct evidence for the existence of specific met-

LABs capable of increasing [Ca

]

in neurons remains

limited. Most published studies have been conduct-

ed using live Lactobacillus cells or complex bacterial

preparations rather than purified metabolites. Never-

theless, in  vivo and in  vitro studies indicate that LAB

synthesize and secrete various metabolites capable of

affecting the host (Table  1). These findings provide

a strong rationale for investigating the influence of

these secreted metabolites on neurons. Concentrated

metLAB preparations were found to increase [Ca

]

cultured brain neurons and PC-12 cells, in a process

that involved store-operated Ca

entry (SOCE)  [130].

SOCE plays an important role in neuronal excitabili-

ty, synaptic plasticity, and cognitive functions and has

been implicated in the pathology of various neurolog-

ical disorders [131]. In addition, it was found that the

rise of [Ca

]

in cultured brain neurons is, at least

in part, associated with the activation of ryanodine

receptors and protein kinase  C  [132]. Another study

showed that exposure of cultured brain neurons to

L.  plantarum and cell-free conditioned culture me-

dium stimulated calcium signaling in neurons, with

the effect depending on the concentration of bacteria

and their metabolic activity, without inducing notice-

able neuronal cell death [12]. Transcriptomic analy-

sis further revealed upregulation of genes associated

with growth factor secretion, neuroplasticity, calcium

signaling, and bioelectrical activity of neurons [12].

Therefore, metLABs can stimulate intracellular signal-

ing in neurons through direct contact with these cells.

However, it should be emphasized that metLABs pro-

duced in the intestine influence the brain biochemis-

try via the MGB axis (Fig.  3), and their effects on the

brain do not require the high concentrations needed

to exert biological activity in the GI tract (Table  2).

Rather, these metabolites act indirectly, through mod-

ulation of systemic circulation, neural pathways (e.g.,

the vagus nerve), and immune signaling, thereby

modulating brain chemistry remotely (Fig.  3). Thus,

the influence of metLABs on the brain is mediat-

ed through various signaling pathways, rather than

through direct accumulation of high concentrations

of GI metabolites in brain tissue.

Antioxidant properties of metLABs and their

effect on mitochondria. Interaction of microorgan-

isms among themselves and with host cells results

in the production of significant amounts of reactive

oxygen species (ROS). The content of ROS is regulated

by both the microbiota and host cellular systems  [46].

Mitochondria are primary targets of ROS-induced

damage, which causes oxidative stress, mutations in

mitochondrial DNA, protein oxidation, and lipid per-

oxidation [46,  133]. Elevated ROS disrupt the func-

tioning of the electron transport chain, reduce ATP

production, decrease mitochondrial membrane poten-

tial, and trigger apoptosis by increasing mitochondri-

al membrane permeability  [133]. Symbiotic microbi-

ota and its metabolites, in particular metLABs, help

reduce oxidative stress and ROS levels across various

tissues  [46]. Conversely, metabolites of pathogenic mi-

crobiota disrupt the redox balance in the CNS and

cause neurodegeneration (Fig.  3)  [15].

Recent studies have shown that metLABs mark-

edly enhance the transcriptional activity of nuclear

factor erythroid 2-related factor  2 (Nrf2) in human

microglial cells, both under normal conditions and

during inflammation (Fig.  4). Furthermore, this acti-

vation is accompanied by the increase in the tran-

scription of key antioxidant defense genes, including

heme oxygenase  1, superoxide dismutase (SOD), glu-

tathione S-transferase, glutathione peroxidase, and

catalase (Fig.  4)  [18]. Nrf2 is a central regulator of

cellular defense against oxidative stress and inflam-

mation. Accordingly, Nrf2 signaling has been wide-

ly recognized as a promising therapeutic target for

attenuating neurodegenerative changes in disorders

such as Alzheimer’s and Parkinson’s diseases  [134].

In this context, metLABs can protect microglial cells

from inflammation and oxidative stress through ac-

tivation of the Nrf2 signaling pathway  [18]. MetLABs

have been shown to modulate inflammatory and ox-

idative responses both in  vitro [135] and in  vivo  [19].

The anti-inflammatory and antioxidant effects of met-

LABs from L.  plantarum T1 have been linked to the

suppression of proinflammatory cytokine production

and modulation of nuclear factor kappa  B (NF-κB)

and mitogen-activated protein kinase (MAPK) activi-

ty  [135]. Moreover, SCFAs are able to cross the BBB

and serve as an important energy source in nervous

tissue cells via β-oxidation [40, 114]. Among these, bu-

tyrate is particularly notable for its role in supporting

mitochondrial function and reducing oxidative stress

through modulation of the Nrf2 signaling pathway,

thereby contributing to the maintenance of cellular

redox homeostasis in the brain (Fig.  4) [18, 114].

In intestinal epithelial cells, sodium butyrate at-

tenuated H

-induced oxidative stress, reduced ROS

levels, increased mitochondrial membrane potential

(ΔΨm), and inhibited mitochondrial cytochrome c

release, thereby blocking triggering of the intrinsic

apoptotic pathway. In parallel, butyrate stimulated

mitophagy, which helps maintain the intestinal bar-

rier integrity under oxidative stress conditions  [140].

Oral administration of butyrate has also been shown

to improve cognitive impairment in diabetic mice

by increasing mitophagy in the hippocampus  [141].

In epileptic mouse models, butyrate prevented mito-

chondrial structural damage, reduced ROS accumula-

tion, and increased NAD

and ATP levels in the brain.

These effects were presumably associated with the

Nrf2 pathway activation, as evidenced by the increase

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

Fig.  4. Effect of butyrate on nervous tissue cells. Butyrate binds to GPCRs (GPR41/43 and GPR109A), whose stimulation

activates PLC, leading to the increase in [Ca

]

and activation of the MAPK pathway. Butyrate-induced Ca

release from

intracellular stores promotes Ca

influx via the SOCE mechanism [136]. After entering the cell through transporters, e.g.,

sodium-linked monocarboxylate transporter (SMCT1), butyrate activates AMP-activated protein kinase (AMPK) and stimu-

lates nuclear translocation of Nrf2. In neurons, AMPK acts as a key stress sensor, including during ischemia  [63]. In the

nucleus, Nrf2 binds to antioxidant response elements (AREs) in DNA, driving expression of genes involved in oxidative

stress (OS) responses. In addition to activating AMPK, butyrate directly inhibits class I and  II HDACs  [137], resulting in en-

hanced transcription of genes encoding neurotrophic factors (NF) [63, 138, 139]. In neurons, butyrate enters the mitochon-

dria, where it is converted to acetyl-CoA (Ac-CoA) and utilized in the tricarboxylic acid (TCA) cycle for energy production.

Butyrate inhibits the NF-κB pathway, thereby suppressing chronic neuroinflammation and neurodegenerative processes.

It also enhances glutathione (GSH) and reduces ROS levels. Graphic elements from Servier Medical Art (https://smart.

servier.com) were used in creating the figure.

in the activity of SOD, catalase, and glutathione per-

oxidase in the mouse brain  [142] (Fig.  4) These find-

ings suggest that butyrate ameliorates seizure-induced

brain damage and neurological impairment through

the activation of Nrf2 signaling and enhancement of

mitochondrial function. Similarly, butyrate has been

reported to improve mitochondrial function in autism

spectrum disorders [143].

Some species of LAB can synthesize ferulic acid

(FA) or metabolize its precursors, converting them

into the active form. FA has been shown to inhibit the

formation and aggregation of Aβ fibrils in  vitro  [144].

Lactate is the main end product of carbohydrate

fermentation by LAB, as well as of anaerobic glycol-

ysis in tissues, and serves as a major alternative en-

ergy substrate for neurons [41,  145]. According to the

astrocyte–neuron lactate shuttle hypothesis, lactate is

provided primarily by astrocytes  [145]. Neurons can

take up lactate and oxidize it via conversion to py-

ruvate and subsequent entry to the TCA cycle, which

ensures efficient ATP synthesis, especially during pe-

riods of heightened neuronal activity  [41,  42]. Under

these conditions, lactate utilization increases oxygen

consumption by approximately  9%  [42]. The astro-

cyte–neuron lactate shuttle plays an important role in

long-term potentiation (LTP), which is induced by in-

tense synaptic stimulation  [146]. Lactate enhances ox-

idative phosphorylation in neurons [41, 145] and can

reduce ROS generation, thereby increasing mitochon-

drial resistance to stress [145]. It also prevents excito-

toxicity-associated neuronal death and stabilizes ΔΨm

during Ca

overload induced by excessive NMDA re-

ceptor activation [147]. Therefore, lactate is not mere-

ly a byproduct, but an active metabolic substrate that

supports mitochondrial function and promotes neuro-

nal survival. However, a high lactate-to-glucose ratio

may contribute to cognitive impairment and epileptic

seizures, e.g., during exhaustive exercise, hypoglyce-

mia, or neuroinflammation [42].

To neutralize ROS, metLABs can act on mitochon-

dria in neurons indirectly through modulating the

activity of microglia, in particular, by enhancing its

antioxidant defense, via activation of NF-κB signaling

and increased SOD1 activity (Fig.4) [18]. In mice sub-

jected to alcohol intoxication, metLAB administration

demonstrated neuroprotective effects, including oxi-

EFFECTS OF LAB METABOLITES ON NERVE CELLS OF MGB AXIS 877

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

dative stress reduction, inhibition of NF-κB signaling,

suppression of inflammation, and synaptic plasticity

improvement. In the hippocampus, such increase in

the antioxidant defense was due to the upregulation

of Nrf2 and SOD2 (Fig. 4) [148].

Interestingly, the culture medium of A. muciniph-

ila (mucin-free fraction) increased [Ca

]

in EECs,

while simultaneously reducing ΔΨm and promoting

α-synuclein aggregation in these cells [129]. Sustained

deviation of ΔΨm from the physiological value (either

decrease or increase) can compromise cell viability

and lead to various pathologies  [149]. In contrast,

Lactobacillus paracasei TJB8 and Bifidobacterium

species have been shown to increase ΔΨm in SHSY-5Y

cells in a novel co-culture model using two human

cell lines (Caco-2 and SHSY-5Y). Moreover, metabolites

of these bacteria reduced lipid peroxidation and pre-

vented glutamate-induced decline in ΔΨm [150].

Due to high oxygen consumption, the brain is

extremely vulnerable to oxidative stress. Hence, sym-

biotic microbial communities and their metabolic

products exhibiting antioxidant and anti-inflammato-

ry properties may attenuate the symptoms of neuro-

degenerative diseases (Fig. 3) [18, 46, 142-144, 151].

Effect of metLABs on neuronal plasticity and

neuritogenesis. The ability of metLABs to promote

neuroplasticity is mediated by several signaling path-

ways. Some LAB synthesize SCFAs and lactate, which

penetrate the BBB and modulate neuronal function.

LAB can also synthesize neurotransmitters such as

γ-aminobutyric acid (GABA), serotonin, dopamine, and

glutamate, as well as their precursors, and participate

in their metabolism and release in the host organ-

ism (Fig.  3, Table  1) [1, 5, 6, 8, 21, 47, 64, 65]. These

metabolites can activate their receptors on EECs, im-

mune cells, and neurons, thereby regulating the func-

tion of the latter through the MGB axis (Fig.  3) [1, 5,

8, 30, 47]. Finally, LAB continuously synthesize vita-

mins and release CO

in the process of carbohydrate

fermentation (Table  1). These compounds modulate

brain chemistry, support neurogenesis, and influence

neurotrophic factors essential for synaptic plasticity

and cognitive function [21, 64, 65].

It should be emphasized that neurotransmitters

synthesized by gut microbiota act primarily by mod-

ulating the ENS rather than by directly crossing the

BBB  [5]. GABA is a dynamic regulator of neuroplasti-

city, whose action requires precise control to support

learning, memory, and adaptation. Dysregulation of

GABAergic signaling has been implicated in various

neurological diseases  [64,  152]. Although only minor

amounts of GABA can penetrate the BBB, microbio-

ta-derived GABA can indirectly influence brain func-

tion by acting locally on the ENS or via the vagus

nerve  [47]. Administration of the probiotic Lactoba-

cillus rhamnosus stimulated the production of neu-

rometabolites in the CNS, including GABA  [153], and

affected the expression of GABA receptors in various

brain regions  [47]. By contrast, precursors of other

neurotransmitters such as 5-hydroxytryptophan for

serotonin and L-3,4-dihydroxyphenylalanine (L-DOPA,

levodopa) for dopamine, are capable of crossing the

BBB. In the brain, they are converted into neurotrans-

mitters and contribute to neuroplasticity through the

involvement in a wide range of complex cognitive

and emotional processes  [47, 64].

Acetate, propionate, and butyrate produced by gut

bacteria nourish colonocytes, strengthen the BBB, reg-

ulate inflammation, and modulate microglial activity

(Fig.  3)  [110]. Among SCFAs, butyrate and, to a lesser

extent, propionate and acetate act as HDAC inhibi-

tors and can influence gene transcription (Fig.  4)  [47].

Thus, physiological doses of SCFAs were found to alter

gene expression in primary cortical astrocytes  [154].

Feeding formate and acetate to mice reduced anx-

iety and induced neurogenesis and expression of

neurotrophic factors, such as BDNF and vascular en-

dothelial growth factor  A, in the hippocampus  [155].

Butyrate is the primary energy source for colonocytes

and is essential for maintaining the integrity of the

GI tract, intestinal motility, and stability of the BBB.

It also exhibits the anti-inflammatory properties and

promotes autophagy, a process that removes dam-

aged cells and organelles [110, 156]. Butyrate inhibits

HDACs and increases histone acetylation, which leads

to a more open chromatin structure and facilitates

access of transcription factors to DNA, ultimately

regulating expression of genes involved in cell cycle,

differentiation, and apoptosis (Fig.  4) [47, 156, 157].

Butyrate reduces the amounts of proinflammatory

cytokines and suppresses excessive microglial activa-

tion  [110]. It upregulates BDNF expression, improves

mitochondrial respiration, and reduces oxidative

stress  [110]. NF-κB is known to play a central role in

the induction of inflammatory neurodegeneration in

Alzheimer’s disease  [145]. Butyrate suppresses NF-κB

signaling, suggesting its inhibitory effect on neuroin-

flammation in this neurodegenerative disorder  [32].

The protective effect of butyrate was also demonstrat-

ed in animals with ischemic brain injury, where it

significantly increased BDNF levels and reduced cere-

bral infarct volume  [158]. In rats subjected to chronic

cerebral ischemia, butyrate stimulated neurogenesis

in the hippocampus, striatum, and frontal cortex  [63].

Lactate, one of the most important metabolites

produced by LAB, plays an important role in neuro-

chemistry and brain function. Beyond serving as an

energy substrate, lactate acts as a signaling molecule

that promotes neuroplasticity by upregulating genes

involved in synaptic plasticity and LTP. It induces

BDNF expression in the hippocampus by increasing

sirtuin 1 deacetylase activity  [66]. Lactate affects

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

neuronal plasticity and improves learning and mem-

ory in mice  [66]. It may be involved in the long-term

memory formation in mice through the activation of

genes participating in synaptic plasticity modulation.

This effect of lactate appears to depend, in part, on

the activation of glutamate NMDA receptors  [159].

Lactate released by muscles during exercise can cross

the BBB and stimulate BDNF expression and TrkB sig-

naling in the hippocampus  [66]. By increasing BDNF

levels, lactate promotes neurogenesis and improves

cognitive function  [57]. Astrocytes generate lactate via

aerobic glycolysis and transport it to neurons, where

it modulates NMDA receptor activity, increases intra-

cellular Ca

levels, and alters the NADH/NAD

ratio,

leading to the activation of Erk1/2 signaling and up-

regulation of genes involved in neuroplasticity, includ-

ing BDNF. This process supports learning, memory,

and cognitive function, and its disruption is associat-

ed with neurodegeneration  [160]. In 3xTg-AD mouse

model of early stages of Alzheimer’s disease, L-lactate

supplementation restored hippocampal lactate levels

and improved LTP, synaptic density, synaptophysin

expression, and spatial memory  [161]. However, ex-

cessive lactate accumulation can promote the growth

of pathogenic bacteria and may be associated with

a shift from aerobic to anaerobic respiration due to

mitochondrial dysfunction or damage  [151].

Lactobacilli and bifidobacteria can synthesize in-

dole-3-lactic acid by metabolizing dietary tryptophan.

Indole-3-lactic acid activates the aryl hydrocarbon re-

ceptor and Nrf2 signaling pathways, thereby reducing

inflammatory responses, enhancing cellular antioxi-

dant defense, and affecting epigenetic regulation of

gene activity [162].

Probiotics and prebiotics also modulate the gut–

brain signaling. In the study  [22], pregnant female

rats with the LPS-induced inflammation were fed a

mixture of probiotics (Bifidobacterium bifidum and

Lactobacillus salivarius). After the delivery, signifi-

cant decreases in the levels of Aβ

1-42

, amyloid pre-

cursor protein (APP), γ-secretase, and β-secretase,

together with a simultaneous elevation in the BDNF

mRNA content, were found in brain samples in the

probiotic-treated females and neonates compared to

the control group. Consistent with these findings,

Bifidobacterium- and Lactobacillus-based probiotics

have been shown to increase BDNF levels, there-

by supporting nerve cell growth and brain plastici-

ty  [21]. L.  rhamnosus GG administration ameliorat-

ed sepsis-associated cognitive impairment in mice

and preserved hippocampal expression of BDNF and

phosphorylated TrkB (p-TrkB), thus positively influ-

encing neuronal plasticity [163]. L.  plantarum DP189

increased serotonin and dopamine levels and exert-

ed neuroprotective effects in substantia nigra dopa-

minergic neurons in the mouse model of Parkinson

disease by prevented apoptotic death of neurons

through the activation of AKT/mTOR and Bcl-2 signal-

ing pathways [20]. Combined probiotic administration

attenuated LPS-induced neuronal apoptosis in the rat

hippocampus  [164]. MetLABs also influence enteric

neuronal plasticity by modulating neurotransmission,

reducing inflammation, and altering gene expression,

thus affecting neuronal excitability and signaling [6,

64]. Feeding rats with Lactobacillus reuteri increased

the excitability of enteric sensory neurons involved

in visceral pain signaling in intestinal disorders,

presumably due to a decrease in the level of calci-

um-dependent potassium channels, leading to reduc-

tion in the action potential threshold and increase in

neuronal excitability  [13]. In mice, administration of

L.  reuteri DSM 17938 and its metabolic products de-

creased the hyperactivity of spinal nerves innervating

the small intestine and responsible for detection of

pain stimuli  [165]. Thus, L.  reuteri decreased excit-

atory responses induced by capsaicin, accompanied

by a downregulated expression of transient receptor

potential vanilloid type  1 (TRPV1)  [165]. Hence, LAB

can modulate neuronal activity by stimulating it un-

der physiological conditions, while dampening hyper-

excitability during pathological states.

MetLABs have been shown to promote neur-

ite outgrowth. For example, supplementation with

L.  rhamnosus GR-1 increased the production of gran-

ulocyte colony-stimulating factor, which was report-

ed to rescue lead-induced impairments in neurite

outgrowth in PC-12 cells [166]. In a novel co-culture

model of human Caco2Bbe1 and SH-SY5Y cell lines,

lactobacilli applied to the upper epithelial Caco2Bbe1

cell layer enhanced neurite outgrowth in the under-

lying neuronal SH-SY5Y cells  [167]. Indole-3-lactic acid

potentiated the nerve growth factor (NGF)-induced

neurite outgrowth in PC-12 cells  [168]. Moreover, con-

centrated metLABs stimulated neurite outgrowth in

PC-12 cells even in the absence of exogenous neuro-

trophic factors. Beyond morphological differentiation,

exposure to metLABs may also influence neuronal

phenotype and functional properties over time. Thus,

the neurotransmitter phenotype of differentiated cells

may be altered by such exposure, including the emer-

gence of glutamate-induced elevation in [Ca

]

  [130].

SOCE has been proposed as a mechanism contribut-

ing to these processes  [72,  130]. Recent studies have

demonstrated that direct exposure of cultured brain

neurons to live L.  plantarum bacteria and their me-

tabolites stimulates the expression of hundreds of

genes encoding neuronal proteins, such as synapsin  I

(cytoplasmic marker associated with synapse forma-

tion) and pCREB (marker of early neuronal activi-

ty)  [12], indicating that signaling properties of neu-

rons and their plasticity can be altered in response

to the presence of LAB and their metabolites.

EFFECTS OF LAB METABOLITES ON NERVE CELLS OF MGB AXIS 879

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

Some microbial metabolites help maintain

the integrity of the intestinal barrier and the BBB

(Fig.  3), preventing inflammation-triggering factors

from entering systemic circulation and the brain and

indirectly supporting neuroplasticity  [21,  110,  140].

MetLABs modulate host immune responses and in-

hibit gut colonization by pathogenic microorganisms

[38, 40, 46]. Recent studies have shown that metLABs

reduce the levels of proinflammatory cytokines, e.g.,

tumor necrosis factor-α, both in  vivo and in  vitro [18].

Essentially, metLABs act as critical mediators, influ-

encing the ENS function and its connectivity with the

brain and supporting healthy neural plasticity and re-

silience to stress and disease. MetLABs are actively

involved in modulating brain neuroplasticity through

the activation of various MGB axis-associated path-

ways, including attenuation of neuroinflammation

and oxidative stress. Emerging evidence increasingly

links the gut microbiome to the induction and main-

tenance of synaptic plasticity in both the ENS and

CNS, suggesting that this interaction may be a fun-

damental component of the MGB axis. Furthermore,

enhanced production of neurotropic factors mediated

by metLABs may constitute one of the key mecha-

nisms for enhancing neuroplasticity.

MetLABs stimulate the release and expression

of neurotropic factors in nervous tissue through

several mechanisms associated with the MGB axis.

MetLABs including SCFAs, neurotransmitters (GABA,

serotonin, etc., Table  1), other microbial signaling mol-

ecules, as well as extracellular vesicles (EVs) secret-

ed by LAB, can directly influence neurotropic factor

secretion  [169]. In addition, metLABs such as SCFAs,

stimulate enterochromaffin cells to release neurotrans-

mitters (Figs.  1 and  3). Precursors and neurotransmit-

ters synthesized by both LABs and enterochromaffin

cells can enter systemic circulation, reach other parts

of the body, as well as cross the BBB into the brain,

where they participate in mechanisms underlying

neural plasticity [47, 64, 93]. In addition, metLAB-as-

sociated neurotransmitters can transmit sensory sig-

nals to the brain via both the vagus nerve and the

ENS (Fig.  3) [47, 93], inducing expression of neuro-

tropic factors in the hippocampus  [93]. For example,

increased levels of serotonin and neurotropic factors

were observed in the brain of rats supplemented with

L.  plantarum IS-10506  [94]. Inzebrafish (Danio rerio),

dietary administration of the probiotic L.  rhamnosus

IMC 501 upregulated expression of BDNF gene and

genes involved in serotonin signaling [170].

SCFAs can cross the intestinal barrier and the

BBB and directly affect the activity of neurons and

glial cells in the ENS and CNS [110, 115-117]. SCFAs

also stimulate EECs to release gut hormones (Fig.  3)

[40], which activate vagal afferent pathways relay-

ing information to the CNS and stimulate expression

of neurotropic factors in the CNS  [93]. In additions,

SCFAs act as HDAC inhibitors [137], thereby enhanc-

ing transcription of neurotrophins [63, 138, 139, 155]

and promoting neurogenesis, synaptic plasticity, and

resistance to stress  [63,  155]. Thus, dietary SCFA sup-

plementation in mice increased brain neurotrophin

levels and improved cognitive function of the ani-

mals  [155].

MetLABs can reduce inflammatory processes in

microglia by activating Nrf2, which promotes the

release of neurotrophic factors and increases neu-

ronal survival  [18]. LAB produce EVs that can cross

the intestinal barrier and reach hippocampal neu-

rons  [171]. In animal studies and in  vitro experiments

in HT22 cells, these EVs have been shown to stim-

ulate neurotrophic factor expression  [171]. It should

be noted that EVs secreted by the gut microbiota are

small phospholipid vesicles that contain a variety of

biologically active compounds, including proteins,

mRNA, microRNA, DNA, carbohydrates, and lipids

[172, 173]. EVs can cross the BBB and other tissue

barriers by interacting with receptors on glial cells,

such as Toll-like receptors  [174]; they are also capable

of penetrating nerve cells directly  [175]. EVs secret-

ed by pathobionts can stimulate glial cells to release

proinflammatory cytokines and mediators (Fig.  3)

[174], leading to reduced expression of neurotroph-

ic factors and neuronal damage  [176]. Conversely,

EVs synthesized by lactobacilli reduced LPS-induced

inflammation in cultured glial cells and decreased

apoptosis in post-ischemic neurons both in vivo and

in  vitro  [177]. In another study, EVs secreted by lacto-

bacilli prevented Aβ-induced downregulation of neu-

rotrophic factors and stimulated cognitive functions

in Tg-APP/PS1 mice. The authors suggested that these

EVs may contain neuroactive components capable of

enhancing the expression of both neurotrophic fac-

tors and proteases that cleave Aβ  [178]. Collective-

ly, these findings indicate that LAB-derived EVs can

modulate neurotrophic factor expression in the brain.

MetLABs also stimulate the release of neurotroph-

ic factors in cultured cell. For example, increased

BDNF levels were observed in neuronal cultures af-

ter 24-h exposure to live B.  bifidum TMC3115  [179].

Lactobacillus casei HY2782 and Bifidobacterium lactis

HY8002 stimulated BDNF expression in LPS-treated

SH-SY5Y cells  [180]. Supernatants obtained from 24-h

fermentation of Bifidobacterium longum ssp. infantis

alone and in combination with Bifidobacteriumbreve

induced BDNF release from retinoic acid-differentiat-

ed SH-SY5Y cells  [181]. L.  plantarum stimulated the

expression of growth factor-related genes in rat cere-

bral cortex neuronal cultures  [12].

Studies in Alzheimer’s disease animal models

have demonstrated a beneficial effect of probiotic

intake on the hippocampal synaptic plasticity  [68].

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

A similar effect was observed in aged rats treated

with the probiotic formulation VSL#3 [182]. In pre-

clinical studies, several Lactobacillus and Bifidobac-

terium strains have been found to modulate enteric

neuronal activity, microglial activation, and expres-

sion of neurotrophic and neurotransmitter molecules,

such as BDNF and serotonin [20-23]. In addition to

direct effects on neurons and microglia, metLABs in-

directly stimulate expression of neurotrophic factors

by reducing systemic inflammation and improving

the integrity of the intestinal barrier and the BBB

[183]. Probiotic administration in both animals and

humans has been shown to increase the content of

neurotrophic factors in the blood and cerebrospinal

fluid [170, 184]. Overall, probiotic bacteria stimu-

late expression of neurotrophic factors by host cells

through various pathways, including the synthesis of

metabolites such as SCFAs and neurotransmitters, im-

mune signaling, and regulation of neural and endo-

crine pathways (Fig. 3) [1, 8, 12, 20-23, 179-181].

THE BENEFITS OF SHIFTING

THE GUT MICROBIOTA TOWARDS

SYMBIONTIC MICROORGANISMS

In 1907, our compatriot and an eminent scientist

Ilya Ilyich Mechnikov (Élie Metchnikoff) in his book

The Prolongation of Life, first provided a scientific ra-

tionale for the use of LAB to improve health and slow

the aging process with the goal of achieving active

longevity  [185]. Metchnikoff noted that residents of

African countries, Bulgaria, the Caucasus, and parts

of the Arab world, where fermented foods containing

LAB were commonly consumed, had excellent health

and lived to old age  [185]. He articulated several key

concepts that remain relevant almost 120 years lat-

er. First, Metchnikoff sought to identify LAB strains

capable of strong lactic acid fermentation and sub-

stantial lactic acid production. Second, he suggested

that LAB may produce not only lactic acid but also

other beneficial metabolites. Third, he pointed to the

potential for lactic acid fermentation to be applied to

a wide range of foods beyond dairy products. Finally,

Metchnikoff claimed that certain bacterial organisms

in the large intestine generate toxic substances that

contribute to disease and accelerate aging. He sug-

gested that “as lactic acid fermentation serves so well

to arrest putrefaction in general, why should it not

be used for the same purpose within the digestive

tube?”  [185]. In his book, Metchnikoff further demon-

strated the dependence of gut microbiota on diet and

proposed that consumption of fermented foods could

shift the microbial balance from pathogenic to sym-

biotic microorganisms  [185]. Metchnikoff also empha-

sized that such dietary intake should be regular, as

discontinuation of fermented food consumption may

allow the intestinal microbiota to revert to its origi-

nal composition.

Restoring gut microbiota toward symbiotic micro-

organisms involves a combination of various meth-

ods and actions, such as dietary adjustments, lifestyle

changes, and, if necessary, therapeutic interventions

to correct gut dysbiosis. Key strategies include in-

creasing the intake of dietary fiber, fermented foods,

probiotics, and prebiotics, while engaging in regu-

lar physical activity and reducing stress. Among the

simplest and most effective methods for improving

the composition and function of the gut microbio-

ta and, therefore, overall health, is consumption of

fermented foods, as had been originally proposed by

Metchnikoff. As noted above, food fermentation with

LAB has been practiced by humans for thousands

of years  [69,  70]. During fermentation, LAB synthe-

size a large number of biologically active substances

(Table  1). Unlike isolated probiotic supplements, fer-

mented foods contain complex microbial ecosystems

that provide a variety of live microorganisms and

bioactive metabolites capable of influencing the resi-

dent microbiota and the host. Many fermented foods

contain biologically active vitamins, enzymes, neuro-

peptides, SCFAs, lactate, etc. (Table  1) that can direct-

ly participate in host’s biochemical and physiological

processes, independently of live microorganisms that

produce them  [72]. Moreover, fermentation-derived

metabolites can be optimized to maximize benefits for

the nervous system and mental health [72, 186, 187].

Clinical studies suggest that regular consumption of

fermented foods can affect brain activity via the MGB

axis [187-190]. Daily intake of fermented products re-

duces neuroinflammation and oxidative stress asso-

ciated with intestinal dysbiosis, improves microglial

function and integrity of the intestinal tract and the

BBB, collectively supporting neuronal function during

aging  [168,  190]. Furthermore, limited clinical trials

have demonstrated that increased immune activation

and inflammation in Alzheimer’s disease may be as-

sociated with age-related changes in the gut microbi-

ota  [191]. Fermented products have also been shown

to stimulate EECs to release GLP-1 and cholecystoki-

nin, while reducing serum levels of leptin, insulin,

and ghrelin  [187]. Finding from human and preclin-

ical studies indicate that consumption of fermented

foods has a neuroprotective effect and slows age-re-

lated cognitive decline by increasing BDNF levels and

reducing Aβ accumulation  [178,  187,  190]. Clinical

studies have shown that fermented foods reduce sys-

temic inflammation and HPA axis dysfunction [187,

190]. Consumption for eight weeks of milk fermented

with Lactobacillus helveticus improved both attention

and delayed memory in healthy middle-aged individ-

uals  [189]. Similarly, consumption of milk fermented

EFFECTS OF LAB METABOLITES ON NERVE CELLS OF MGB AXIS 881

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

with L.  helveticus enhanced cognitive performance

in healthy elderly individuals, although no effects on

BDNF levels or whole blood viscosity were observed

[192]. In a double-blind, placebo-controlled trial, sup-

plementation with the probiotics B.  bifidum BGN4 and

B.  longum BORI for 12 weeks reduced the relative

abundance of pro-inflammatory gut bacteria and in-

crease serum BDNF levels in healthy elderly individ-

uals. Moreover, participants receiving the probiotics

showed significantly lower stress levels and greater

cognitive flexibility  [193]. Therefore, normalization of

the gut microbiota may alleviate cognitive decline and

symptoms of depressive disorders via the MGB axis.

In  vitro studies have demonstrated that fermented

foods reduced glutamate-induced neurotoxicity and

protected SH-SY5Y cells against Aβ-induced damage,

which was accompanied by reduction in oxidative

stress and significant increase in cell viability  [188].

A biotechnological probiotic product produced by

food fermentation with lactobacilli stimulated neu-

rite outgrowth in PC-12 cells  [130]. Evidence from

numerous animal models indicates that fermented

products reduce inflammation and Aβ deposition in

the brain and decrease acetylcholinesterase activi-

ty in the hippocampus. Moreover, supplementation

with fermented products prevented memory deficits,

stimulated neurogenesis, and increased expression

of BDNF and phosphorylated cAMP response ele-

ment-binding protein (pCREB) in the hippocampus of

scopolamine-treated mice [188, 194]. In experimental

animal models, consumption of kefir (fermented milk

drink) attenuated inflammation, reduced Aβ deposi-

tion, and alleviated vascular damage characteristic

of Alzheimer’s disease  [195]. In patients with Alzhei-

mer’s disease, dietary supplementation with kefir re-

duced the levels of inflammatory cytokines, ROS, and

oxidative proteins, and was associated with memory

improvement  [195].

Collectively, preclinical and clinical studies sup-

port the role of fermented foods and probiotics in im-

mune regulation, metabolic health, inflammation con-

trol, and preservation of cognitive function. However,

current body of evidence is constrained by the limit-

ed number of large-scale, randomized controlled tri-

als. Further research is required, particularly studies

evaluating the long-term effects of fermented food

consumption. Sustained benefits are likely dependent

on the continuous inclusion of fermented foods in the

diet, as the gut microbiota tends to gradually revert

to its original composition following the cessation of

such interventions, a phenomenon already noted by

Metchnikoff  [185]. A deeper understanding of interac-

tions between microorganisms and their metabolites

may lead to the discovery of innovative fermentation

methods and creation of fermented foods with im-

proved therapeutic properties, capable of delaying

the onset or slowing the progression of neurodegen-

erative processes in the nervous system.

CONCLUSION

Modern science increasingly recognizes gut mi-

crobiome as a fully-fledged endocrine and neurochem-

ical organ. Current research supports the hypothesis

that intestinal dysbiosis may initiate and/or accelerate

neurodegenerative processes through the MGB axis.

Healthy intestinal microbiota is characterized by the

predominance of Bifidobacterium and Lactobacillus

species, which support digestion and immunity and

influence the development and normal functioning

of the nervous system. Therefore, normalization of

gut microbiota with fermented foods may become a

promising therapeutic approach to preventing demen-

tia and other age-related pathologies.

Abbreviations

BBB blood-brain barrier

BDNF brain-derived neurotrophic factor

CNS central nervous system

EEC enteroendocrine cell

ENS enteric nervous system

EV extracellular vesicle

GALT gut-associated lymphoid tissue

GLP-1/2 glucagon-like peptides 1 and 2

GPCR G protein-coupled receptor

GI gastrointestinal

HDAC histone deacetylase

HPA axis hypothalamic–pituitary–adrenal axis

MGB axis microbiota–gut–brain axis

LAB lactic acid bacteria

LPS lipopolysaccharide

metLAB metabolite of LAB

Nrf2 nuclear factor erythroid 2-related factor 2

PYY peptide tyrosine–tyrosine

ROS reactive oxygen species

SCFA short-chain fatty acid

SOCE store-operated Ca

entry

VIP vasoactive intestinal peptide

Funding

This work was supported by the State Contract

no. 075-00264-26-00 to the Sechenov Institute of Evo-

lutionary Physiology and Biochemistry.

Ethics approval and consent to participate

This work does not contain any studies involving hu-

man or animal subjects.

Conflict of interest

The author of this work declares that he has no con-

flicts of interest.

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 6 2026

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