IBRO Neuroscience Reports 19 (2025) 491–506

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IBRO Neuroscience Reports

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How the gut microbiome shapes learning and memory: A

comprehensive review
Firoozeh Alavian a,* , Motahareh Safaeian b
a
Department of Biology Education, Farhangian University, PO Box 889-14665, Tehran, Iran
b
Bachelor’s degree student in Experimental Science Education, Fatemeh Zahra Isfahan Campus, Shahid Rajaee Higher Education Center, Isfahan, Iran

A R T I C L E I N F O A B S T R A C T

Keywords: Cognitive functions, such as learning and memory processes, are closely related to the gut microbiome. The
Microbiome gut–brain axis (GBA), a complex network of bidirectional communications between the central nervous system
Gut–brain axis (GBA) and the gastrointestinal tract, plays an important role in regulating these functions. This study aims to investigate
Hippocampus
the impact of the gut microbiome on learning and memory and to provide new insights into the role of the GBA in
Memory
Learning
these cognitive processes. This narrative review explores various mechanisms through which the gut microbiome
affects cognitive functions by reviewing scientific articles related to the gut microbiome, GBA, learning, and
memory. The focus is on studies that have investigated the relationship between the gut microbiome, changes in
microbial composition, and cognitive functions. The results indicate that the gut microbiome influences brain
function and behavior through various mechanisms, such as vagus nerve signaling, effects on the enteric nervous
system, the production of neurotransmitters, the regulation of inflammation and the immune system, and the
production of metabolites such as short-chain fatty acids (SCFAs). Dysbiosis of the gut microbiota affects hip­
pocampal function, learning, and stress regulation. Additionally, probiotics and prebiotics, along with nutritional
status, affect the composition and function of the gut microbiome; therefore, maintaining the balance of the gut
microbiome and paying attention to the GBA may lead to improved cognitive functions and the prevention of
learning and memory-related disorders. Microbiome-based interventions, such as probiotics and dietary changes,
have the potential to increase performance.

Introduction the infant’s body. During the first few weeks of life, changes in its
composition occur, and specific areas of the body are uniquely affected
Learning and memory processes, which are considered to be part of by these microbes. To this end, a study used sequencing methods to
cognitive functions, have traditionally been recognized as unique analyze stool and saliva samples from 83 children at four time points
functions of the central nervous system (CNS). However, existing evi­ during the first two years of life, as well as samples from their mothers.
dence demonstrates that the gut microbiome (a collection of microor­ The results indicated that the composition of the gut microbiota signif­
ganisms residing in the digestive tract) plays an important role in icantly advances toward a mature microbiome resembling that of adults
regulating cognitive functions and learning. This connection occurs via during the first 2 years of life. The most significant changes in the
the GBA, which is a complex network of bidirectional communications microbiome composition occurred during the first year of life. The
between the CNS and the digestive system, including neural, hormonal, microbiome influences not only physical growth but also the develop­
immune, and metabolic pathways that work in concert to regulate ment of the brain and nervous system, such as the hippocampus and
cognitive functions such as memory and learning (Fig. 1) (Bhalla et al., amygdala, which are involved in learning and memory. The composition
2024; Qansuwa et al., 2023). of the microbiota in early life is highly variable and flexible, and as the
The gut microbiome comprises trillions of microorganisms living in infant continues to grow, this composition begins to mature. The first
the digestive tract and plays a crucial role in regulating the GBA. In early major change occurs when the infant stops breastfeeding, leading to
life, there is a period during which the infant is rapidly growing and alterations in the microbiota population and causing the diversity and
developing. Immediately after birth, the microbiome quickly colonizes number of microbial species to gradually resemble those of adult

* Corresponding author.
E-mail address: [Link]@[Link] (F. Alavian).

[Link]
Received 10 June 2025; Received in revised form 23 July 2025; Accepted 8 August 2025
Available online 11 August 2025
2667-2421/© 2025 The Author(s). Published by Elsevier Inc. on behalf of International Brain Research Organization. This is an open access article under the CC
BY license ([Link]
F. Alavian and M. Safaeian IBRO Neuroscience Reports 19 (2025) 491–506

microbiomes from approximately 2 to 3 years of age in humans. These involved in learning and memory processes (Sarkar et al., 2016a). This
changes in the microbiota can affect cognitive function and memory study also revealed that probiotics help improve cognitive function in
throughout life (Wernroth et al., 2022a; Jagodzinski et al., 2019; Moore individuals with mental disorders. In another study, Mayer et al. (2014)
and Townsend, 2019; Wernroth et al., 2022b). reported that the gut microbiome affects brain function through neural
Microorganisms influence brain function and behavior through and hormonal pathways. This study specifically focused on the role of
various mechanisms, such as vagus nerve signaling, impacts on the the vagus nerve in transmitting signals between the gut and the brain.
enteric nervous system (ENS), the production of neurotransmitters, the They demonstrated that changes in the composition of the gut micro­
regulation of inflammation and the immune system, and the production biome impact stress-related behaviors and memory (Mayer et al., 2014).
of metabolites such as SCFAs. These processes directly and indirectly In the study by Desbonnet and colleagues (2015), germ-free (GF)
affect cognitive processes, including learning and memory. The normal mice exhibited deficiencies in memory and learning (Desbonnet et al.,
functioning of the brain is heavily dependent on the microbiome 2014). In this study, the gut microbiome was associated with cognitive
composition. On the other hand, dysbiosis refers to decreased gut functions through the production of SCFAs and the regulation of the
biodiversity or an increase in pathogenic bacteria, leading to unhealthy immune system. The results from other studies indicate that changes in
signals being sent to the brain and resulting in inflammation, oxidative the gut microbiome affect the cognitive functions of individuals with
stress, energy imbalance, and increased cellular degeneration. These mental disorders such as depression and anxiety. This study specifically
changes affect many aspects of the hippocampus, such as memory and focused on the role of systemic inflammation and SCFA production in
learning, through various pathways, including the vagus nerve, and regulating cognitive functions (Kelly et al., 2016). Foster and McVey
increase the permeability of the intestinal mucosal barrier and the Neufeld (2013)) also demonstrated that the gut microbiome can influ­
blood–brain barrier (BBB) (Salami and Soheili, 2022). ence cognitive functions through its effects on the immun system and the
Learning and memory are two main processes that play crucial roles production of neurotransmitters. This study specifically focused on the
in shaping cognition and behavior. These processes depend on hippo­ role of inflammation and oxidative stress in individuals with cognitive
campal synaptic plasticity, a part of the brain involved in declarative disorders (Foster and McVey Neufeld, 2013).
episodic memory in humans. Episodic memory helps us shape our In another study, Dinan and Cryan (2017) reported that probiotics
identity and recall past experiences (Lisman et al., 2017). Disorders in help improve cognitive functions in healthy individuals and those with
the gut microbiota affect hippocampal function, healthy learning, and mental disorders. This study specifically focused on the role of probiotics
stress regulation. Furthermore, prebiotics improve hippocampal-related in reducing inflammation and improving cognitive functions (Dinan and
memory (Papalini et al., 2019), whereas dysbiosis caused by antibiotics Cryan, 2017).
reduces hippocampal function (Fröhlich et al., 2016a). This study aimed to investigate the effects of the gut microbiome on
In recent years, extensive research has been conducted on the rela­ cognitive functions, particularly learning and memory, and to provide
tionship between the gut microbiome and cognitive functions. A study new insights into the role of GBA in cognitive discussions, especially
by Cryan and Dinan (2012) demonstrated that the gut microbiome in­ concerning learning and memory. Given the importance of the gut
fluences behavior and cognitive functions through the production of microbiome in neuroscience and psychiatry research, this article seeks
neurotransmitters and the regulation of the immune system (Cryan and to achieve a better understanding of this complex relationship by
Dinan, 2012). This study specifically focused on the role of serotonin and examining the various mechanisms through which the gut microbiome
GABA in regulating anxiety and depression, both of which are linked to affects cognitive functions. Additionally, this article explores the po­
learning and memory. Additionally, Sarkar and colleagues (2016) tential role of microbiome-based interventions, such as probiotics and
established that changes in the gut microbiome affect the production of dietary changes, in enhancing cognitive functions.
neurotransmitters such as dopamine and serotonin, both of which are This article is a narrative review that evaluates the role of the gut

Fig. 1. Communication between the brain and gut microbiome.

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microbiome in cognitive functions such as learning and memory. This contributes to learning and memory formation, in situations where this
study provides a comprehensive and analytical perspective on the cur­ process is diminished, existing neurons in the hippocampus may be able
rent state of research in this field by gathering and qualitatively to retain information better (Lu et al., 2018; Kim and Shim, 2023; Deng
analyzing information from various sources. et al., 2010).
Research has shown that disturbances in the microbiota lead to
Research method abnormal neurogenesis and affect individuals’ cognitive functions. GF
mice show a significant increase in neuron production in the dorsal
This article is a narrative review that examines the role of the gut hippocampal region, which is essential for spatial learning and memory
microbiome in cognitive functions such as learning and memory. This (Mashayekhi and Salehi, 2024). GF mice also exhibit changes in the
study provides a comprehensive and analytical perspective on the cur­ morphology of the amygdala and hippocampus, indicating the role of
rent state of research in this field by gathering and qualitatively the microbiome in the development of brain structures related to
analyzing information from various sources. memory and learning (Luczynski et al., 2016). Importantly, if mice are
recolonized with microbes after infancy, the level of neurogenesis does
Results not return to its natural state. This finding suggests that the regulation of
neurogenesis by the microbiota must occur early in life, that is, when the
The connection between the gut microbiome and brain development microbiota is being formed and gut physiology is developing; in other
words, early life is a critical period in which the microbiota influences
Recent research has shown that there is a close relationship between brain growth and the production of new neurons (Ogbonnaya et al.,
the gut microbiome and brain development, particularly in areas such as 2015). Support for the role of the microbiota in regulating neurogenesis
learning, attention, and memory (de Weerth, 2017). is based on findings that show a decrease in hippocampal neurogenesis
Immediately after birth, microbes rapidly colonize the host’s body. due to stress can be prevented by pretreatment with a combination of
The composition of the microbiome undergoes significant changes in the the probiotics Lactobacillus helveticus and Bifidobacterium longum
first few weeks of life and gradually progresses toward a mature mi­ (Ait-Belgnaoui et al., 2014).
crobial community over time. The cessation of breastfeeding and the Hippocampal neurogenesis in adults, as shown in mice, is also
introduction of solid foods cause a major shift in the microbiome controlled by signaling from Toll-like receptor (TLR) types, indicating
composition. These changes ultimately lead to the formation of a stable the role of microbes or microbial components in regulating neuro­
microbial community resembling that of adults. Concurrent with the genesis. In the study by Rolls and colleagues (2007), a deficiency in
formation of the microbiome, the digestive system is also evolving. The TLR2 reduced neurogenesis and hippocampal volume, whereas TLR4
function of the intestinal mucosal barrier, including ion transport and knockout mice presented increased neurogenesis (Rolls et al., 2007) and
macromolecule permeability, improved with the onset of solid feeding. decreased learning ability (Okun et al., 2012). Mechanically, the binding
Additionally, early-life stress, such as when infants are separated from of lipopolysaccharide to TLR4 on neural progenitor cells (NPCs) inhibits
their mothers, delays the development of the intestinal mucosal barrier proliferation and neuronal differentiation through MyD88 signaling,
and increases macromolecule permeability, negatively impacting the and NF-κB is dependent on PKC α/β (Rolls et al., 2007).
development of the digestive system (Moore and Townsend, 2019; These studies clarify the role of bacteria and bacterial products and
Turroni et al., 2020; Fehr et al., 2020; Younge, 2024). The microbiome their interaction with their respective receptors in the CNS in neuro­
also plays a crucial role in early human growth, including the matura­ development and their potential impact on the regulation of cognitive
tion of the immune and digestive systems. In the gut microbiome of function.
premature infants, often only a few bacterial species dominate, indi­
cating that host growth processes influence the accumulation of gut Relationship between the gut microbiota and brain centers of memory and
microbial communities (Younge, 2024). GBA is highly important for learning involves interactions among the
premature infants because of their high sensitivity to dysbiosis. Pre­
mature infants are at a high risk of dysbiosis, which is associated with The GBA refers to a bidirectional communication network that in­
adverse neurological outcomes such as neurodevelopmental disorders, volves interactions among the central nervous system, the autonomic
cognitive deficits, and behavioral problems. nervous system, the endocrine system, the immune system, and the gut
The gut microbiome and nervous system evolve simultaneously microbiota. This network allows microbes to interact with the brain;
during early life, making premature infants a unique population, where conversely, the brain can also communicate with the gut. Findings show
optimizing gut microbiome colonization has a positive impact on their that these microorganisms affect memory, learning, stress, and mood, as
brain development (Lu and Claud, 2019); the slowest rate of microbiome well as certain brain disorders (Bhalla et al., 2024; Qansuwa et al., 2023;
formation occurs in extremely preterm infants (between 25 and 30 Gareau et al., 2011). The cognitive function of the hippocampus in ro­
weeks) (Korpela et al., 2018). However, differences in bacterial diversity dents and, to some extent, in humans is well established. The hippo­
between preterm infants and full-term infants have not been observed at campus seems to be particularly exposed to signaling from the
4 or 12 months after birth (Claud et al., 2013). microbiota–gut–brain axis related to neuroplasticity, neurogenesis,
The limbic system, which includes the hippocampus and amygdala, and neurotransmission (Salami and Soheili, 2022; Moloney et al., 2017).
plays a role in regulating emotions and memory storage. The gut Specifically, the hippocampus plays a role in the formation of short-term
microbiome also affects brain development and function through the and long-term memory, learning, and spatial orientation (Salami and
GBA by influencing the production of neurotransmitters and neuro­ Soheili, 2022).
developmental processes (Vaher et al., 2022). The volume of the hip­ Since the limbic system and certain other brain centers are involved
pocampus, which plays a crucial role in memory and learning, increases in both learning and stress regulation and considering the increasing
rapidly until the age of two. Neurogenesis (the formation of new neu­ influence of the microbiota on cognitive processes and memory (Salami
rons) occurs throughout life in specific areas of the brain, including the and Soheili, 2022), the question arises as to how the gut microbiota
hippocampus. Reduced neurogenesis early in life may enhance the affects learning and memory mechanisms dependent on relevant brain
retention of hippocampus-dependent memories. Because new neurons centers, particularly the hippocampus, and how these effects combine
play a vital role in processing and storing information, when the number with emotional processing to lead to therapeutic outcomes.
of new neurons decreases, the existing neurons in the hippocampus can The beneficial impact of the gut microbiota on certain cognitive
communicate more effectively with each other, resulting in greater functions of the brain undoubtedly occurs through effects on the limbic
memory retention. In other words, although neurogenesis generally system, particularly the hippocampus. The hippocampus is crucial for

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regulating complex emotions, learning, and memory storage. This cholinergic anti-inflammatory pathway. This bidirectional communi­
development begins in the early stages of gestation and continues cation allows the central nervous system to modulate gut function in
throughout postnatal life (Utsunomiya et al., 1999). The gut microbiota response to internal and external stimuli, while the gut, particularly
interacts with the hippocampus through several bidirectional pathways. through its microbial inhabitants, can influence brain activity, behavior,
These pathways, which interact and overlap with one another, include and cognitive performance. Therefore, the vagus nerve is not merely a
the vagus nerve and enteric nervous system (ENS), the metabolism of passive conduit for signal transmission but rather an active modulator of
neurotransmitters or their precursors, such as SCFAs, the hypothal­ neurophysiological processes, integrating peripheral signals into central
amic–pituitary–adrenal (HPA) axis, and immunity, and the modula­ neural circuits that govern learning, memory, and emotional regulation
tion of inflammation. (Srinivasan et al., 2023; Forsythe et al., 2014; Bonaz et al., 2018).
Multiple studies have shown that the gut microbiota is related to Animal studies have shown that vagus nerve stimulation (VNS) af­
behaviors associated with the limbic system, including learning and fects various cognitive functions, including learning and attention,
memory. Brain imaging in children aged 10–14 years with Crohn’s alertness, short-term memory, verbal memory recognition, working
disease, a type of inflammatory bowel disease (IBD), has shown that memory, and decision-making (Olsen et al., 2023); in one study, elec­
these patients experience a reduction in the thickness of the cerebral trical stimulation of the vagus nerve in mice led to memory consolida­
cortex in specific areas of the brain, including the posterior regions and tion, enhanced learning ability, and retention of new information
gyri of the medial frontal lobe. Additionally, the subcortical volume of (Childs et al., 2015). These improvements are associated with changes in
these patients decreased, and changes in the structure of the limbic the levels of neurotransmitters such as gamma-aminobutyric acid
pathways (related to emotions and memory) occurred. These changes (GABA), glutamate, serotonin, dopamine, and norepinephrine, which
were also associated with poorer verbal and cognitive memory perfor­ help facilitate synaptic plasticity and enhance memory-related processes
mance. The authors of this study also identified a connection between (Fig. 2) (Olsen et al., 2023).
inflammation during active disease and cortical thinning, indicating that The gut microbiota potentially may activate vagal afferent nerves
the greater the degree of inflammation in the body, the greater the (VANs) and influence hippocampal processing. The role of the VN in
likelihood that cortical thinning and decreased cognitive performance mediating microbiota’s effects on the hippocampus is underscored by
are to occur. For example, in children with Crohn’s disease, which is an evidence showing that transferring microbiota from feces to GF mice can
inflammatory bowel disease, a reduction in the thickness of the cerebral reverse hippocampal-dependent spatial learning deficits. Moreover,
cortex in specific areas of the brain and changes in the structure of the administering the probiotic Lactobacillus rhamnosus (JB-1) to a distinct
limbic pathways have been observed. These changes are also associated section of the small intestine enhances VAN activity, a response that
with weaker verbal and cognitive memory performance (Mrakotsky requires an intact and functional vagus nerve (Bharwani et al., 2020).
et al., 2016). VAN activity is likely altered by the microbiota under normal con­
The gut–brain axis facilitates communication between the gut and ditions via enteroendocrine cells. These cells constitute only 1 % of the
the brain through several mechanisms, including the following: intestinal epithelium but are among the largest endocrine systems in
mammals. Anatomically, these cells are located between the terminals of
Neural pathway sensory nerves and the intestinal lumen, where the microbiota resides.
They sense the microbiota directly through toll-like receptors (TLRs)
The GBA is a complex communication network that facilitates in­ and indirectly through metabolites such as SCFAs, nutrients, etc., and
teractions between the gut microbiota and the CNS. Among the
communication pathways of the GBA, neural pathways play an impor­
tant role in transmitting signals and influencing cognitive functions,
learning, and emotional states. This section details the neural pathways,
particularly the vagus nerve and the enteric nervous system (ENS), and
provides supporting empirical evidence for these interactions.

Vagus nerve

Role of the vagus nerve in GBA communication

The vagus nerve (VN), also known as the tenth cranial nerve (CN X),
is one of the most important and functionally significant neural path­
ways within the GBA and serves as a primary conduit for bidirectional
communication between the gastrointestinal tract and the CNS. This
nerve is a mixed nerve composed of both sensory (afferent) and motor
(efferent) fibers. The vagus nerve originates in the medullary region of
the brainstem within the CNS and extends through the thoracic and
abdominal cavities, innervating multiple internal organs, including the
heart, lungs, and particularly the gastrointestinal tract. Within the
gastrointestinal system, vagal sensory fibers form an extensive sensory
network that monitors various physiological parameters, such as
luminal content, nutrient availability, microbial composition, and im­
mune status. These sensory signals are transmitted to the nucleus tractus
solitarius (NTS) in the brainstem, which serves as the first central inte­
gration site for peripheral visceral information. These signals relay to
higher brain regions critically involved in autonomic regulation,
emotional processing, and cognitive function, such as the hypothalamus,
amygdala, and prefrontal cortex. In parallel, the efferent branch of the
vagus nerve provides parasympathetic motor innervation to the Fig. 2. How some substances produced by the gut microbiome connect with the
gastrointestinal tract, regulating key physiological functions such as brain. BBB: Blood-Brain Barrier, GABA: Gamma-Aminobutyric Acid, SCFAs:
peristalsis, gastric acid secretion, and mucosal immune responses via the Short-Chain Fatty Acids.

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transmit this information to VANs (Bonaz et al., 2018; Sternini et al., Glutamine can be converted to glutamate. The relationship between
2008; Abreu et al., 2005). brain glutamate levels and the VN is crucial for learning processes,
cognitive performance enhancement, and memory. Glutamate, the pri­
Enteric nervous system (ENS) mary excitatory neurotransmitter in the brain and a precursor to GABA,
Owing to its extensive network of neurons within the digestive tract, is effective in maintaining synaptic plasticity, which is essential for
the ENS is referred to as the "second brain" of the body. The neuronal learning and memory formation. Research has shown that VNS regulates
connections of the ENS involve nearly 100 million neurons and are the release of various neurotransmitters, including glutamate. When the
capable of processing information locally within the gut. The gut vagus nerve is stimulated, specific areas of the brain, such as the NTS,
microbiota also communicates with the CNS through the ENS in the are activated, which in turn affects glutamate signaling in areas related
GBA. This bidirectional communication includes neural pathways, to memory, such as the hippocampus, enhancing the synaptic trans­
endocrine glands, immunity, and hormones that connect the emotional mission and plasticity, which are vital for learning. In addition, VNS
and cognitive centers of the brain with the intestinal functions increases long-term potentiation (LTP) in the hippocampus; LTP
(Schneider et al., 2019; Sharkey and Mawe, 2023). strengthens synapses on the basis of patterns of new activity. This
Similar to the fate of the vagus nerve, the gut microbiome influences strengthening occurs partly owing to increased activity of glutamate
and regulates ENS activity by producing metabolites such as SCFAs, receptors, particularly NMDA receptors, which are essential for LTP. The
neurotransmitters, and other signaling molecules. These metabolites act activation of NMDA receptors causes an influx of calcium into neurons,
as local chemical compounds and play a role in signaling and regulating resulting in further strengthening of synapses to facilitate the process of
ENS activity (Balasubramaniam and Srinivasan, 2025). Studies have memory consolidation (Olsen et al., 2023, 2022). The gut microbiome
shown that SCFAs such as acetate, propionate, and butyrate produced modulates glutamate dynamics by influencing its bioavailability, ab­
from the fermentation of dietary fibers and other carbohydrates by gut sorption, and conversion to other metabolites, such as GABA, which
bacteria increase neuronal excitability in the ENS. This connection is affects brain health and neurotransmitter systems. This interaction oc­
particularly important due to the GBA, which involves the exchange of curs as part of the GBA and has important implications for neuro­
signals between the CNS and ENS. Increased neuronal excitability in the inflammation, synaptic plasticity, and cognitive functions such as
ENS also has positive effects on cognitive centers and learning functions learning and memory (Fig. 3) (Perna et al., 2019; Gruenbaum et al.,
(Ray and Mukherjee, 2024; Geng et al., 2022). Studies on GF animals 2024).
have also shown that bacterial colonization in the gut is essential for the
development and maturation of both the ENS and CNS. The lack of Dopamine
microbial colonization is associated with changes in the expression and Dopamine is recognized as an important neurotransmitter in the
turnover of neurotransmitters in both nervous systems (Carabotti et al., brain’s reward system and is closely linked to cognitive functions. This
2015). interaction not only affects how learning and decision-making occur but
also influences motivation and emotions related to reward seeking.
Metabolic pathway Studies have shown that activation of the VN leads to increased dopa­
The metabolic pathway of the GBA involves the production and mine release in areas such as the ventral tegmental area (VTA) and the
release of metabolites and neurotransmitters by the gut microbiota, substantia nigra, which are essential for neural plasticity related to
which influences brain function and behavior. Some of these metabolites reward and learning processes, as dopamine is crucial for encoding re­
include the following: wards and guiding behavior (Han et al., 2018; Copas, 2023). Signals
from the vagus nerve play a role in shaping how individuals learn from
GABA rewards and punishments. Research has demonstrated that VNS affects
GABA blocks neural signals from one neuron to another by binding to individuals’ selection accuracy such that people act more slowly when
its receptors. This action reduces the excessive activity of neurons, helps learning from positive experiences, especially when faced with negative
prevent cognitive disorders, and reinforces learning. Increased levels of feedback. This finding suggests that the vagus nerve may play a role in
GABA in the brain also lead to increased synaptic connections between regulating decision-making processes on the basis of dopamine signals;
neurons and increased synaptic plasticity, which are essential for in other words, the function of the vagus nerve influences how we learn
learning and memory. Additionally, the GABAergic system influences from good and bad experiences (Teckentrup and Kroemer, 2024).
areas such as the hippocampus and amygdala, which are involved in Additionally, the vagus nerve transmits internal signals related to
memory and emotion processing. Vagus nerve stimulation, which in­ metabolic states that affect dopamine levels and, consequently, learning
volves increasing levels of norepinephrine and GABA in these areas, aids outcomes. For example, in states of hunger or metabolic need, VNS
in memory enhancement (Olsen et al., 2023; Chiu et al., 2019). Research enhances the motivation to learn about food-related rewards. These
has indicated that dietary GABA supplements, when taken with a meal, findings indicate that physiological conditions influence cognitive
activate the vagal afferent nerves in mice (Chiu et al., 2019). This functions through the regulation of dopamine by the vagus nerve (Olsen
finding supports the existence of an alternative pathway through which et al., 2023; Berthoud and Neuhuber, 2019; Habib, 2024).
microbiota-derived GABA affects hippocampal function. Dopamine is connected to the gut microbiome via the GBA, where
Evidence shows that the VNS facilitates the synaptic localization of gut microbes affect dopamine levels through metabolic pathways. Spe­
GABA A receptors, which is effective in learning and cognitive cific bacteria, such as Lactobacillus and Bifidobacterium, modulate
enhancement (Olsen et al., 2023; Chiu et al., 2019). dopamine synthesis and metabolism by producing precursors such as
tyrosine or influencing neurotransmitter pathways. Furthermore, mi­
Glutamine and glutamate crobial metabolites and vagus nerve signaling play a role in regulating
Glutamine is the most common nonessential amino acid in the dopamine activity and affect cognitive functions such as motivation,
human body, especially in the gut and muscles. This substance is pro­ reward processing, and learning (González-Arancibia et al., 2019;
duced by gut bacteria such as Firmicutes (Ma and Ma, 2019). Addi­ Hamamah et al., 2022; Mhanna et al., 2024).
tionally, oral glutamine supplementation improves the composition of
the microbiota, reduces inflammation, and strengthens the tight junc­ Serotonin
tions of the intestinal epithelium; therefore, a synbiotic supplement (a Serotonin is a type of neurotransmitter that plays a role in synaptic
combination of probiotics and prebiotics) that increases glutamine may plasticity, mood regulation, and cognitive functions. This substance is
be effective in treating dysbiosis and related hippocampal processing primarily produced in the gut and activates afferent fibers of the vagus
disorders (Rao and Samak, 2011). nerve that send signals to the NTS in the brainstem. The NTS integrates

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Fig. 3. Impact of vagus nerve on increasing ion entry into the neurons and reinforcement of synaptic transmission. VNS: vagus nerve stimulation, LTP: long-term
potentiation, NMDA: N-methyl-D-aspartate, AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.

serotonergic signals and sends them to higher brain areas that regulate NE levels in these areas and enhances synaptic plasticity and LTP, which
mood and cognitive processes; thus, the vagus nerve acts as a commu­ are associated with learning and memory. Research indicates that VNS
nication pathway between the gut and the brain, facilitating the effects enhances memory and learning by increasing alertness and attention
of serotonin produced in the gut on brain functions (Johnson and Wil­ mechanisms. This is partly due to the activation of the noradrenergic
son, 2018; Bonaz et al., 2019). Research has shown that VNS enhances system, which modulates cortical excitability and memory formation
serotonin signaling in the brain. Additionally, studies have shown that (Olsen et al., 2023). The increase in norepinephrine levels aids in further
when selective serotonin reuptake inhibitors (SSRIs) are administered, regulating glutamate signaling pathways in the hippocampus,
the vagus nerve is activated, which enhances serotonin signaling be­ strengthens synaptic plasticity, and supports learning processes.
tween the gut and the brain. This interaction indicates that VNS am­ Notably, the gut microbiota also participates in the production of
plifies the effects of serotonin on mood and cognitive function (McVey neuroendocrine molecules such as norepinephrine and adrenaline
Neufeld et al., 2019). Furthermore, following vagotomy, the ability of (Olsen et al., 2022; Dehhaghi et al., 2019).
SSRIs to reduce depressive symptoms in animal models decreases,
highlighting the importance of vagal pathways in modulating the effects SCFAs
of serotonin (Lee et al., 2025; Siopi et al., 2023). The VN also influences SCFAs are produced as fermentation products of dietary fibers by gut
learning outcomes by transmitting signals related to physiological states bacteria such as Firmicutes, Bacteroidetes, Actinobacteria, and Rumi­
such as hunger or stress, which affect serotonin levels. Hunger leads to a nococcaceae (Portincasa et al., 2022). These acids include acetate,
severe reduction in blood serotonin levels. This reduction in serotonin butyrate, and propionate, each produced by different species of bacteria.
levels, also known as the happiness hormone, leads to feelings of anxi­ SCFAs influence the CNS by interacting with gut hormones and crossing
ety, anger, and sadness in individuals, which in turn reduces the level of the BBB. Butyrate specifically enhances BDNF, which is crucial for
learning (Breit et al., 2018; Hope, 2023; Armstrong, 2024). Evidence has memory and the growth of neural cells (Vinelli et al., 2022; Silva et al.,
shown that dysbiosis of serotonin levels in the hippocampus decreases 2020). Research has shown that decreased BDNF levels are associated
and specifically disrupts hippocampus-dependent spatial memory (Tang with diminished learning and memory since the deletion of BDNF in
et al., 2021). Additionally, Lactobacillus helveticus bacteria in animals mice disrupts object recognition and spatial learning (Fig. 4) (Heldt
under chronic stress restore hippocampal serotonin levels to improve et al., 2007). Butyrate affects histone acetylation and influences the
cognitive functions, especially learning and memory, thereby helping to expression of memory-related genes. Additionally, it improves memory
reduce the negative effects of stress on the brain (Yousefzadeh et al., performance by enhancing the storage and retrieval of fear memories
2020). over a long duration or long-term contextual fear memories through
various mechanisms, including effects on the epigenome and the regu­
Norepinephrine lation of gene expression. This type of memory is part of the long-term
Norepinephrine (NE), a neurotransmitter, plays a significant role in memory that helps us remember fears or defensive reactions to certain
learning and helps improve cognitive performance by increasing alert­ environments or conditions (Vinelli et al., 2022; Silva et al., 2020;
ness and concentration. This chemical is released in response to stress Peixoto and Abel, 2013; Mohammadi-Farani et al., 2021). Additionally,
and excitement and aids in regulating arousal and attention in learning the anti-inflammatory property of butyrate helps to maintain cognitive
and memory processes. The locus coeruleus, an adrenergic center in the function by inhibiting inflammatory factors. Butyrate is particularly
brain, plays a crucial role in enhancing memory induced by VNS. The important for learning and memory formation because it enhances
noradrenergic neurons from this area project to the hippocampus, synaptic plasticity (GdCÁ et al., 2024). Recent studies on GF mice have
assisting in spatial learning (Olsen et al., 2023; Ross and Van Bockstaele, shown changes in the acetylation of histone lysines. These changes are
2021). These neurons are involved in increasing brain alertness and likely related to mitochondrial dysfunction in the hippocampus, which
arousal, thus facilitating learning. The locus coeruleus is primarily plays a crucial role in regulating brain function and behavior (Yu et al.,
recognized as the main source of NE, which is produced from dopamine 2021). Furthermore, in an interesting study, mice that experienced
by the enzyme dopamine beta-hydroxylase in this region. VNS increases bilateral carotid artery obstruction presented reduced numbers of

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memory and learning (McEwen et al., 2016). The high sensitivity of the
hippocampus to changes in the HPA axis is atributted to the high density
of glucocorticoid (cortisol) receptors (GRs) in this region. Specifically,
hippocampal pyramidal cells, which play a vital role in the consolidation
of long-term memories, strongly express GR; however, GR expression is
reduced with chronic microbiota depletion (Hoban et al., 2016a).
Research has shown that stress decreases microbial diversity and in­
creases the growth of harmful bacteria. When stress disrupts the balance
of the gut microbiome, these disturbances can affect signals sent through
the vagus nerve and lead to cognitive problems such as reduced learning
and memory (McVey Neufeld et al., 2019). Evidence indicates that GF
mice exhibit an exaggerated HPA stress response and an altered limbic
system, including the prefrontal cortex, hippocampus, and amygdala
(Sudo et al., 2004). The Gut microbiota also affects serum glucocorticoid
levels. For example, Bifidobacterium supplementation can help reduce
chronic stress by lowering blood cortisol levels, thereby improving
learning and memory (Tian et al., 2020). Similarly, chronic exposure to
glucocorticoids leads to decreased activity in the prefrontal cortex,
which is responsible for higher-order thinking and decision-making,
whereas activity in the amygdala, which plays a role in emotional re­
sponses and survival instincts, increases (Šimić et al., 2021). This change
in brain function can disrupt the complex cognitive processes essential
for effective learning.
In their research, Warren and colleagues (2024) examined the
Fig. 4. Impact of SCFAs on plasticity reinforcement. SCFAs: Short-chain fatty mechanisms linking chronic stress and dysbiosis (imbalance in the gut
acids, BDNF: Brain-Derived Neurotrophic Factor. microbiome) and demonstrated how dysbiosis leads to neurological
disorders and impacts mental health. These findings suggest that chronic
beneficial bacteria in the gut and decreased SCFA levels in the brain. stress influences the GBA and cognitive functions such as memory and
This damaged their hippocampal function and gut barrier; however, learning through the gut microbiota (Warren et al., 2024). In another
when beneficial bacteria from the feces of healthy mice were transferred study, stress increased the secretion of glucocorticoid hormones, leading
to them, their gut barrier function and SCFA levels in the hippocampus to increased intestinal permeability and the release of interleukin-17A
improved, and their cognitive impairments significantly improved (Xiao (IL-17A) from T helper 17 (Th17) cells in the lamina propria. This
et al., 2022). Preclinical studies on GF mice also revealed that SCFAs process then leads to the expansion of older neutrophils in the blood­
participate in maintaining brain homeostasis and influence learning and stream. Segmented filamentous bacteria in the gut have been identified
cognition. SCFA supplements such as butyrate, acetate, and propionate as essential microbes for the expansion of stress-induced senescent
in drinking water enhance reward-seeking learning behaviors and stress neutrophils, which increase stress in mice (Fig. 5). More importantly, by
responses in mice (Frost et al., 2014; Zhang et al., 2015). inhibiting glucocorticoid production, blocking IL-17A, or reducing the
SCFAs bind to specific receptors in the body, such as GPR41 and gut microbiome that stimulates Th17 cells, stress is alleviated (Xu et al.,
GPR43, which play roles in regulating various physiological processes, 2020) and naturally, in these conditions, learning and attention
including metabolism and the immune system. As noted by Liao and improve.
colleagues (2022), although these receptors are not found in the brain, In the study by Dehhaghi et al. (2019), mice subjected to chronic
they are important for regulating processes related to learning and stress and displaying despair behaviors presented changes in their gut
memory by influencing the nervous system and neuroinflammation. microbiota composition. Notably, the number of beneficial bacteria
They reported that in mice with sepsis-associated encephalopathy called Lactobacillus decreased, and the level of a chemical substance
(SAE), the levels of SCFAs such as acetate and propionate were signifi­ called kynurenine increased in the blood. The use of supplements con­
cantly decreased. This reduction was accompanied by an imbalance in taining Lactobacillus reuteri returned these changes in the microbiota to
the gut microbiome, leading to a decrease in SCFA-producing bacteria. normal. Interestingly, this treatment not only aided in improving the
In this study, SCFA injection improved cognitive impairment in these state of the microbiota but also ameliorated the behavioral abnormal­
mice and reduced neuroinflammation, but this effect was reversed by a ities of the mice. These results indicate that changes in the gut micro­
GPR43 antagonist; therefore, GPR43 receptors are crucial for the pro­ biota composition contribute to better metabolic regulation and
tective effects of SCFAs against neuroinflammation and the protection of increased resilience to stress (Dehhaghi et al., 2019); thus, manipulating
cognitive function in SAE (Liao et al., 2022). the microbiota may be an effective way to counteract the negative ef­
fects of stress, which is one of the adverse factors in learning.
Hypothalamic–pituitary–adrenal (HPA) axis Recent research has also shown that different types of stress
The HPA axis acts as a stress response system that impacts cognitive (cognitive stress, stressful life events, and biological stress) have sig­
function and memory. Stress is typically induced by stressors or the nificant effects on the gut microbiome composition. Individuals who
absence of immune signaling. The stress response generally involves the have experienced high levels of perceived stress have shown less mi­
lack of inhibition of two main adaptive systems: the fast-acting sympa­ crobial diversity, which is typically associated with negative health
thetic system and the slower-acting HPA, which results in the release of outcomes, including reduced cognitive performance (Delgadillo et al.,
cortisol from the adrenal gland. Cortisol can cross the BBB and exert 2025; Davidson et al., 2018). A comprehensive study conducted on 24,
relatively rapid nongenomic effects as well as slower genomic effects 448 older adults indicated that those who experienced high levels of
(Joëls and Baram, 2009). perceived stress were 1.37 times more likely to be at risk for cognitive
Exposure to the microbiome early in life is essential for the devel­ disorders. Interestingly, these findings remain valid even after ac­
opment of the HPA axis. The microbiota influences cognitive perfor­ counting for factors such as age and cardiovascular health status. These
mance and memory via stress-related mechanisms. Chronic stress and findings demonstrate that chronic stress not only affects cognitive
exposure to cortisol caused by dysbiosis and infection typically disrupts function and learning but also increases the likelihood of developing

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Fig. 5. The effect of increased glucocorticoid hormones on increased stress in mice.

more serious diseases, such as Alzheimer’s disease (Kulshreshtha et al., pathogenic bacteria from attaching to the gut epithelium, and increasing
2023); therefore, stress management and maintaining a healthy gut gut mucus production. The origin of these bacteria is still under dis­
microbiome contribute to improved cognitive and learning functions. cussion, but the entero-mammary route (the transfer of microbes from
the mother’s gut to the mammary gland) is a possible explanation. The
Immune response pathway oligosaccharides found in breast milk have a bifidogenic effect, meaning
The gut microbiome is involved in the development and regulation of that they promote the growth of Bifidobacterium species, which are
the immune system. The relationships among the gut microbiome, im­ considered beneficial for infant immunity. Recent research has focused
mune responses, and learning and memory processes are shaped on isolating potential probiotic strains from breast milk, primarily Bifi­
through complex interactions in the GBA. The gut microbiota and the dobacteria and Lactobacillus, to improve the immune system, reduce the
immune system naturally work together to identify pathogens and incidence of infant illnesses, and increase longevity (Lyons et al., 2020).
trigger an adaptive inflammatory response to restore homeostasis.
However, this inflammatory response may extend to the brain, including Gut–oligodendrocyte pathway
the hippocampus, leading to cognitive impairments. Brain inflammation Oligodendrocytes in the CNS are responsible for producing myelin.
is also well recognized in the pathogenesis of cognitive decline (Ray and The gut microbiota–oligodendrocyte axis is related to the effects of the
Mukherjee, 2024; Zheng et al., 2023). gut microbiota on the myelination of CNS neurons in the brain. Natu­
The microbiome interacts with immune cells and impacts both innate rally, changes in myelination in areas involved in memory and learning
and adaptive immunity. Metabolites produced by the microbiome, such affect these cognitive functions. The gut–oligodendrocyte microbiota
as SCFAs, help regulate systemic inflammation and strengthen mucosal axis influences social behavior, including memory reflections, by regu­
immunity. These compounds maintain immune balance by increasing lating myelination in the frontal cortex, which is an important area for
the production of antimicrobial peptides and controlling inflammatory predicting multifaceted cognitive behavior and decision-making.
responses; however, during dysbiosis, immune responses become overly Humans experience late myelination of frontal cortex axons in their
activated, leading to chronic inflammation or neuroinflammation and third decade of life, making them vulnerable to external factors such as
cognitive disorders. Research has shown that changes in the gut microbial metabolites (Ray and Mukherjee, 2024).
microbiota due to the use of antibiotics and infectious agents are asso­ Oligodendrocytes have become the focus of research in recent de­
ciated with alterations in circulating pro-/anti-inflammatory cytokine cades because of their vital role in the development, injury, and repair of
levels and other neuroactive/immunological substances derived from the nervous system. Recent studies have shown that the gut microbiota
the gut lumen, which can penetrate the gut mucosa, be transported by during fetal and infant development has a profound impact on central
the bloodstream, pass through the BBB, and affect the CNS (Petra et al., oligodendrogenesis and consequently on subsequent brain injuries.
2015). This inflammatory cascade negatively impacts learning and Thus, proper myelination in the CNS depends on the timely availability
memory by disrupting neuronal circuits and accelerating neuronal of the gut microbiota, leading to the differentiation of oligodendrocyte
degeneration. precursor cells (OPCs) into mature and myelinating oligodendrocytes
Studies have indicated that changes in microbiota composition can (Mayerl and Heuer, 2023).
create immune problems early in life, leading to long-term effects on
hippocampus-dependent memory and learning processes. Consequently, Experimental evidence linking the gut microbiota to myelination
mice with immune deficiencies exhibit impaired hippocampus- Luo and colleagues demonstrated that when GF mice were raised
dependent learning, which can be improved with the use of probiotics with microbiota isolated from rapidly growing neonates, their offspring
early in life (Smith et al., 2014). Interestingly, breast milk is not exhibited increased myelination and less neuroinflammation (Lu et al.,
recognized as a sterile fluid but has a unique microbiome. Breast milk 2018). Huban et al. identified myelination genes with upregulated
plays a crucial role in inoculating the infant’s gut with beneficial bac­ expression in GF mice and demonstrated that hypermyelination is
teria after birth, which is essential for developing a healthy gut micro­ reversed by colonization with normal microbiota after weaning (Hoban
biome. These beneficial bacteria in breast milk contribute to the infant’s et al., 2016b). Interestingly, the use of daily supplements of Lactobacillus
immunity by producing antimicrobial compounds, preventing acidophilus and Bifidobacterium infantis by pregnant mice from day 16

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of pregnancy until weaning significantly facilitates OPC growth in their results showed that (R)-ketamine was able to shift the composition of the
offspring; therefore, maternal probiotic supplementation may provide a gut microbiota toward a healthier profile and decrease lactic acid levels
safe and effective means of enhancing myelination (Lu et al., 2020). in cuprizone-treated mice. Furthermore, a significant correlation was
However, disturbances in the gut microbiome can have the opposite observed between the abundance of certain bacterial species, such as
effect. Several preclinical studies have utilized the cuprizone-induced Eisenbergiella massiliensis, and the extent of demyelination or neuro­
demyelination model to investigate the role of the GBA in myelin pa­ inflammatory microglial activity in the brain (Wang et al., 2022).
thology. Cuprizone, a copper chelator, selectively induces oligoden­ These results clearly show how important maintaining a balanced
drocyte death and demyelination, making it a widely used model for gut microbiota is for supporting oligodendrocyte development and
studying multiple sclerosis and other demyelinating disorders (Zirngibl myelin formation under normal conditions.
et al., 2022; Vega-Riquer et al., 2019; Steelman et al., 2012). The
mechanism of cuprizone-induced demyelination involves two distinct Dysbiosis of the gut microbiota and impaired myelination
modes: first, ‘intrinsic cell damage’, where mitochondrial dysfunction Gut microbiota dysbiosis contributes to impaired oligodendrocyte
and impaired myelin protein synthesis directly affect oligodendrocytes; growth. Alterations in the gut microbiome can modify the microbial
second, ‘extrinsic cellular damage’, in which inflammatory mediators metabolome and impact highly permeable bioactive compounds, such as
and immune cells such as microglia, astrocytes, and peripheral T cells p-cresol, which inhibits oligodendrocyte differentiation and affects the
contribute to oligodendrocyte injury (Zirngibl et al., 2022). myelination process. The transmission of nerve signals is slower and less
Cuprizone administration in mice results in severe demyelination in efficient, and slower signal transmission impacts the speed and effi­
specific hippocampal regions, including the stratum lacunosum- ciency of cognitive processing, making it more difficult to learn new
moleculare, medial alveus, and CA2/3 areas, which are affected simi­ information or retrieve stored memories (Ray and Mukherjee, 2024;
larly in both young and aged animals (Fig. 6). This demyelination is Gacias et al., 2016).
accompanied by astrocytosis, indicating reactive changes in astrocytes Importantly, the GBA also plays a significant role in pathological
but minimal microglial involvement. Hippocampal damage closely demyelination. Bailey et al. (2011) demonstrated that the resident gut
mirrors the demyelination patterns observed in multiple sclerosis (MS) microbiota is essential for the induction of in vitro autoimmune
patients, making it a relevant model for studying cognitive deficits in encephalomyelitis (EAE), a disease model of multiple sclerosis. GF mice
MS. Since the hippocampus plays an important role in learning and are resistant to EAE unless colonized with polysaccharide-degrading
memory, this model emphasizes how myelin loss in pivotal pathways bacteria that enhance inflammatory T-cell responses (Berer et al.,
can contribute to cognitive dysfunction (Norkute et al., 2009). 2011). These findings suggest that certain gut microbes can trigger
In line with these observations, recent evidence suggests that tar­ autoimmune responses against myelin. Similarly, antibiotic treatment
geting the gut–microbiota–brain axis could be a promising approach to reduces EAE severity, whereas reintroduction of filamentous bacteria
mitigate demyelination and promote remyelination. Wang et al. (2022) restores pathogenic Th17 cell responses (Ochoa-Repáraz et al., 2009).
demonstrated that the administration of (R)-ketamine in a These results illustrate the impact of gut microbial communities on
cuprizone-induced animal model of demyelination reduces demyelin­ immune responses that contribute to autoimmune demyelination.
ation and promotes remyelination processes in the mouse brain. These In addition to immune mechanisms, the GBA influences myelin ho­
protective effects are mediated through the activation of the TrkB re­ meostasis via metabolic signaling. Minter et al. (2016) reported that
ceptor and a reduction in microglial activity. Most importantly, the antibiotic-induced disruption of the gut microbiome exacerbated

Fig. 6. The Role of Gut Microbiota in Oligodendrogenesis, Myelination, and the role of Cuprizone Model. OPC: Olygodendrocyt progenitor cell.

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neuroinflammation and altered microglial function, cells essential for may have the potential to improve myelination and cognitive perfor­
maintaining myelin integrity. This study highlighted the systemic effects mance, although further research is needed to fully understand the
of microbiota depletion on inflammatory pathways linked to myelin mechanisms involved.
damage, underscoring the importance of a balanced gut microbiome in
preserving CNS health (Minter et al., 2016). The role of probiotics and prebiotics in learning and memory
Humans experience myelination of the prefrontal cortex (an impor­ The beneficial effects of gut microbial symbiosis are facilitated by
tant brain region for higher cognitive functions) until their third decade probiotics (live beneficial bacteria) and prebiotics (indigestible fibers
of life. This prolonged period of myelinogenesis renders the brain that promote the growth of beneficial bacteria). They help restore mi­
vulnerable to external factors such as microbial metabolites; therefore, crobial balance and reduce inflammation, thus improving cognitive
dysbiosis during this critical period has long-term effects on cognition function. Probiotics enhance hippocampus-dependent memory by
(Ray and Mukherjee, 2024; Gacias et al., 2016). regulating the HPA axis response to stress (Papalini et al., 2019).
Papalini and colleagues (2019) reported that the consumption of a
Microbial metabolites and myelin regulation probiotic supplement for four weeks protects active memory against
In addition to their direct effects on oligodendrocytes, the gut acute stress disruption and improves hippocampus-dependent learning
microbiota influences myelination through their metabolic products. performance (Papalini et al., 2019). The probiotic Clostridium butyr­
Short-chain fatty acids (SCFAs) such as acetate promote oligodendrocyte icum aids gastrointestinal health by increasing the production of buty­
differentiation and myelin-related gene expression (Li et al., 2024; rate, which is an important energy source for gut cells. This probiotic can
Keogh et al., 2021). Conversely, dysbiosis can lead to the accumulation also increase BDNF levels in the CA1 region of the hippocampus, which
of inhibitory metabolites such as p-cresol, which impair oligodendrocyte is crucial for brain health, memory, and combating cognitive decline
function (Gacias et al., 2016). The gut microbiome also regulates (Fig. 7) (Liu et al., 2015). Additionally, the use of a synbiotic that in­
microglia, the immune cells of the CNS that support myelin mainte­ cludes a probiotic (E. faecium) and a prebiotic (agave inulin) increases
nance. GF mice exhibit defective microglial function and abnormal butyrate production and improves specific hippocampus-dependent
myelin dynamics, which can be restored by microbial recolonization or memory and learning performance in mice (Romo-Araiza et al., 2018).
SCFA administration (Erny et al., 2015). In a study by Liang et al. (2015), the consumption of Lactobacillus
helveticus NS8 in a chronic stress model improved anxiety- and
Linking myelin deficits to learning and memory impairment depression-related behaviors, enhanced cognitive functions, and
Myelin integrity is essential not only for rapid neural conduction but reduced biochemical disorders. This probiotic showed effects similar to
also for synchronizing brain networks involved in cognition. The pre­ or better than those of the drug citalopram and improved memory and
frontal cortex and hippocampal connectivity, both heavily dependent on behavior through the GBA by regulating neural, immune, and endocrine
myelinated axons, are crucial for working memory, spatial learning, and pathways. It also restored the levels of serotonin and norepinephrine in
emotional memory processing. Disruptions in myelination, whether the hippocampus and increased BDNF expression (Liang et al., 2015).
caused by inflammation, microglial dysfunction, or metabolic insuffi­ Furthermore, specific probiotic strains enhance
ciency, have direct consequences on synaptic plasticity and network hippocampus-dependent memory by reducing plasma cortisol hormone
stability, impairing cognitive performance. Disrupted myelination in levels (Bailey et al., 2011). Stress induced by intestinal infection with C.
cognitive regions such as the prefrontal cortex due to dysbiosis or neu­ rodentium increases behaviorally induced corticosterone levels.
roinflammation leads to slower signal transmission, directly impairing Elevated corticosterone disrupts the expression of c-Fos and BDNF in the
information processing speed and memory function (Ray and Mukher­ CA1 region of the hippocampus, consequently affecting
jee, 2024; Gacias et al., 2016). Interventions targeting the gut micro­ hippocampus-dependent nonspatial memory. Fortunately, probiotics
biome, including probiotic supplementation or SCFA administration, help improve these conditions (Gareau et al., 2011). In the study by

Fig. 7. The effect of the probiotic Clostridium butyricum on increasing BDNF. BDFN: Brain-Derived Neurotrophic Factor.

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Savignac et al. supplementation with Bifidobacterium longum micro­ probiotics in enhancing neurogenesis and synaptic plasticity related to
biota helped enhance memory consolidation in mice (Carabotti et al., learning.
2015). This microbiota, a type of gram-positive bacteria found in the
human gastrointestinal tract, plays a role in the production of lactic acid The microbiome’s connection to two gastrointestinal diseases related to
and acetic acid and helps improve cognitive function while reducing cognitive function
anxiety and depression. Additionally, prebiotics such as inulin and Many initial studies on the relationship between the microbiome and
fructooligosaccharides (FOSs) promote the growth of beneficial bacteria the brain began by observing cognitive and psychological disorders
such as Bifidobacteria and Lactobacillus. These bacteria help produce concomitantly in patients with gastrointestinal diseases. Patients with
SCFAs, which are effective in improving cognitive performance and inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)
protecting against neurodegenerative diseases (Roupar et al., 2022). often suffer from mood disorders and cognitive deficits in addition to
Some probiotic strains produce neurotransmitters such as serotonin, gastrointestinal symptoms. This connection has a significant negative
dopamine, GABA, and their receptors, which are essential for brain impact on quality of life and complicates treatment strategies (Bernstein,
function and learning. Thus, gut dysbiosis early in life leads to reduced 2016). Next, we explain each of these diseases:
expression of the α5 and δ subunits of the GABA-A receptor in the hip­
pocampus and impairment of spatial memory in rodents. Fortunately, Irritable bowel syndrome (IBS)
these negative effects can be improved by the use of a probiotic com­ IBS is a common gastrointestinal disorder characterized by symp­
bination that includes Lactobacillus rhamnosus and Bifidobacterium lon­ toms such as abdominal pain, bloating, and changes in bowel habits
gum(Strandwitz et al., 2019; Liang et al., 2017; Almutairi et al., 2024). (such as diarrhea or constipation). This condition typically presents
Prebiotics and probiotics reduce systemic inflammation, which is chronically with periods of flare-ups and remission, and its exact cause is
often associated with cognitive decline. Chronic inflammation in the gut still not fully understood (Camilleri, 2021). While anxiety and depres­
results in neuroinflammation, which disrupts synaptic plasticity and sion are the main behaviors observed in these patients, mild changes in
cognitive function. Probiotics such as Bifidobacterium have helped cognitive function have also been observed in different subgroups of
reduce inflammatory cytokines, boos the immune system, and improve patients, especially in children and adolescents. Mild verbal memory
cognitive outcomes in both animal and human studies (Lyons et al., problems have been reported in patients aged 13–19 with IBD, partic­
2020; Sarkar et al., 2016b). Other studies have shown that some pro­ ularly during the acute phase of the disease (Castaneda et al., 2013).
biotics, particularly Lactobacillus strains, can reduce the levels of Additionally, in children aged 8–17 years, the administration of the
corticosterone (CORT) and adrenocorticotropic hormone (ACTH) in the corticosteroid prednisolone, a common treatment for IBD, has led to
blood. This reduction is linked to improved hippocampal-related spatial cognitive deficits compared with patients who are in remission and do
memory (Liang et al., 2015). Some probiotics also stimulate the release not use steroids (Mrakotsky et al., 2013).
of acetylcholine in vagal neurons by activating the cholinergic Changes in the gut microbiome are proposed as one of the potential
anti-inflammatory pathway. This pathway prevents the release of causes of IBS. Patients with IBS often suffer from cognitive disorders,
proinflammatory cytokines and may help normalize systemic inflam­ including memory issues and information processing problems
mation and improve dysbiosis (Fig. 8). (Angoorani et al., 2021). Researchers believe that there is a correlation
A study on middle-aged mice indicated that the use of synbiotics (a between reduced bacterial diversity in the gut microbiome and the onset
combination of probiotics and prebiotics) improved age-related spatial of IBS, such that the diversity of gut bacteria in patients with IBS is lower
memory (Han et al., 2022). Memory enhancement was associated with a than that in healthy individuals. Furthermore, the abundance levels of
reduction in proinflammatory cytokines and an increase in BDNF and certain specific bacterial species differ between IBS patients and healthy
butyrate levels. Moreover, synbiotics induced changes in the electrophys­ individuals (Chung et al. 2016; Pittayanon et al., 2019).
iological properties of CA1 pyramidal cells in the hippocampus, indicating Studies indicate that Fusicatenibacter saccharivorans is associated
strengthened synaptic connections, an increase in the N-methyl-­ with changes in the gut microbiota composition in patients with IBS,
D-aspartate (NMDA)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic particularly in individuals who respond positively to probiotic treat­
acid (AMPA) receptor ratio, and robust long-term potentiation (LTP) ments. The abundance of this bacterium significantly increased after
(Romo-Araiza et al., 2018). treatment, suggesting its potential role in alleviating IBS symptoms by
Probiotics can also prevent cognitive disturbances caused by a modulating the gut microbiota. Fusicatenibacter saccharivorans likely
Western diet. For example, the administration of Lactobacillus helveti­ contributes to gut health by inducing the expression of IL-10, an anti-
cus to mice fed a high-fat diet improved memory and increased BDNF inflammatory cytokine that suppresses intestinal inflammation (Pang
expression in the hippocampus (Lof et al., 2022), indicating the role of et al., 2021; Tomita et al., 2023). This highlights a mechanism whereby

Fig. 8. The effect of some probiotics on normalization of lemistic inflammation.

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improved gut health can positively affect conditions such as IBS. imbalance in gut microbes. When antibiotics are administered from in­
Research has shown that in individuals with IBS suffering from fancy onward, the number of bacteria and the diversity of the fecal
dysbiosis, the ratio of glutamate to glutamine in the hippocampus de­ microbiota significantly decrease. These changes have been associated
creases. This reduction negatively impacts memory and learning. with cognitive problems, as evidenced in tests such as object recogni­
Conversely, an increase in this ratio is associated with better perfor­ tion. Additionally, the levels of certain functional proteins in the hip­
mance in memory tests (Fig. 9) (Baj et al., 2019). pocampus of adult mice decrease (Fröhlich et al., 2016a).
Whether antibiotics are consumed for a short period or over pro­
Inflammatory bowel diseases (IBD) longed and repeated durations, they inflict serious damage to the natural
IBD is a chronic inflammatory disease of the gastrointestinal tract gut microbiome. These alterations disrupt metabolic activities in the gut
that involves a complex interplay of genetic, environmental, and and can even lead to the emergence of antibiotic-resistant bacteria and
immunological factors. Studies have shown that patients with IBD have pathogenicity, which is particularly concerning in premature infants
reduced diversity in their gut microbiome; a decrease in beneficial who are typically treated with antibiotics in the NICU (Lu and Claud,
bacteria such as Faecalibacterium prausnitzii and an increase in patho­ 2019). Owing to their weaker immune system, premature infants are
genic bacteria such as Escherichia coli have been observed (Lopez-Siles exposed to more stress. This stress renders them more susceptible to
et al., 2014). infections, necessitating antibiotic treatments. These factors, by exac­
Dysbiosis and chronic inflammation in IBD negatively correlate with erbating inflammatory processes in the body and altering the gut
cognitive processes, including learning, through mechanisms involving microbiome composition, which is essentially the community of bacteria
neuronal inflammation, alterations in neurotransmitter production, and in the gut, affect the neurodevelopment of infants (Maroney, 2003)
disruption of neurogenesis (Masanetz et al., 2022). Chronic inflamma­ Studies have indicated that antibiotic use can have short-term effects
tion in IBD leads to the release of inflammatory cytokines such as IL-6 on the gut microbiome and cognitive function. Research conducted by
and TNF-α. These cytokines can cross the BBB and contribute to Fröhlich and colleagues (2016) revealed that antibiotics cause signifi­
neuronal inflammation (Bonaz and Bernstein, 2013). cant changes in the composition of the gastrointestinal microbiome.
If this occurs in learning and memory centers, synaptic flexibility and These changes are associated with different cognitive behaviors in mice
cognitive function are disrupted. Additionally, changes in the gut and lead to abnormal levels of body metabolites and alterations in
microbiota in patients with IBD affect the production of beneficial me­ signaling pathways in the brain. Additionally, the amount of antibiotic
tabolites such as SCFAs, which are important for maintaining brain absorbed in this study was below the detection limit, and the researchers
health and supporting learning processes; for example, a study by Dong argued that cognitive impairment in antibiotic-treated mice must be due
et al. (2019) revealed that, in IBD patients, the biodiversity of the gut to gut dysbiosis rather than systemic responses from antibiotic admin­
microbiota decreases, resulting in reduced production of SCFAs (Dong istration. In this study, gut dysbiosis was associated with a reduction in
et al., 2019). metabolites produced by bacteria in the large intestine and changes in
Patients with IBD, particularly children and adolescents, may expe­ the types of fats and molecules produced by microbes in the plasma.
rience mild cognitive impairments, including verbal memory problems Mice treated with antibiotics and subsequently had changes in their gut
(Castaneda et al., 2013; Masanetz et al., 2022). Specifically, research microbiome did not perform well in memory tests. The antibiotic-
conducted by Castaneda et al. in 2013 indicated that adolescents with treated mice exhibited impaired recognition of novel objects, but
IBD in the acute phase may experience mild verbal memory difficulties. spatial memory was not affected. This cognitive deficit is related to
Notably, these individuals made more repeated errors on the California specific changes in the expression of signaling molecules associated with
Verbal Learning Test (CVLT) than did their peers with juvenile idio­ cognition, particularly the BDNF factor, the 2B subunit of the N-methyl-
pathic arthritis (JIA). Furthermore, the IBD group exhibited more D-aspartate (NMDA) receptor, the serotonin transporter, and the neu­
symptoms of depression than did the JIA group, with approximately ropeptide Y system, in various brain regions (Fröhlich et al., 2016b).
one-third of them experiencing at least mild depressive symptoms, Understanding the impact of antibiotics on the gut microbiome and
particularly during acute illness (Castaneda et al., 2013). These findings cognitive function is crucial for developing strategies to mitigate these
suggest that while IBD affects mental health and verbal memory, these effects. Future research should focus on identifying specific bacteria that
effects are generally mild and do not lead to significant cognitive contribute to cognitive health and finding ways to restore balance to the
deficits. microbiome after antibiotic use. Additionally, studies on the long-term
On the other hand, malnutrition and nutrient deficiencies during IBD effects of antibiotic exposure in early life are essential for a complete
lead to improper absorption of essential nutrients such as vitamins B12, understanding of its implications for human health. This knowledge
D, and folic acid (Massironi et al., 2013), which are vital for brain helps in creating personalized treatment programs that minimize dam­
function and cognitive processes (Fig. 10). age to the microbiome. By addressing these concerns, we can move to­
ward preserving cognitive function and overall health.
Relationships among antibiotic use, microbiome, memory, and learning
Research has shown that antibiotics significantly alter the composi­
tion of the gut microbiota. For this reason, they are used to create an

Fig. 9. Impact of IBS on Hippocampus. IBS: Irritable Bowel Syndrome.

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Fig. 10. The effect of IBD on Material absorption, memory and learning. SCFAs: Short-chain fatty acids, BBB: Blood-Brain Barrier.

Conclusion Informed consent

This review underscores the emerging and multifaceted role of the N/A
gut microbiome in shaping learning and memory through its in­
teractions with the GBA. We emphasize previously underexplored
mechanisms, including microbiota-driven regulation of hippocampal Declaration of Competing Interest
neurogenesis, neurotransmitter systems, and metabolic–inflammatory
pathways, that provide a foundation for understanding cognition The authors declare no conflict of interest. This article is a review
beyond traditional CNS-centric models. paper and does not involve any human or animal studies requiring
Our study found that disruptions in the microbial composition during ethical approval.
critical developmental stages, especially early in life, can have long-
lasting effects on cognitive function. This underscores the importance
Acknowledgments
of safeguarding microbiome integrity from infancy. Additionally, we
identified promising therapeutic approaches, including microbiome-
The authors would like to extend their sincere gratitude to the arti­
targeted interventions such as probiotics and dietary modifications.
ficial intelligence system that provided invaluable assistance during the
These strategies demonstrate potential not only in supporting cognitive
translation process of this article.
health but also in mitigating stress-related impairments and neurolog­
ical complications associated with to dysbiosis.
Data availability statement
This work contributes to the growing body of research on the
connection between gut health and brain function, highlighting the need
N/A
for more precise and targeted investigations into how microbial changes
can be leveraged to enhance cognitive performance and prevent dis­
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