Linking Psychological Stress to Epigenetic Regulation via the Gut–Liver–Brain Axis in Irritable Bowel Syndrome and Metabolic Dysfunction-Associated Fatty Liver Disease

Abstract

Irritable Bowel Syndrome (IBS) and Metabolic dysfunction-associated fatty liver disease (MAFLD) have traditionally been viewed as disorders of distinct organ systems. IBS is a gut–brain axis disorder characterized by abdominal pain, altered bowel habits, and psychological comorbidities. MAFLD, recently redefined to emphasize its metabolic underpinnings, is the hepatic manifestation of systemic metabolic dysfunction. Growing evidence suggests that these conditions share overlapping pathophysiological mechanisms linked through disruption of the gut–liver–brain axis (GLBA), including psychological stress, gut dysbiosis, impaired intestinal permeability, systemic inflammation, and altered neuroendocrine signaling. Neuroimaging studies further reveal functional alterations in brain regions responsible for interoception, emotional regulation, and stress responsiveness in both disorders. This narrative review explores how psychological distress influences the onset and progression of IBS and MAFLD via GLBA dysfunction and stress-induced epigenetic reprogramming. A targeted literature search of major biomedical databases, supplemented by manual screening, identified relevant observational, clinical, neuroimaging, and molecular studies. Findings indicate that chronic psychological distress activates the hypothalamic–pituitary–adrenal (HPA) axis, elevates cortisol, disrupts gut microbiota, and reduces vagal tone; amplifying intestinal permeability and microbial translocation. These changes promote hepatic inflammation and gastrointestinal symptoms. Stress-related epigenetic modifications further impair GLBA communication, while psychological and lifestyle interventions may reverse some of these molecular imprints. Recognizing the shared neuromodulation and epigenetic mechanisms that link IBS and MAFLD opens promising avenues for integrated therapeutic strategies targeting the GLBA to improve outcomes across both conditions.

1. Introduction

Long before modern medicine understood the microbiome, early physicians recognized a powerful link between the gut and the liver. As early as the 4th century, traditional Chinese medicine used fecal preparations to treat food poisoning, an approach that survives today as fecal microbiota transplantation [1]. In the early 1900s, Ivan Pavlov’s Nobel-winning experiments showed that the brain could influence digestion by triggering stomach and pancreatic secretions, a foundational discovery in brain–gut communication [2].

Today, a growing body of evidence converges on the concept of the gut–liver–brain axis (GLBA), a tridirectional communication system involving the gastrointestinal tract, liver, and central nervous system (CNS). This axis functions through neural, immune, endocrine, and microbial pathways, all of which are influenced by chronic and acute stress [3,4,5,6]. Psychological distress can alter barrier function, gut microbiota, hepatic metabolism, and brain connectivity, through epigenetic mechanisms that reprogram gene expression across this axis. This review explores the hypothesis that epigenetic regulation is a key biological mechanism linking psychological distress to the pathophysiology of both irritable bowel syndrome (IBS) and metabolic dysfunction-associated fatty liver disease (MAFLD).

Central to GLBA regulation are the gut microbiota and intestinal epithelial integrity. When this barrier is compromised, microbial metabolites like lipopolysaccharides (LPS) can enter the portal circulation, triggering hepatic inflammation and systemic metabolic changes [7]. The enteric nervous system, connected to the CNS via the vagus nerve and spinal afferents, relays information about microbial composition and immune activation [5,8,9]. In turn, stress-induced top-down signals can disrupt gut permeability and liver function through HPA axis activation and autonomic dysregulation.

This communication is particularly relevant in IBS and MAFLD, two conditions once viewed as unrelated but now recognized as interconnected. Though they affect different organs, both are linked by common mechanisms: gut microbiota dysbiosis, intestinal barrier dysfunction, altered motility, and dysregulation of the GLBA. These disruptions lead to immune activation, low-grade inflammation, and neuroendocrine imbalance [6].

IBS affects up to 23% of the global population and is marked by recurrent abdominal pain, bowel habit changes, visceral hypersensitivity, psychological symptoms, and fatigue [10]. Its development is linked to dysfunction in gut–brain signaling, with downstream effects on motility, neurotransmission, immune responses, and barrier integrity [6,11]. These processes are further shaped by genetic pre-disposition, environmental exposures, stress, and epigenetic changes [10]. Notably, both IBS prevalence and stress reactivity show sex differences, with higher rates and heightened HPA axis sensitivity reported in women, suggesting potential sex-dependent vulnerability [10].

MAFLD, formerly termed NAFLD, is considered the hepatic manifestation of metabolic syndrome and affects up to 30% of the population worldwide [12]. The updated nomenclature reflects a shift from excluding alcohol consumption to focusing on underlying metabolic dysfunction. We use the term MAFLD throughout this review to align with current consensus and highlight the metabolic and neuroimmune overlap with IBS. MAFLD is characterized by triglyceride accumulation in hepatocytes and is often associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease [11,13]. It ranges from simple steatosis to more severe stages such as steatohepatitis, fibrosis, and cirrhosis. Like IBS, MAFLD is now seen as a systemic disorder rooted in GLBA disruption.

Recent evidence also links MAFLD with colonic diverticulosis, a condition characterized by small pouches in the colon wall. While often asymptomatic, diverticulosis is associated with metabolic dysfunction and low-grade inflammation. It shares common risk factors with MAFLD, including obesity, insulin resistance, and chronic inflammation [14]. Although not explored in detail here, its overlap with IBS-like symptoms supports a broader role of the GLBA in interconnected gastrointestinal and hepatic disorders.

The GLBA also serves as a key interface through which psychological distress drives physiological dysfunction. In IBS, stress activates the HPA axis and disrupts brain–gut signaling. Neuroimaging studies reveal altered connectivity in brain regions involved in emotion, interoception, and sensorimotor regulation [9,15]. Similar patterns are observed in individuals with metabolic syndrome and MAFLD, pointing to shared impairments in central autonomic control [16].

These changes are not transient. Chronic stress leaves stable biological imprints through epigenetic mechanisms such as DNA methylation, histone modification, and microRNA regulation [13,17]. Neuromodulatory systems, such as the corticoid signaling, are particularly susceptible to this type of re-modeling, linking psychological factors to dysfunction across brain, gut, and liver.

In this review, we examine how psychological distress may contribute to the progression of IBS and MAFLD through neuroepigenetic mechanisms. We summarize evidence from clinical, imaging, and molecular studies to outline shared features of GLBA dysfunction and discuss potential implications for clinical management.

2. Literature Search Strategy and Integration of Findings

This narrative review was conducted through a targeted literature search of major biomedical databases, including PubMed and Embase Library. Search terms included combinations IBS, NAFLD, MAFLD, psychological distress, GLBA, neuroimaging, and epigenetics. No geographic restrictions were applied. Articles published through June 2025 were considered, and additional studies were identified through manual screening of reference lists.

Eligible studies included observational, clinical, neuroimaging, and molecular research exploring the shared pathophysiological underpinnings of IBS and MAFLD, with emphasis on the influence of psychological distress and neuroepigenetic regulation on GLBA dysfunction.

The literature reveals consistent evidence of a close interplay between psychological factors, GLBA alterations, and overlapping symptomatology in IBS and MAFLD. Epidemiological, neuroimaging, and molecular studies collectively suggest that disruptions in brain–gut–liver communication, mediated by stress-related neuroendocrine and epigenetic mechanisms, may underlie disease progression and comorbidity.

This review integrates these findings into a cohesive framework that underscores shared mechanisms and identifies potential therapeutic targets at the intersection of brain, gut, and liver function.

3. Co-Prevalence of IBS and MAFLD

Epidemiological studies consistently report a significant co-prevalence of IBS and MAFLD, suggesting shared mechanistic pathways. In a large cross-sectional study from China, 23% of MAFLD patients experienced IBS symptoms, while 66% of individuals with IBS-like complaints also met criteria for MAFLD [18]. Similarly, 74% of IBS patients had MAFLD, with greater liver disease severity correlating with worse gastrointestinal symptoms [19]. Supporting these findings, a retrospective analysis from India reported a 29% prevalence of IBS among patients with MAFLD [20]. Likewise, IBS patients exhibit a threefold higher likelihood of developing MAFLD, and up to 74% of MAFLD patients may report IBS-like symptoms [11]. This association has been corroborated by broader systematic reviews and observational studies [6,11,20].

Beyond their epidemiological overlap, IBS and MAFLD appear to share common upstream biological mechanisms that point to a unified pathophysiological framework. Lee et al. (2016) reported increased levels of liver enzymes, alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), as well as a higher incidence of metabolic syndrome in patients with IBS [21]. Similarly, Sadik et al. (2010) found that higher body mass index (BMI) in IBS subjects correlates with faster colonic and rectosigmoid transit as well as increased bowel frequency [22]. A cross-sectional study from Japan demonstrated a positive association between IBS and higher triglyceride levels and prevalence of metabolic syndrome [23]. Additionally, higher rates of pre-diabetes and elevated LDL cholesterol have been observed in IBS patients [24,25]. These molecular and metabolic links are especially prominent among individuals with insulin resistance, visceral adiposity, and chronic inflammation, hallmarks of both disorders [6,12].

4. Psychological Distress and the Gut–Liver–Brain Axis in IBS and MAFLD

Psychological comorbidities have been shown to exacerbate the onset, severity, and progression of both IBS and MAFLD [10,26,27,28]. IBS is strongly associated with emotional dysregulation, heightened stress reactivity, anxiety, and depressive symptoms [10,29]. A comprehensive systematic review and meta-analysis by Zamani et al. (2019) reported that 39% of IBS patients exhibit anxiety symptoms, 23% had anxiety disorders, 29% experienced depressive symptoms, and 23.3% suffered from clinical depression [29]. Notably, IBS symptoms can precede the onset of psychological distress, triggering mood disorders in nearly half of patients, while pre-existing anxiety and depression triple the risk of developing IBS [10,29].

In MAFLD, psychological distress similarly contributes to disease onset and progression through both neuroendocrine and metabolic pathways. Clinical and epidemiological studies showed that elevated stress correlates with more severe hepatic histopathology, including steatosis, lobular inflammation, and fibrosis [26,30]. In a large cross-sectional study involving over 170,000 Korean adults, Kang et al. (2020) demonstrated a significant independent association between high perceived stress levels and MAFLD risk, even after adjusting for metabolic and lifestyle confounders [31].

Both acute and chronic psychological distress result in the hyperactivation of HPA axis, resulting in prolonged elevations of cortisol and norepinephrine. While this HPA axis hyperactivation constitutes the core stress response, it is accompanied by broader physiological disturbances, including auto-nomic nervous system dysregulation, vagal tone suppression, neuroimmune signaling disruption, neurotransmitter imbalance, and gut microbial dysbiosis [11,13].

These alterations collectively disrupt the GLBA, a complex bidirectional system that integrates emotional and physiological states. Depending on an individual’s genetic, epigenetic, microbial, and metabolic makeup, this dysregulation may manifest primarily as gastrointestinal symptoms typical of IBS or as hepatic disturbances characteristic of MAFLD. In IBS, the cascade contributes to gut dysfunction, visceral hypersensitivity, altered motility, and mucosal inflammation, while in MAFLD, it promotes insulin resistance, hepatic lipid accumulation, steatosis, and inflammatory signaling.

Crucially, these neuroendocrine stress responses are tightly interwoven with the gut microbiota, whose composition and function are highly sensitive to psychological and hormonal shifts. Thus, psychological distress acts not only as a trigger of HPA axis dysfunction but also as a driver of microbial imbalance, perpetuating a pathogenic feedback loop that links emotional, gastrointestinal, and metabolic disturbances across both IBS and MAFLD [12,13].

5. Critical Mechanisms Linking Psychological Distress to IBS and MAFLD

Psychological distress translates into biological dysfunction across multiple levels of the GLBA, initiating a cascade of events that impair intestinal smooth muscle function in IBS and drive hepatic lipid accumulation in MAFLD.

5.1. Microbial Alterations in IBS and MAFLD

At the microbial level, gut dysbiosis acts both as a cause and a consequence of the pathophysiology observed in IBS and MAFLD. Microbial communities are central to GLBA communication, producing approximately 90% of the body’s neurotransmitters [32]. This microbial system generates a diverse array of neuroactive compounds, such as short-chain fatty acids (SCFAs), tryptophan metabolites, and gamma-aminobutyric acid, that are essential for maintaining intestinal homeostasis, epithelial barrier integrity, and CNS regulation (Table 1) [10,33,34,35,36].

Disruption of the gut microbial ecosystem in both IBS and MAFLD is associated with a significant decline in these beneficial metabolites, leading to compromised barrier integrity and increased permeability [6]. This allows the translocation of pro-inflammatory molecules and bacterial components from the intestinal lumen into systemic circulation. Psychological distress exacerbates these changes via HPA axis activation and cortisol release, which can further disrupt gut microbial composition and amplify neuroimmune signaling [6,11].

Specific bacterial taxa and their metabolites also directly influence host neural activity and behavior by modulating immune pathways and interacting with neural circuits. For example, Bifidobacterium longum NCC3001 has been shown to upregulate brain-derived neurotrophic factor (BDNF), promote neuroplasticity in the enteric nervous system, and alleviate mood disturbances in IBS. In terms of composition, IBS is frequently characterized by reduced alpha diversity, a relative abundance of potentially pro-inflammatory species such as Ruminococcus gnavus, Streptococcus spp., and other Firmicutes, and a depletion of anti-inflammatory genera like Faecalibacterium prausnitzii, Lactobacillus, and Bifidobacterium [11,21,36,37,38,39,40,41,42,43,44,45,46].

MAFLD exhibits a similar dysbiotic pattern, with increased representation of Proteobacteria, particularly Enterobacteriaceae (e.g., Escherichia coli) and Clostridium spp., alongside reductions in Faecalibacterium, Bifidobacterium, Prevotella, and Roseburia [11,21,35,36,37,38,39,40,41,42,43,44,47,48]. These shifts are associated with impaired bile acid metabolism, reduced choline availability, and increased gut permeability, all of which favor the translocation of lipopolysaccharide (LPS) into the portal vein. The hepatic immune response elicited by this translocation promotes liver steatosis, inflammation, and fibrosis.

Table 1. Summary of microbial features associated with Irritable Bowel Syndrome (IBS) and Non-Alcoholic Fatty Liver Disease (MAFLD). The table highlights overlapping and condition-specific microbial alterations. Arrows indicate directional changes in abundance. SCFAs = short-chain fatty acids; LPS = lipopolysaccharide; TLR4 = Toll-like receptor 4. “Shared?” indicates whether the microbial feature is common to both disorders.

Microbial Features Associated with IBS and MAFLD
Microbial Feature	IBS	MAFLD	Shared?	Mechanistic Role	Refs
↓ Faecalibacterium prausnitzii	Significantly reduced Anti-inflammatory SCFA producer. Linked to visceral pain.	Reduced in MAFLD Correlates with systemic inflammation.	Yes	Key anti-inflammatory taxa Its loss contributes to gut and hepatic inflammation.	[38,39,40]
↓ Bifidobacterium spp.	Depleted in IBS Affects SCFA production, immune modulation, barrier function.	Decreased in MAFLD, especially in advanced fibrosis.	Yes	Loss impacts mucosal immunity and SCFA levels Common sign of dysbiosis.	[41,42,43]
↓ Lactobacillus spp.	Reduced in IBS Affects motility and epithelial barrier integrity.	Less consistent findings Some studies show reduction	Partial	May influence mucosal homeostasis and motility Role in MAFLD still debated.	[21,36,44]
↑ Ruminococcus gnavus	Elevated Involved in mucin degradation and pro-inflammatory metabolite production.	Not consistently elevated or implicated.	No	Increases gut permeability and inflammation in IBS Unclear role in MAFLD.	[11,45]
↑ Streptococcus spp.	Enriched Linked to gas production, bloating, and fermentation shifts.	Detected in some MAFLD cohorts but not considered a key feature.	No	Contributes to dysbiosis in IBS Unclear hepatic relevance.	[37,38,46]
↑ Proteobacteria/ E. coli	Mild increase Associated with mucosal inflammation	Strongly increased Linked to endotoxemia and liver injury.	Yes	Gram-negative bloom promotes LPS translocation and systemic inflammation.	[38,41,47]
↑ Clostridium spp.	Not significantly enriched.	Elevated in MAFLD Disrupts bile acid metabolism and promotes inflammation.	No	Impacts liver metabolism Specific to hepatic pathophysiology.	[34,35,37]
↓ SCFAs	Lower levels due to depletion of key producers	Same trend Leads to impaired gut–liver anti-inflammatory signaling.	Yes	Reduced SCFA availability weakens barrier integrity and immune regulation in both conditions.	[41,48]
↑ LPS translocation	Due to Gram-negative overgrowth Activates immune responses	Drives hepatic inflammation via TLR4 signaling and Kupffer cell activation.	Yes	A critical mediator linking dysbiosis to systemic and hepatic inflammation.	[36,49]

Table 1. Summary of microbial features associated with Irritable Bowel Syndrome (IBS) and Non-Alcoholic Fatty Liver Disease (MAFLD). The table highlights overlapping and condition-specific microbial alterations. Arrows indicate directional changes in abundance. SCFAs = short-chain fatty acids; LPS = lipopolysaccharide; TLR4 = Toll-like receptor 4. “Shared?” indicates whether the microbial feature is common to both disorders.

Microbial Features Associated with IBS and MAFLD
Microbial Feature	IBS	MAFLD	Shared?	Mechanistic Role	Refs
↓ Faecalibacterium prausnitzii	Significantly reduced Anti-inflammatory SCFA producer. Linked to visceral pain.	Reduced in MAFLD Correlates with systemic inflammation.	Yes	Key anti-inflammatory taxa Its loss contributes to gut and hepatic inflammation.	[38,39,40]
↓ Bifidobacterium spp.	Depleted in IBS Affects SCFA production, immune modulation, barrier function.	Decreased in MAFLD, especially in advanced fibrosis.	Yes	Loss impacts mucosal immunity and SCFA levels Common sign of dysbiosis.	[41,42,43]
↓ Lactobacillus spp.	Reduced in IBS Affects motility and epithelial barrier integrity.	Less consistent findings Some studies show reduction	Partial	May influence mucosal homeostasis and motility Role in MAFLD still debated.	[21,36,44]
↑ Ruminococcus gnavus	Elevated Involved in mucin degradation and pro-inflammatory metabolite production.	Not consistently elevated or implicated.	No	Increases gut permeability and inflammation in IBS Unclear role in MAFLD.	[11,45]
↑ Streptococcus spp.	Enriched Linked to gas production, bloating, and fermentation shifts.	Detected in some MAFLD cohorts but not considered a key feature.	No	Contributes to dysbiosis in IBS Unclear hepatic relevance.	[37,38,46]
↑ Proteobacteria/ E. coli	Mild increase Associated with mucosal inflammation	Strongly increased Linked to endotoxemia and liver injury.	Yes	Gram-negative bloom promotes LPS translocation and systemic inflammation.	[38,41,47]
↑ Clostridium spp.	Not significantly enriched.	Elevated in MAFLD Disrupts bile acid metabolism and promotes inflammation.	No	Impacts liver metabolism Specific to hepatic pathophysiology.	[34,35,37]
↓ SCFAs	Lower levels due to depletion of key producers	Same trend Leads to impaired gut–liver anti-inflammatory signaling.	Yes	Reduced SCFA availability weakens barrier integrity and immune regulation in both conditions.	[41,48]
↑ LPS translocation	Due to Gram-negative overgrowth Activates immune responses	Drives hepatic inflammation via TLR4 signaling and Kupffer cell activation.	Yes	A critical mediator linking dysbiosis to systemic and hepatic inflammation.	[36,49]

5.2. Stress-Induced HPA Axis Dysregulation

Psychological and physical stressors initiate a cascade within the HPA, leading to the release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and ultimately cortisol (Figure 1). Chronic activation of this system results in sustained cortisol exposure, which disrupts immune function, metabolic regulation, and gut–brain signaling [13]. In IBS, patients often show heightened HPA responsiveness and elevated cortisol levels, particularly in the presence of stress sensitivity or anxiety [27,33,50,51]. CRH and cortisol impair gut motility, increase intestinal permeability, and enhance mucosal inflammation and visceral hypersensitivity, increasing susceptibility to inflammation and altered sensory perception [27,33,50,51]. The gut microbiota amplifies these effects by modulating neuroendocrine signaling pathways through the production of short-chain fatty acids and neuroactive metabolites [11].

In MAFLD, cortisol dysregulation contributes to the metabolic and inflammatory milieu underlying disease progression. Cortisol excess promotes insulin resistance, hepatic fat accumulation, and immune activation, while dysbiosis facilitates LPS translocation across a compromised intestinal barrier, triggering Kupffer cell activation and hepatic injury [11,13]. Both IBS and MAFLD exhibit self-reinforcing feedback loops within the GLBA. Stress-induced microbial dysbiosis amplifies HPA axis hyperactivity, which in turn exacerbates dysbiosis and systemic inflammation, thereby sustaining the pathophysiology of both disorders [11,13].

Importantly, while the gut microbiota modulates HPA axis reactivity, the reverse is also true, chronic HPA axis hyperactivity feeds back on the gut ecosystem, reducing microbial diversity and selectively depleting beneficial genera such as Lactobacillus and Bifidobacterium, while enriching pro-inflammatory taxa such as Clostridium difficile and Streptococcus spp. [52,53].

5.3. Neurotransmitter and Neuromodulator Imbalances

Hyperactivation of the HPA axis leads to elevated levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol (Figure 1). This persistent neuroendocrine activity alters key neurotransmitter systems, including serotonin (5-HT), dopamine, gamma-aminobutyric acid (GABA), norepinephrine (NE), and histamine. In IBS, stress-induced HPA hyperactivity is associated with altered 5-HT signaling; increased serotonin and 5-HT₃ receptor activity contribute to diarrhea and visceral pain, while reduced levels are linked to constipation [10,54,55]. Altered GABA, norepinephrine, histamine, and dopamine levels are also linked to heightened pain perception and abnormal motility [10,55].

In MAFLD, though less extensively studied, similar neuromodulator disruptions have been observed [54]. Chronic HPA axis activation sustains cortisol increase, promoting insulin resistance, hepatic steatosis, and inflammation [6,13]. Stress also affects serotonergic signaling and gut hormone re-lease, including GLP-1 and PYY, influencing hepatic metabolism and mood regulation [13,56]. Micro-biota-derived deficits in SCFAs and secondary bile acids impair serotonin synthesis and vagal communication, further disturbing neuroimmune and hepatic pathways [13,56]. Stress intensifies these alterations by increasing pro-inflammatory cytokines, exacerbating gut permeability, neuroinflammation, and visceral sensitivity, thus reinforcing a feed-forward loop with microbial dysbiosis [55].

5.4. Low-Grade Inflammation

Low-grade inflammation is a key driver of disease progression in both IBS and MAFLD (Figure 1). Chronic stress induces a series of immune changes that contribute to low-grade, systemic inflammation in both IBS and MAFLD via the LGBA (Figure 1). Elevated pro-inflammatory cytokines, including IL-6, TNF-α, IL-1β, and IL-8, are common to both disorders, originating from the colonic mucosa in IBS and the liver in MAFLD, and circulate systemically to promote neuroinflammation and immune activation across organs [6,11,56]. Glucocorticoid resistance, caused by chronic HPA axis stimulation, further amplifies these responses by weakening cortisol’s anti-inflammatory effects [6,11]. Furthermore, in both conditions, increased intestinal permeability allows microbial products such as LPS to enter the circulation, activating TLR4 in gut and liver tissue and triggering NF-κB-mediated cytokine release [11]. The result is a self-sustaining inflammatory loop, reinforced by elevated IL-6 and CRP, linking gut, liver, and brain dysfunction under chronic stress.

5.5. Autonomic Nervous System (ANS) Dysregulation

Both IBS and MAFLD are characterized by autonomic imbalance, with a shift toward sympathetic dominance and reduced parasympathetic (vagal) activity (Figure 1) [6]. This dysregulation contributes to altered motility, inflammation, and metabolic dysfunction across the GLBA [11]. Stress-induced ANS changes also impair neuroimmune communication and may exacerbate visceral hyper-sensitivity in IBS and hepatic inflammation in MAFLD [11,56,57]. Reduced vagal tone impairs the cholinergic anti-inflammatory pathway, weakening the body’s ability to suppress cytokine production and maintain gut–liver immune homeostasis. In both IBS and MAFLD, vagal dysfunction under stress contributes to systemic inflammation and reinforces microbiota–brain dysregulation.

5.6. Personality Traits

In both IBS and MAFLD, high neuroticism is associated with increased stress sensitivity, maladaptive coping, and heightened physiological reactivity [58,59]. These traits contribute to low-grade inflammation, behavioral dysregulation (e.g., poor diet, inactivity), and worse clinical outcomes [26,28,58].

5.7. Bidirectional Feedback Loops

Personality traits, psychological distress, and maladaptive cognitive styles, such as rumination and threat anticipation, contribute to HPA axis hyperactivation in both IBS and MAFLD, by disrupting the GLBA (Figure 1). Stress-related cortisol elevation and autonomic imbalance alter the microbiota, im-pair barrier function, and weaken immune control [6]. This promotes microbial translocation and inflammation, which then feed back to the brain, reinforcing emotional dysregulation and sustaining a vicious cycle of GLBA dysfunction.

6. Neuroimaging and Central Processing

Functional MRI studies in both IBS and MAFLD show altered activity and connectivity in brain regions involved in interoception, emotional regulation, and stress response—including the amygdala, insula, prefrontal cortex, and hippocampus [60,61,62,63,64]. These changes often involve disruptions in networks such as the Default Mode Network (DMN), which support internally directed thought, sensory integration, and pain modulation [65,66]. Central alterations appear to be shaped by psychological traits, stress exposure, and gut microbiota composition, reflecting bidirectional influences along the gut–liver–brain axis [60,64,67]. Preliminary evidence suggests that microbiota-targeted interventions, such as probiotic supplementation, may reduce amygdala and insula hyperactivity and partially restore DMN connectivity [9].

7. Epigenetic Mechanisms of Stress-Induced GLBA Dysfunction

Epigenetic mechanisms are considered a crucial link between psychological stress and the persistent alterations observed in the GLBA. Stress and early-life adversity can trigger stable modifications such as DNA methylation, histone changes, and altered microRNA expression [54,68,69,70,71]. These changes affect genes involved in stress response, neurotransmission, immune regulation, and intestinal barrier function (

Table 2. Summary of key epigenetic targets linked to gut–liver–brain axis (GLBA) dysfunction in IBS and MAFLD. The table reports each gene or miRNA’s function, response to early stress, modulation by CBT or MBT, and involvement in GLBA pathways. Arrows indicate regulatory direction: ↑ upregulation, or ↓ downregulation.

Epigenetic Regulation of Key Genes and miRNAs in the Gut–Liver–Brain Axis (GLBA)
Gene/miRNA	Regulation and Function in GLBA	Functional Impact on GLBA	References
FKBP5	↓ DNA methylation	Increases glucocorticoid receptor sensitivity Amplifies HPA axis reactivity and stress response	[70,71,73]
NR3C1 (Glucocorticoid Receptor)	↑ DNA methylation	Reduces receptor expression; prolongs cortisol elevation and impairs stress regulation	[74,75]
CLDN1 (Claudin-1)	↑ DNA methylation	Weakens tight junctions Increases gut permeability and systemic endotoxemia	[51,76]
TRPV1	↑ DNA methylation	Enhances visceral pain sensitivity and pro-inflammatory signaling	[51,57]
BDNF	↑ DNA methylation	Impairs neuroplasticity and emotional regulation; contributes to neuroimmune dysregulation	[70,77]
CRF/NR3C1	Histone acetylation and methylation	Modulates HPA axis tone and stress responsiveness	[13,54]
Tight Junction Proteins (Claudin-1, -2, Occludin, ZO-1)	Histone acetylation supports expression	Enhances gut and liver epithelial barrier integrity	[17,72]
miR-122	Dysregulated expression	Alters hepatic lipid metabolism and gut–liver immune signaling	[69]
miR-29a	Dysregulated expression	Impairs gut barrier function; modulates fibrotic pathways in liver and intestine	[51]
miR-34a	Upregulated	Promotes inflammation, apoptosis, and insulin resistance across the GLBA	[78]
miR-155	Upregulated	Enhances production of pro-inflammatory cytokines in liver and gut mucosa	[70,79]
miR-21	Upregulated	Promotes fibrosis, inflammation, and impaired tissue repair	[68]

) [54,69,70,71]. Key epigenetically modified targets include the glucocorticoid receptor (NR3C1), corticotropin-releasing factor (CRF), serotonin transporter (SERT) (Table 2) [13,17,54,70,71,72]. These genes are critical for maintaining homeostasis across the GLBA and are increasingly shown to respond to stress signals at the molecular level [13,17].

7.1. DNA Methylation and Disease-Relevant Targets

Chronic stress triggers convergent methylation patterns across IBS and MAFLD, reinforcing dysfunction along the GLBA. DNA methylation, especially at promoter regions and CpG islands, represses gene transcription and plays a key role in shaping long-term disease trajectories. Among the most consistently affected genes, FKBP5, which expresses a regulator of glucocorticoid receptor sensitivity, is hypomethylated under stress, leading to exaggerated HPA axis responses and impaired cortisol feedback (Table 2) [13,70,71]. Likewise, NR3C1, which encodes the glucocorticoid receptor itself, is frequently hypermethylated, particularly in early-life stress models, reducing receptor expression and further dysregulating HPA axis control [54,80].

Methylation of CLDN1, which encodes the tight junction protein claudin-1, weakens epithelial barrier integrity, contributing to increased gut permeability in IBS and metabolic endotoxemia in MAFLD [3,17,50,70,80,81]. The TRPV1 gene, which encodes a pain-sensing ion channel, also exhibits altered methylation under stress, amplifying visceral hypersensitivity in IBS and inflammatory signaling in MAFLD [13,17,50,70,80,81]. Furthermore, BDNF, which is crucial for neuroplasticity and emotional regulation, shows stress-induced methylation changes that impair neuronal adaptability and im-mune-neuroendocrine balance along the GLBA [13,17,70,81].

7.2. Histone Modifications and Microbial Mediators

Histone modifications further contribute to transcriptional reprogramming across the GLBA. Stress-altered microbial metabolites, especially short-chain fatty acids (SCFAs) like butyrate, act as histone deacetylase (HDAC) inhibitors, promoting or repressing gene expression via changes in chromatin accessibility. TRPV1 gene undergoes increased histone acetylation, enhancing its expression and contributing to visceral pain in IBS and hepatic inflammation in MAFLD (Table 2) [3,17,50,70,80,81]. Similarly, CRF and NR3C1, key regulators of the HPA axis, are subject to histone acetylation and methylation that modulate stress responses and downstream immune activity [13,17,51,70,81].

Tight junction proteins such as Claudin-1, Occludin, and ZO-1 also undergo histone modifications that affect barrier permeability [17,70,81]. Under homeostatic conditions, SCFA-driven acetylation pre-serves barrier integrity. However, stress and dysbiosis reduce SCFA production, leading to histone deacetylation, decreased protective gene expression, and increased epithelial and hepatic permeability [17].

7.3. MicroRNAs in Stress and Barrier Regulation

MicroRNAs (miRNAs) serve as fine-tuning regulators of gene expression and are increasingly implicated in GLBA disruption in both IBS and MAFLD. These small non-coding RNAs bind to complementary sequences on target mRNAs, leading to translational repression or degradation. In the context of GLBA dysfunction, miRNAs respond to psychological stress and microbial cues, thereby acting as dynamic mediators between environmental stimuli and long-term physiological outcomes. Their dysregulation sustains neuroimmune imbalance, epithelial permeability, and chronic inflammation, reinforcing the pathophysiological overlap between IBS and MAFLD.

MiR-122 is highly expressed in the liver and regulates lipid metabolism and inflammation [70]. Its downregulation is linked to hepatic steatosis in MAFLD, while altered expression in IBS may modulate gut immune activity. In addition, miR-29a regulates intestinal permeability and fibrogenic signaling and it is found to be elevated in both disorders, contributing to mucosal inflammation in IBS and hepatic stellate cell activation in MAFLD [17,70,81].

In both disorders, miR-34a upregulation has been shown to promote inflammatory signaling and insulin resistance [13]. Similarly, miR-155, a stress-responsive and pro-inflammatory miRNA, influences cytokine expression in the gut and liver [51,81]. Furthermore, there an overexpression of miR-21 has also been found, which is associated with tissue remodeling and fibrosis and is known to induce chronic inflammation and impaired repair mechanisms [17,70,81]. These miRNAs, often stress-sensitive and microbiota-responsive, reinforce maladaptive signaling cascades across GLBA organs. They are also emerging as potential biomarkers and therapeutic targets for both IBS and MAFLD.

7.4. Therapeutic and Transgenerational Relevance of Epigenetic Changes

These epigenetic signatures act together as molecular imprints of chronic stress, reinforcing a cycle of low-grade inflammation, and epithelial and hepatic dysfunction, anchoring long-term symptomatology across both disorders. Reduced vagal tone and HPA axis hyperactivation exacerbate these epigenetic shifts, reinforcing barrier dysfunction and neuroinflammation [11,17]. While tissue-specific evidence in humans remains limited, preclinical studies confirm that sustained stress triggers stable epigenetic reprogramming across gut and brain circuits in IBS, and in liver and gut epithelial cells in MAFLD [17,70]. These changes collectively fuel a feedback loop of dysregulation within the GLBA, positioning epigenetic control as a key shared mechanism driving the progression of both dis-orders.

In both IBS and MAFLD, persistent epigenetic changes may sustain aberrant gene expression patterns that perpetuate inflammation and metabolic dysfunction, even after the initial stressor has sub-sided. This chronicity highlights a compelling paradox: while these epigenetic modifications are long-lasting, they are not permanent. Unlike genetic mutations, epigenetic marks, such as DNA methylation and histone modifications, do not alter the underlying DNA sequence and are, in principle, reversible.

Environmental changes (e.g., microbiota modulation, diet, or stress reduction), pharmacological agents (such as HDAC inhibitors), and psychological therapies like Cognitive-Behavioral Therapy (CBT) and Mentalization-Based Therapy (MBT) have all shown potential to reverse stress-induced epigenetic alterations. Clinical and experimental studies reveal that CBT can modify methylation of key stress-regulation genes: increasing methylation of SLC6A4 (serotonin transporter) and decreasing methylation of FKBP5 (a glucocorticoid receptor co-chaperone), thereby improving HPA axis regulation and emotional resilience [73,82,83]. Likewise, psychotherapeutic engagement has been shown to normalize BDNF methylation, a gene critical for neuroplasticity and mood regulation [84].

Moreover, growing evidence suggests that certain epigenetic marks can escape erasure during gamete formation and early embryonic development, raising the possibility of transgenerational inheritance. Stress-related methylation changes, particularly in FKBP5 and NR3C1, can be transmitted to offspring when exposures occur during sensitive developmental periods, such as pregnancy or early childhood [13,85]. As a result, unresolved stress may “prime” future generations for increased vulnerability to immune dysregulation, emotional disorders, or metabolic conditions, even in the absence of direct exposure.

Psychotherapeutic interventions, therefore, may hold intergenerational value, by normalizing stress-related epigenetic patterns in parents, such therapies could potentially reduce the transmission of maladaptive marks to offspring or mitigate their effects. This dual potential, both therapeutic and preventive, highlights the plasticity of epigenetic regulation and offers a compelling avenue for addressing the chronic and systemic nature of both IBS and MAFLD.

8. Biomarkers of Gut–Liver–Brain Axis Dysfunction

In parallel with epigenetic modifications, a range of biomarkers has emerged as promising indicators of gut–liver–brain axis (GLBA) dysfunction in both IBS and MAFLD. Inflammatory cytokines such as IL-6, TNF-α, and C-reactive protein (CRP) consistently signal the presence of chronic low-grade systemic inflammation in both conditions [13]. Lipopolysaccharide (LPS), a hallmark of gut barrier disruption and microbial translocation, is frequently elevated, contributing to hepatic stress and neuro-immune activation [12,53].

Neuroendocrine mediators such as serotonin, glucagon-like peptide-1 (GLP-1), and fibroblast growth factor 19 (FGF19), along with microbial-derived metabolites like short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO), further reflect the complex interplay between microbial, metabolic, and neurohormonal dysregulation [6,51,54]. Together, these biomarkers offer a valuable translational window into GLBA disruption and hold potential for monitoring disease progression and treatment response.

To further elucidate the molecular landscape of these disorders, epigenome-wide association studies (EWAS) are currently underway to identify differential DNA methylation patterns in genes regulating inflammation, metabolism, and neurotransmission [85]. These investigations aim to advance predictive models for disease trajectory and therapeutic responsiveness in both IBS and MAFLD.

9. Therapeutic Perspectives

Recent advances in understanding the gut–liver–brain axis (GLBA) have opened promising therapeutic avenues to restore systemic balance and slow disease progression in IBS and MAFLD. One such strategy targets epigenetic mechanisms—DNA methylation, histone modification, and microRNA ex-pression. Although epigenetic marks are relatively stable, they are reversible, making them attractive targets. Preclinical studies show that agents like HDAC inhibitors and DNA methylation modulators can counteract stress-induced gene expression changes [17]. CRISPR/dCas9-based tools also offer potential for site-specific correction of epigenetic alterations [86].

Lifestyle interventions further expand therapeutic options. Physical activity can restore m6A RNA methylation in the medial prefrontal cortex, producing anxiolytic effects via the GLBA. This process depends on hepatic methyl donor synthesis, underscoring the liver’s central role in regulating brain function [6,87]. Dietary strategies, particularly probiotics, have shown promise in modulating gut microbiota and reducing systemic inflammation [11]. Bifidobacterium and Lactobacillus strains are under evaluation in phase III trials [13].

Psychological therapies also show efficacy. Cognitive Behavioral Therapy (CBT) and Mindfulness-Based Stress Reduction (MBSR) normalize stress-responsive gene methylation—such as FKBP5 and BDNF—and reduce HPA axis overactivation [73,82,83]. These effects may help relieve symptoms and prevent transgenerational transmission of stress-induced epigenetic marks [84].

Despite these advances, clinical translation is still limited. Most supporting data come from small, uncontrolled studies, and causal links between epigenetic alterations and outcomes in IBS or MAFLD remain unproven [13,17]. Large-scale trials are lacking, and concerns about off-target effects and broad transcriptional changes raise safety and specificity issues [13].

Looking ahead, multimodal strategies integrating microbial, psychological, and epigenetic interventions are needed. Stratified trial designs using biomarkers (e.g., cytokines, LPS, SCFAs, miRNAs) could support personalized therapy. However, robust longitudinal studies with adequate power and mechanistic validation will be essential to move the field forward.

10. Conclusions

Psychological distress, by activating the HPA axis and suppressing vagal tone, initiates a cascade of physiological disruptions across the gut–liver–brain axis (GLBA). These include neuroimmune dysregulation, microbiota shifts, and inflammation, which together contribute to a self-reinforcing loop of dysfunction. Depending on genetic, epigenetic, and metabolic predispositions, this dysregulation may manifest as IBS, characterized by gut sensitivity and motility issues, or as MAFLD, marked by hepatic steatosis and insulin resistance. The central role of stress in reshaping both microbial and metabolic environments underscores the GLBA not only as a shared mechanistic pathway but also as a promising target for integrated interventions aimed at restoring homeostasis across body and brain.

Because epigenetic modifications are dynamic and potentially reversible, they provide a biological framework through which psychological stress exerts lasting effects, yet also open avenues for therapeutic modulation. Interventions such as cognitive-behavioral therapy and mentalization-based treatment may not only alleviate symptoms but actively reshape the epigenetic landscape driving dysfunction across the GLBA.