Gut feeling gone wrong: Tangled relationship between disorders of gut-brain interaction and liver disease

Abstract

Functional gastrointestinal disorders, now termed “disorders of gut-brain interaction” (DGBI), are characterized by a spectrum of chronic gastrointestinal symptoms driven by dysregulated gut-brain interaction. DGBIs frequently coexist with liver diseases, including cirrhosis, thereby exacerbating clinical manifestations and complicating management; this overlap is underpinned by shared mechanisms, including gut dysbiosis, increased intestinal permeability, systemic inflammation, and altered neuroimmune signaling. Portal hypertension in cirrhosis promotes small intestinal bacterial overgrowth and microbial translocation, thereby triggering inflammatory pathways that worsen gut and liver function. This minireview explores the gut-liver axis as a central mediator in the interplay between DGBIs and liver disease/cirrhosis. Clinically, these interactions manifest as refractory gastrointestinal symptoms, nutritional deficiencies, and impaired quality of life. Emerging research emphasizes the need for integrative diagnostic approaches, such as combining advanced imaging, microbiome analysis, and biomarker profiling, to unravel the complex interplay between DGBIs and liver disease/cirrhosis. Therapeutic interventions targeting the gut microbiome, neuroimmune pathways, and lifestyle modification can mitigate disease burden. This review underscores the importance of a multidisciplinary framework for enhancing patient outcomes and guiding future research in this intersectional field.

Key Words: Disorders of gut-brain interaction; Liver diseases; Gut-liver axis; Dysbiosis; Cirrhosis; Intestinal permeability; Neuroimmune dysregulation

Core Tip: The review highlights the complex bidirectional relationship between disorders of gut-brain interaction and liver diseases, particularly cirrhosis. It emphasizes shared pathophysiological mechanisms such as gut dysbiosis, increased intestinal permeability, and neuroimmune dysregulation, which exacerbate clinical manifestations and complicate management. The article suggests integrative diagnostic approaches and therapeutic strategies targeting the gut microbiome and neuroimmune pathways to improve patient outcomes.

INTRODUCTION

Functional gastrointestinal disorders, now more accurately termed “disorders of gut-brain interaction” (DGBI), comprise a diverse group of chronic gastrointestinal conditions driven by multifactorial mechanisms, including dysregulated communication between the gut and the brain[1]. The most prevalent of these disorders include irritable bowel syndrome (IBS), functional dyspepsia (FD), functional diarrhea, functional constipation, etc[2]. IBS and FD together affect > 20% of the global population and have a significant impact on quality of life and increased healthcare utilization[1-3]. In parallel, liver diseases such as metabolic-associated steatotic liver disease (MASLD) and cirrhosis constitute a substantial global health burden, with MASLD alone affecting approximately one in four individuals worldwide[4]. Cirrhosis, the end-stage manifestation of liver disease, impacts over 112 million individuals worldwide, remaining a significant cause of morbidity and mortality. With the advancement of collaborative research, the coexistence of DGBIs and liver disease/cirrhosis has been increasingly recognized[5-7]. Emerging data suggest a significant interplay between DGBIs and liver disease, particularly MASLD and its progression. A review by Ng et al[5] estimated that 23.2%-29.4% of patients with MASLD had IBS, which was significantly higher than in non-MASLD populations (12.5%). Conversely, 65.8%-74.0% of patients with IBS exhibit evidence of MASLD, highlighting a bidirectional association between these conditions. The severity of MASLD has been shown to correlate directly with the prevalence and intensity of IBS symptoms, underscoring the intricate relationship between metabolic liver dysfunction and DGBIs[4-6].

Despite the growing recognition of this overlap, there remains a paucity of literature addressing the interplay between DGBIs and liver diseases. The lack of awareness of these interactions may lead to underdiagnosis and mismanagement, as symptoms of DGBIs are often overlooked in patients with liver disease, and vice versa. The gut-liver axis serves as a pivotal mediator of this relationship, involving complex mechanisms such as intestinal dysbiosis, increased gut permeability, systemic inflammation, and altered neuroimmune signaling. This minireview aimed to bridge the gap in our understanding by exploring the shared pathophysiological mechanisms between DGBIs and liver diseases; it further discusses the clinical implications of this overlap, current diagnostic challenges, and potential therapeutic strategies, emphasizing the need for a multidisciplinary approach to these increasingly prevalent and coexisting conditions.

PATHOPHYSIOLOGY: UNRAVELING THE SHARED MECHANISMS

The pathophysiological interplay between DGBIs and advanced liver disease/cirrhosis is primarily mediated through the gut-liver axis. This bidirectional communication network integrates the gut microbiota, intestinal barrier, liver, and central nervous system, with disruption in any component leading to cascading dysfunction. In both DGBIs and cirrhosis, alterations in the microbiome, intestinal permeability, and immune signaling serve as critical mediators (Table 1, Figure 1)[8-18].

Figure 1  Schematic representation of the gut-liver-brain axis.

Table 1 The table outlines converging pathophysiological mechanisms shared between disorders of gut-brain interaction, and liver diseases.

Mechanism	DGBIs (e.g., IBS, FD)	Liver disease (e.g., MASLD, cirrhosis)	Shared pathophysiological outcomes
Microbiota dysbiosis[8,9]	Altered Firmicutes-to-Bacteroidetes ratio; increased proteobacteria; dysbiosis in > 70% of IBS patients	Decreased microbial diversity; increased Enterobacteriaceae and SIBO in 39%-50% cirrhotics	Immune activation; systemic inflammation endotoxemia; abnormal motility
Increased intestinal permeability[12,13]	Zonulin upregulation; CRH-induced tight junction breakdown; zonulin elevated in 55%-68% of diarrhea IBS patients	Decreased claudin-1, occludin, ZO-1 in cirrhosis and MASLD; tight junction protein loss in 60%-70% of cirrhosis; increased plasma LPS in 80%	Systemic inflammation; LPS-driven immune response; endotoxemia
Neuroimmune dysregulation[10,11]	HPA axis hyperactivity; increased CRH, visceral hypersensitivity; increased CRH and altered HPA axis in approximately 60% of IBS patients	Hepatic encephalopathy; ammonia and indole neurotoxicity	Cognitive impairment; visceral pain; mood disorders
Immune activation[14,15,18]	Increased IL-6, TNF-α, IL-1β; mucosal T-cell infiltration; IL-6 and TNF-α elevated in > 50% of IBS patients	TLR4 activation; Kupffer cell stimulation; systemic cytokinemia	Hepatocellular injury, fibrosis, chronic inflammation
Bile acid dysregulation[16,17]	Excess bile acids in colon; impaired FXR-FGF19 signaling; bile acid malabsorption in approximately 33% of IBS-diarrhea patients	Reduced bile acid recirculation; cholestasis; FXR/FGF19 pathway disruption in 60%-80% of MASLD; increased colonic bile acids	Dysbiosis, altered intestinal transit, diarrhea

IBS: Irritable bowel syndrome; FD: Functional dyspepsia; MASLD: Metabolic associated steatotic liver disease; SIBO: Small intestinal bacterial overgrowth; CRH: Corticotropin-releasing hormone; ZO-1: Zonula occludens-1; LPS: Lipopolysaccharides; HPA: Hypothalamus pituitary axis; IL: Interleukin; TNF: Tumor necrosis factor; TLR: Toll-like receptor; FXR: Farnesoid X receptor; FGF: Fibroblast growth factor.

Gut dysbiosis and microbial translocation

Gut dysbiosis is a hallmark of both DGBIs and cirrhosis; it is characterized by a reduction in beneficial bacteria, such as Lactobacillus and Bifidobacterium, and an overrepresentation of pathogenic taxa like Enterobacteriaceae and Escherichia coli. In cirrhosis, microbial diversity is significantly diminished, leading to the proliferation of pathogenic species that produce endotoxins such as lipopolysaccharides[8]. A significant reduction in the alpha diversity of oral and gut microbiomes was observed in patients with decompensated cirrhosis and acute on chronic liver failure compared with healthy controls[19]. Moreover, the severity of cirrhosis was correlated with increased numbers of pathobionts and decreased commensals in oral and gut microbiomes[18].

Distinct microbial clusters in the gastrointestinal tract of patients with advanced cirrhosis harbor virulence factors and antimicrobial resistance genes. Furthermore, portal hypertension exacerbates this dysbiosis by slowing intestinal motility, thereby promoting small intestinal bacterial overgrowth (SIBO). SIBO prevalence is reported to be as high as 50% in patients with cirrhosis, directly correlating with liver dysfunction severity. This microbial overgrowth facilitates the translocation of bacterial products through the intestinal barrier, activating toll-like receptor 4 in Kupffer cells in the liver, which triggers inflammatory cascades and hepatic fibrosis[18].

Similarly, microbial dysbiosis has been implicated in patients with IBS, with alterations in the Firmicutes-to-Bacteroidetes ratio. Reduced microbial diversity and overproduction of short-chain fatty acids further exacerbate symptoms such as visceral hypersensitivity and altered motility[9]. Emerging data are available on the relationship between gut dysbiosis and FD. A study by Zhong et al[20] reported that in patients with FD, the bacterial load in the duodenum correlated positively with symptom severity and negatively with bacterial diversity. Improvement of FD symptoms with rifaximin and a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) supports the role of gut microbiome in the pathophysiology of FD[21,22].

Intestinal permeability and “leaky gut”

The compromised barrier function also facilitates systemic inflammation through the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These inflammatory mediators further impair the intestinal barrier and liver function, creating a vicious cycle. Similarly, increased intestinal permeability is particularly evident in diarrhea-predominant IBS, in which heightened permeability correlates with symptom severity. Chronic stress, a known worsening factor in DGBIs, has been shown to increase intestinal permeability via the activation of mast cells and the release of corticotropin-releasing hormone[13,23,24].

Neuroimmune dysregulation

The gut-brain axis integrates the enteric nervous system with central neural circuits that modulate motility, sensitivity, and immune responses. In DGBIs, hyperactivation of the hypothalamic-pituitary-adrenal axis and dysregulation of autonomic function exacerbate gastrointestinal symptoms. Stress-induced increases in cortisol and corticotropin-releasing hormone disrupt gut motility and enhance visceral hypersensitivity[10,25]. In cirrhosis, neuroimmune dysregulation is exemplified by hepatic encephalopathy (HE), in which gut-derived neurotoxins such as ammonia and indoles disrupt neural function. There has been an ongoing debate about whether HE is a perfect example of DGBI, a disorder in which gut dysfunction may lead to brain dysfunction. All the more, DGBI criteria are fulfilled by HE[11]. The interaction between gut dysbiosis and the liver-brain axis has been shown to impair neurocognitive function, with HE representing an extreme manifestation of gut-brain dysfunction[26].

Immune activation and systemic inflammation

Systemic inflammation plays a pivotal role in the pathogenesis of cirrhosis and DGBI. In cirrhosis, microbial translocation activates the innate immune system via toll-like receptor 4, leading to cytokine production and Kupffer cell activation. This inflammatory cascade contributes to hepatocellular injury and fibrosis[18]. Similarly, DGBIs are associated with low-grade inflammation and are characterized by increased mucosal infiltration of immune cells, such as CD3⁺, CD4⁺, and CD8⁺ T cells. Elevated levels of TNF-α, IL-1β, and IL-8 are directly correlated with symptom severity in IBS[27].

Bile acid dysregulation

Bile acid signaling, which is mediated through the farnesoid X receptor and fibroblast growth factor 19, is disrupted in both cirrhosis and DGBI. In cirrhosis, impaired bile acid metabolism exacerbates dysbiosis and intestinal inflammation. In diarrhea-predominant IBS, increased colonic bile acid exposure is associated with accelerated colonic transit and heightened visceral sensitivity, further complicating symptomatology[16,17].

CLINICAL MANIFESTATIONS: A CONVERGENCE OF SYMPTOMS

The clinical manifestations of DGBI and cirrhosis reflect a complex interplay of overlapping symptoms that significantly impair quality of life and present diagnostic challenges[28]. Gastrointestinal symptoms are among the most prominent, affecting up to 80% of patients with cirrhosis; these include bloating, abdominal pain, belching, diarrhea, and constipation, which arise from motility disturbances, visceral hypersensitivity, and gut microbiota changes (Figure 2). Delayed gastric emptying and small bowel transit are common in patients with cirrhosis and are caused by altered gut motility and hormonal imbalances involving insulin, ghrelin, and gastrin. Ascites and portal hypertension exacerbate these issues by disrupting gastric sensorimotor function, leading to discomfort and reflux[29,30].

Figure 2  Multisystem clinical manifestations associated with gut-liver-brain axis dysfunction.

Nutritional deficiencies and malnutrition are prevalent in advanced cirrhosis, affecting 50%-90% of patients. Malnutrition manifests as sarcopenia, micronutrient deficiencies, and reduced dietary intake. Appetite loss, reported in over one-third of cirrhotic individuals, is influenced by systemic inflammation, chemosensory dysfunction, and anorexia related to dysregulated leptin and ghrelin. Sarcopenia, a severe complication, independently predicts mortality and contributes to physical debilitation. Dietary restrictions implemented to manage ascites or encephalopathy often exacerbate nutritional deficiencies, creating a cycle of deteriorating health[31].

Sleep disturbances, including insomnia, excessive daytime sleepiness, and restless leg syndrome, are reported in nearly 50% of patients with cirrhosis and as many as 80% of those with HE. These issues are linked to disrupted circadian rhythms, elevated ammonia levels, and neuroimmune dysregulation, which significantly affect cognitive function and overall wellbeing. Pain is another critical manifestation that affects 40%-79% of patients with cirrhosis. The condition may present as nociceptive, neuropathic, or nociplastic pain and is often accompanied by fibromyalgia-like symptoms, such as fatigue, widespread discomfort, and cognitive impairment. These conditions further reduce functional capacity and quality of life[32].

The psychological burden of cirrhosis is profound, with anxiety and depression affecting a substantial proportion of patients. The prevalence of anxiety ranges from 25% to 45%, whereas depression rates can reach as high as 72%. The chronic nature of cirrhosis, combined with unpredictable symptoms and social stigmatization, exacerbates these mental health challenges. This psychological condition frequently intensifies physical symptoms, creating a vicious cycle that complicates disease management[33].

Overall, the interplay of gastrointestinal symptoms, nutritional deficits, pain, sleep disturbances, and psychological distress culminates in significant quality of life impairment. However, data demonstrating that patients with coexisting DGBI and cirrhosis have poorer health outcomes than those with either condition alone remain unexplored. Persistent pain, chronic fatigue, and unpredictable bowel habits drive frequent healthcare utilization and pose substantial challenges for clinicians. This intricate web of symptoms underscores the necessity of a comprehensive and multidisciplinary approach to management that integrates physical and mental health strategies to improve patient outcomes.

ADVANCING DIAGNOSTICS: INTEGRATIVE APPROACHES

The diagnostic challenges posed by the overlapping manifestations of DGBIs and cirrhosis necessitate a more integrative and technologically advanced approach. Traditional diagnostic methods, such as liver function tests, imaging, and endoscopic evaluation, often fail in delineating the complex interplay between these conditions. Emerging diagnostic modalities that use cutting-edge technologies are increasingly recognized as indispensable tools for understanding the pathophysiological underpinnings of pathology and guiding targeted therapies.

Microbiome analysis: Deciphering dysbiosis

One of the cornerstone advances in the understanding of DGBIs and cirrhosis is microbiome profiling using next-generation sequencing. Studies consistently revealed significant microbial alterations under both conditions. Patients with cirrhosis exhibit a marked decline in microbial diversity, with overrepresentation of pathogenic species such as Enterobacteriaceae, Escherichia coli, and Streptococcus, alongside a reduction in beneficial genera such as Lactobacillus and Bifidobacterium. Similarly, individuals with IBS exhibit shifts in microbial composition, including decreased Firmicutes and increased Proteobacteria ratios, which influence motility, inflammation, and pain perception[34,35]. Next-generation sequencing allows for a comprehensive analysis of the fecal microbiota, identifying specific dysbiotic patterns and bacterial metabolite profiles linked to symptomatology in DGBIs and cirrhosis. For instance, patients with cirrhosis exhibit elevated levels of microbial metabolites, such as ethanol and trimethylamine-N-oxide, which are associated with systemic inflammation and hepatic decompensation. These findings aid in diagnosis and provide therapeutic targets, enabling precision interventions such as tailored probiotics or microbial transplantation[36].

Biomarker profiling: The leaky gut paradigm

Biomarkers of intestinal permeability and systemic inflammation are emerging as critical tools for assessing gut-liver dysfunction. Zonulin, a regulator of tight junction integrity, has been validated as a marker of intestinal barrier disruption. Elevated serum zonulin levels are correlated with disease severity and systemic endotoxemia in patients with cirrhosis. Similarly, elevated serum zonulin levels have been reported in patients with diarrhea-predominant IBS and even higher levels in patients with non-celiac gluten sensitivity[12,37]. In addition, the level of fecal calprotectin, an inflammatory marker, is significantly elevated in IBS, reflecting mucosal immune activation. The utility of systemic inflammatory biomarkers, such as IL-6, TNF-α, and high-sensitivity C-reactive protein, was demonstrated under both conditions. Elevated IL-6 Levels in cirrhosis indicate microbial translocation, whereas TNF-α is a hallmark of chronic inflammation in DGBIs. These markers not only facilitate diagnosis but also serve as indicators of therapeutic response, particularly in interventions targeting the gut-liver axis[9].

Metabolomic and proteomic profiling: The next frontier

Metabolomic studies have identified distinct metabolite signatures in DGBIs and cirrhosis. For example, increased levels of bile acids and microbial-derived metabolites such as indole and phenylacetate are associated with disease severity. Proteomic profiling further aids in the identification of changes in gut barrier proteins and immune mediators, providing insights into the molecular underpinnings of these conditions[38,39].

THERAPEUTIC INTERVENTIONS: A MULTIDISCIPLINARY APPROACH

Microbiota-targeted therapies

Probiotics and synbiotics: Probiotic strains such as Lactobacillus rhamnosus GG and Bifidobacterium longum have shown significant efficacy in reducing gastrointestinal symptoms associated with IBS and enhancing intestinal barrier integrity in cirrhosis (Figure 3). In randomized clinical trials, patients with MASLD demonstrated reduced liver fat and inflammation following probiotic supplementation, highlighting a potential role in mitigating cirrhosis progression[40,41]. Synbiotics, which combine prebiotics and probiotics, are another promising approach; these molecules support the proliferation of beneficial gastrointestinal bacteria while modulating host immune responses. Evidence suggests that synbiotics improve serum endotoxin levels and reduce hepatic inflammation, providing a dual benefit in gastrointestinal and liver conditions[42,43].

Figure 3 Therapeutic interventions for disorders of gut-brain interaction and associated liver dysfunction: A multidisciplinary approach. GLP-1: Glucagon-like peptide-1; CBT: Cognitive-behavioral therapy; FODMAP: Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols.

Rifaximin: Rifaximin, a non-absorbable antibiotic, has emerged as a key therapy for SIBO, HE, IBS, and even FD[21,44]. The ability of this agent to modulate the gastrointestinal microbiome by reducing gram-negative bacteria has demonstrated significant clinical benefits. Studies have shown that rifaximin not only improves IBS symptoms such as bloating and diarrhea but also decreases serum endotoxins and inflammatory markers in cirrhosis, ultimately improving patient outcomes[45].

Fecal microbiota transplantation: Fecal microbiota transplantation (FMT) is efficacious for reshaping the gut microbiome and reducing disease severity in cirrhosis and IBS. Pilot studies suggest that FMT improves cognitive symptoms in HE by re-establishing microbial diversity and reducing the abundance of pathobionts; however, its application remains experimental, and further trials are required[46].

Neuroimmune modulation

DGBIs often involve heightened visceral sensitivity mediated through neuroimmune dysregulation. Novel therapies targeting these pathways are currently receiving increasing attention.

Glucagon-like peptide-1 receptor agonists: Traditionally used for managing diabetes, glucagon-like peptide-1 receptor agonists have demonstrated promising results in reducing systemic inflammation and abdominal pain in DGBIs. These agents modulate gut motility and inflammation, offering a potential dual benefit in IBS and liver conditions associated with inflammation[47].

Cognitive-behavioral therapy and psychosocial support: Cognitive-behavioral therapy improves psychological distress and gastrointestinal symptoms in patients with DGBIs. By addressing anxiety and depression, which are common comorbidities in cirrhosis and IBS, cognitive-behavioral therapy contributes to enhanced quality of life and symptom management[1].

Dietary and lifestyle interventions

Low FODMAP diet: Restricting FODMAPs alleviates symptoms in patients with IBS and FD[22,48]. These diets also reduce the fermentation substrates for SIBO, a common complication of cirrhosis, thereby improving overall gastrointestinal health.

Nutritional counseling: Nutritional deficiencies in cirrhosis necessitate specialized interventions. Adequate protein intake prevents sarcopenia, whereas micronutrient supplementation addresses deficiencies in vitamins A, D, and K, which are common in liver dysfunction. Tailored nutritional plans have been shown to significantly improve outcomes in patients with overlapping gastrointestinal and hepatic conditions[31].

CONCLUSION

The intersection of DGBIs and cirrhosis highlights the complexity of the gut-liver-brain axis. Shared mechanisms such as gut dysbiosis, intestinal permeability, systemic inflammation, and neuroimmune dysregulation create a bidirectional relationship that exacerbates clinical manifestations and complicates management. Although advances in microbiome profiling, biomarker discovery, and imaging techniques have improved our understanding of these conditions, significant gaps remain. Future research should prioritize longitudinal studies to unravel the causative pathways and assess the impact of microbiota-targeted therapies, including probiotics, rifaximin, and FMT. Emerging technologies, such as metabolomics and transcriptomics, can potentially reveal novel biomarkers and guide precision medicine approaches. Tailoring interventions based on individual microbiome profiles and genetic predispositions will revolutionize treatment strategies. Integrating multidisciplinary care - encompassing gastroenterology, hepatology, nutrition, and mental health - is essential for optimizing patient outcomes. By addressing both the symptoms and underlying mechanisms, clinicians can enhance quality of life and reduce disease burden. The continued exploration of the gut-liver axis will not only advance our understanding of these interconnected conditions but also pave the way for innovative and personalized therapies.