Implications of gut microbiota in hepatic and pancreatic diseases: Gut-liver-pancreas axis

Abstract

The gut–liver-pancreas axis (GLPA) is a critical network shaped by gut microbiota (GM) and their metabolites, essential for maintaining metabolic and immune balance. Disruption of this microbial equilibrium, known as dysbiosis, contributes to the development and progression of various hepatic and pancreatic diseases. Through mechanisms such as increased intestinal permeability and exposure to microbial products-including lipopolysaccharide, trimethylamine-N-oxide, and secondary bile acids-dysbiosis promotes inflammation, oxidative stress, insulin resistance, and carcinogenesis. These changes are linked to conditions including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cirrhosis, hepatocellular carcinoma, pancreatitis, pancreatic ductal adenocarcinoma, and diabetes. Emerging tools like stool metagenomics and serum metabolomics help identify microbial biomarkers for diagnosis and risk stratification. While interventions such as probiotics, dietary changes, and fecal microbiota transplantation aim to restore microbial balance, their success remains inconsistent. This work aims to highlight the pathogenic role of GM across the GLPA, with special emphasis on the underexplored gut-pancreas connection. Advancing our understanding of the GLPA can unlock novel microbiota-targeted approaches for early diagnosis and treatment of hepatopancreatic diseases.

Key Words: Microbial metabolites; Dysbiosis; Immune modulation; Therapeutic strategies

Core Tip: This editorial highlights the central role of gut microbiota in regulating the gut-liver-pancreas axis, a dynamic network critical for metabolic and immune homeostasis. Dysbiosis-driven disruptions-via microbial metabolites, barrier dysfunction, and immune imbalance-underlie the pathogenesis of liver and pancreatic diseases. While gut-liver interactions are well studied, gut-pancreas crosstalk remains underexplored. We emphasize emerging biomarkers, microbial-based therapies, and the urgent need for longitudinal studies and metabolomic profiling to translate microbiome science into precision diagnostics and treatments for hepatopancreatic disorders.

INTRODUCTION

The human body hosts trillions of microorganisms, predominantly in the gut, forming a complex ecosystem crucial for health. These microbes, including bacteria, viruses, and fungi, interact symbiotically with the host, influencing metabolism, immunity, and barrier integrity[1]. The gut-liver-pancreas axis (GLPA) exemplifies this interaction, where microbial metabolites like short-chain fatty acids (SCFAs) and bile acids (BAs) regulate metabolic and immune functions. Anatomical connections, such as the portal vein and biliary-pancreatic ducts, facilitate bidirectional communication, allowing gut-derived substances to directly impact liver and pancreas health[2].

Dysbiosis-an imbalance in microbial composition-disrupts GLPA homeostasis, leading to disease. A compromised intestinal barrier permits harmful molecules like lipopolysaccharide (LPS) to enter the liver, triggering inflammation via toll-like receptor 4 (TLR4) and promoting conditions such as metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD)[3]. Similarly, diseases like type 2 diabetes (T2D) involve gut barrier dysfunction and microbial translocation, promoting inflammation and insulin resistance[4]. These processes, along with harmful metabolites like secondary BAs and trimethylamine-N-oxide (TMAO), impair β-cell function and contribute to diabetes, pancreatitis, and cancers such as hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC).

Immune dysregulation plays a pivotal role, with dysbiosis skewing T-cell responses toward pro-inflammatory Th17 cells and away from regulatory T-cells (Tregs). Triggers of inflammasome activation exacerbate inflammation, while oxidative stress from microbial byproducts through reactive oxygen and nitrative species damages tissues, accelerating disease progression. Clinically, microbial signatures (e.g., Proteobacteria overgrowth) and metabolomic profiles (e.g., SCFA depletion) serve as biomarkers for diseases like cirrhosis and PDAC[5].

Emerging therapies targeting the gut microbiota (GM), such as probiotics and fecal microbiota transplantation (FMT), aim to restore microbial balance. However, challenges in standardization and in-depth understanding of gut-pancreas interactions persist. While the gut-liver axis has been extensively studied, the direct interaction between the gut and the pancreas remains insufficiently explored[6]. Most existing studies focus on hepatic outcomes of gut dysbiosis, often overlooking how gut-derived metabolites and immune signaling pathways influence pancreatic function. This editorial aims to address that gap by offering an integrated view of the GLPA, emphasizing how GM contribute to both hepatic and pancreatic pathophysiology. By dissecting microbial metabolites, immune cross-talk, and therapeutic potential, we aim to illuminate strategies for restoring GLPA equilibrium and mitigating the global burden of chronic hepatopancreatic diseases.

THE GLPA: ANATOMICAL AND PHYSIOLOGICAL FRAMEWORK

The GLPA represents a sophisticated network of anatomical and functional interactions that integrate metabolic, immune, and endocrine signaling across organs. Central to this axis is the bidirectional communication mediated by microbial metabolites, which orchestrate systemic homeostasis or, under dysbiotic conditions, drive pathophysiology[2].

Anatomical connectivity

The liver derives approximately 75% of its blood supply from the intestinal portal circulation, facilitating direct exposure to gut-derived nutrients, microbial metabolites, and endotoxins. This vascular linkage ensures that BAs, synthesized in the liver and secreted into the intestines, undergo enterohepatic recirculation-a process modulated by microbial metabolism[7]. The pancreas, anatomically connected to the duodenum via the pancreatic duct, interfaces with the GLPA through endocrine secretion (e.g., insulin, glucagon) and susceptibility to microbial translocation via mesenteric circulation[2].

Physiological mediators

SCFAs, such as acetate, propionate, and butyrate, are produced by the microbial fermentation of dietary fiber. These metabolites play crucial roles in maintaining intestinal barrier integrity, regulating hepatic gluconeogenesis and glycogen storage, and enhancing glucose-stimulated insulin secretion via G-protein-coupled receptors (e.g., FFAR2/3) on pancreatic β-cells[8]. Similarly, BAs undergo microbial modification, transforming primary BAs into secondary forms like deoxycholic acid. These secondary BAs activate nuclear receptors such as FXR and TGR5, which help regulate lipid and glucose metabolism and suppress hepatic inflammation[9]. Additionally, the GM indirectly influences pancreatic function through the stimulation of glucagon-like peptide-1 (GLP-1) secretion by intestinal L-cells in response to SCFAs. GLP-1 promotes insulin secretion, inhibits glucagon release, and delays gastric emptying, highlighting a critical link between microbial metabolites and the GLPA[10].

Dysbiosis and pathophysiological consequences

Dysbiosis-defined as a pathological imbalance in gut microbial composition marked by reduced diversity, overgrowth of harmful pathobionts, and depletion of beneficial taxa[11] serves as the pivotal disruptor of the GLPA. The upcoming section explores how these disruptions drive fibrosis, cancer, and multi-organ disease.

MECHANISTIC PILLARS OF AXIS-MEDIATED INJURY

The gut liver pancreas axis contributes to liver and pancreatic diseases through a network of interconnected mechanisms, including intestinal barrier disruption, imbalanced microbial metabolites, and immune system dysregulation.

Barrier dysfunction & endotoxemia

A compromised intestinal barrier (“leaky gut”) is a hallmark of GLPA axis disruption. Dysbiosis degrades tight junction proteins (e.g., occludin, zonula occludens-1) and thins the mucus layer, enabling translocation of microbial products like LPS into the portal circulation. LPS, a gram-negative bacterial endotoxin, activates hepatic TLR4, triggering Kupffer cells, the liver’s resident macrophages, to release pro-inflammatory cytokines (TNF-α, IL-6) and reactive oxygen species (ROS)[4,12]. Chronic endotoxemia perpetuates systemic inflammation and promotes fibrotic remodeling across multiple organs. Alcohol, high-fat diets, and pathobionts (e.g., Proteobacteria) exacerbate barrier dysfunction, while reduced SCFAs, worsen permeability[13]. In the pancreas, LPS translocation promotes β-cell apoptosis and chronic pancreatitis (CP), linking “leaky gut” to pancreatic dysfunction[2].

Harmful microbial metabolites

Harmful metabolites include TMAO, derived from microbial choline metabolism, which impairs reverse cholesterol transport, promotes hepatic steatosis, and exacerbates insulin resistance[12]; ethanol produced by bacteria (e.g., Klebsiella) that induces oxidative stress and lipid peroxidation, mimicking alcohol-induced liver injury[14]; and excess of secondary bile such as DCA promotes hepatocyte senescence, cholangiocyte damage, and pro-tumorigenic STAT3 signaling[2].

Immune modulation and inflammation

Immune dysregulation is a central mechanism by which gut dysbiosis contributes to liver and pancreatic pathology. Disrupted microbial composition skews host immunity through several interconnected pathways.

One key pathway involves the imbalance between pro-inflammatory T-helper 17 (Th17) cells and regulatory T cells (Tregs). Dysbiosis favors the expansion of Th17 cells while suppressing Treg development. Th17 cells secrete cytokines such as IL-17 and IL-22, which recruit neutrophils and activate inflammatory cascades that contribute to tissue injury. This Th17/Treg imbalance has been implicated in the development of MASLD, autoimmune liver diseases like primary biliary cholangitis (PBC), and pancreatic inflammation[15].

Another major mechanism is the activation of inflammasomes by gut-derived microbial components, including LPS and other pathogen-associated molecular patterns. These molecules activate inflammasome complexes-particularly NLRP3 and NLRP6-in both hepatic and intestinal tissues. The inflammasomes regulate the maturation and secretion of pro-inflammatory cytokines, such as IL-1β and IL-18, which drive chronic inflammation in the liver and pancreas. When dysbiosis disrupts normal inflammasome signaling, it can impair mucosal healing, increase intestinal permeability, and facilitate microbial translocation, thereby perpetuating a vicious cycle of inflammation[14,16].

Oxidative and nitrative stress represent additional mechanisms by which gut-derived microbial products contribute to tissue injury. ROS, generated in response to microbial metabolites such as ethanol and LPS, activate hepatic stellate cells, promote extracellular matrix deposition, and initiate fibrogenesis. ROS also inflicts direct damage on mitochondrial DNA, lipids, and proteins, exacerbating cellular injury. Moreover, nitrative species like peroxynitrite (ONOO^—), formed from the reaction between nitric oxide and superoxide, impair mitochondrial function and protein integrity, thereby amplifying oxidative damage and fibrosis in both hepatic and pancreatic tissues[2,17].

Bidirectional crosstalk and systemic feedback

The mechanistic pillars described above do not function in isolation. The GLPA is a tightly interconnected system, where dysfunction in one organ often propagates reciprocal pathology in others[2]. Liver cirrhosis disrupts BA synthesis, altering microbial composition and weakening the gut barrier, which enhances microbial translocation and promotes pancreatic inflammation[18]. Conversely, pancreatic exocrine insufficiency impairs nutrient digestion and BA signaling, fostering gut dysbiosis that accelerates liver disease[19]. Inflammatory mediators and microbial metabolites such as TMAO and secondary BAs can circulate systemically, compounding insulin resistance and immune activation in both hepatic and pancreatic contexts[20]. These feedback loops underscore the need to treat GLPA dysfunction as a unified, axis-wide pathology rather than isolated organ diseases.

GM and BAS

The interplay between GM, BAs, and the pancreas constitutes a key component of the GLPA. The GM modifies primary BAs into secondary BAs through various enzymatic reactions, including deconjugation and dehydroxylation, thereby altering the composition and function of the BA pool[9]. These microbially modified BAs engage receptors such as FXR and TGR5, which are expressed in multiple tissues, including the pancreas. Activation of TGR5 and FXR not only regulates glucose and lipid metabolism but also enhances insulin secretion and improves pancreatic endocrine function, they also have multiple effects as shown in Figure 1[21]. Dysbiosis, by disrupting BA composition, can impair this signaling, contributing to β-cell dysfunction, insulin resistance, and the development of metabolic disorders like T2D. Thus, the microbiota-BA-pancreas axis plays a critical regulatory role in maintaining pancreatic metabolic homeostasis and represents a potential target for therapeutic intervention[2].

Figure 1 Schematic representation of bile acid relation with gut microbiota. Gut microbiota can metabolize bile acid (BA) into secondary BAs through various enzymatic reactions, including deconjugation and dehydroxylation, which has effects on adipose tissue, pancreas, and immune cells through FXR and TGR-5 signaling pathways. BA: Bile acid.

GM IN HEPATIC DISEASES

MASLD

MASLD progression correlates with Bacteroides enrichment, Firmicutes depletion, and ethanol-producing taxa. Impaired BA conversion reduces FXR activation, promoting lipogenesis, while LPS-TLR4 signaling drives steatohepatitis[22].

ALD

ALD is characterized by Lactobacillus/Bifidobacterium depletion and Proteobacteria expansion. Alcohol metabolism by gut microbes generates acetaldehyde, exacerbating intestinal permeability and Kupffer cell-derived TGF-β-mediated fibrosis[23,24].

Primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is marked by bile duct inflammation and scarring and is associated with intestinal microbiota dysbiosis. Studies have shown reduced microbial diversity and an overrepresentation of proinflammatory genera such as Enterococcus, Veillonella, Streptococcus, and Lactobacillus, regardless of the presence of inflammatory bowel disease. Additionally, there is enrichment of Barnesiellaceae and depletion of Clostridiales. These microbial alterations may contribute to PSC pathogenesis by promoting bacterobilia, which activates proinflammatory responses in cholangiocytes and leads to fibrosis. Endotoxemia may also drive molecular mimicry, triggering antibody production and immune-mediated bile duct damage[14].

PBC

PBC is characterized by progressive bile duct destruction and is associated with significant intestinal microbiota dysbiosis. Studies have shown that PBC patients, especially those not yet treated with ursodeoxycholic acid, exhibit reduced levels of beneficial bacteria (e.g., Bacteroidetes, Ruminococcus bromii) and increased levels of opportunistic pathogens (e.g., Veillonella, Streptococcus, Klebsiella, Proteobacteria). These microbial changes correlate with elevated markers of liver injury and inflammation, suggesting that intestinal microbiota alterations may contribute to PBC pathogenesis through mechanisms similar to those in PSC, such as immune activation and proinflammatory signaling[14].

Cirrhosis and hepatic encephalopathy

Cirrhosis, characterized by severe fibrosis and hepatocyte loss, is associated with intestinal microbiota dysbiosis: Reduced Bacteroidetes and beneficial taxa (Blautia, Lachnospiraceae) alongside pathogenic overgrowth (Proteobacteria, Enterococcus)[25]. Hepatic encephalopathy correlates with elevated Alcaligenaceae, Enterobacteriaceae, and endotoxemia, while Ruminococcaceae depletion impairs ammonia detoxification. Urease-producing bacteria (e.g., Klebsiella) increase intestinal ammonia, overwhelming hepatic clearance[26].

HCC

Pro-inflammatory taxa [Escherichia coli (E. coli), Helicobacter hepaticus] activate TLR4/STAT3, while genotoxins from Enterococcus faecalis induce DNA damage. DCA accumulation promotes stromal inflammation and hepatocarcinogenesis[27,28].

Viral hepatitis

Chronic HBV/HCV infections correlate with reduced beneficial taxa (Lactobacillus, Bifidobacterium) and increased pathogens (E. coli, Enterobacteriaceae), driving inflammation via LPS-TLR activation and impaired butyrate production. HBV progression involves reduced Lachnospiraceae (anti-inflammatory) and elevated LPS-producing bacteria, while HCV dysbiosis elevates Bacteroidetes and endotoxemia[29].

GM IN PANCREATIC DISEASES

The pancreas is indirectly influenced by GM through metabolic, immune, and inflammatory pathways described in Section “Mechanistic Pillars of Axis-Mediated Injury”. Dysbiosis can lead to bacterial translocation, alter metabolite signaling, and compromise endocrine function, contributing to a range of pancreatic disorders.

Pancreatitis

Acute pancreatitis (AP) and CP are exacerbated by gut-derived microbial disturbance[30]. In AP Increasing evidence indicates that intestinal microecological disorder might promote the progression of AP through multiple mechanisms[31]. those mechanisms include reduced zymogen secretion which leads to GM imbalance, disruption of acinar cells and infiltrating immune cells. This, in turn, results in increased excessive production of ROSs, which further exacerbates the impairment of the intestinal barrier and microbial dysbiosis such as the overgrowth of Proteobacteria and Actinobacteria phyla through the TLR4/NF-κB signaling pathways[32]. Mitochondrial dysfunction caused by several gut bacterial metabolites including hydrogen sulfide, indole-3-acetic acid, and LPS, whereas beneficial microbiota-derived nicotinamide mononucleotide could reduce mitochondrial oxidative injury via promoting the activation of mitochondrial deacetylase SIRT3[33].

Other possible mechanisms include increased oxidative stress, imbalance of immunological homeostasis, intestinal microcirculation and barrier disturbance[34]. Therefore, regulating microbial metabolites may represent a promising strategy to protect AP-mediated oxidative damage[35]. While in CP the GM dysbiosis play critical role, particularly the depletion of SCFA-producing bacteria, in the progression of CP. Disruption of Gram-positive (G+) bacteria, such as Ruminococcus, Lactobacillus, and Roseburia, reduces SCFA levels, impairing gut barrier function and exacerbating pancreatic fibrosis, monocyte recruitment, and M2 macrophage polarization thereby aggravating the progression of CP[36]. Small intestinal bacterial overgrowth (SIBO) is common in CP and worsens exocrine insufficiency. Dysbiosis also promotes chronic inflammation and fibrosis via barrier breach and inflammatory triggers[37].

PDAC

PDAC is marked by an altered tumor-associated microbiota, which modulates the immune microenvironment and contributes to chemoresistance. Certain taxa may influence tumor signaling, while microbial metabolites affect the efficacy of immune checkpoint inhibitors. Dysbiosis-induced inflammation and BA imbalance support tumor progression[38].

Diabetes mellitus

GM alterations contribute to both type 1 and T2D by: Inducing β-cell inflammation and apoptosis, and by modifying GLP-1 secretion and incretin responsiveness, and Promoting insulin resistance.

Low butyrate levels correlate with pancreatic steatosis and impaired glucose metabolism. SCFA supplementation and dietary modulation show promise in preserving pancreatic endocrine function[39].

CLINICAL AND THERAPEUTIC INSIGHTS: DIAGNOSTICS AND PROGNOSTICS

The gut microbiome plays a key role in liver and pancreatic diseases, offering new ways to diagnose and predict outcomes. Advanced tools like stool metagenomics and blood metabolomics help identify microbial imbalances linked to conditions such as fatty liver disease, cirrhosis, and pancreatic cancer. These microbial and metabolic patterns could lead to earlier detection and personalized treatments, though more research is needed (Table 1).

Table 1 Clinical and therapeutic insights-diagnostics and prognostics.

Disease	Key microbiota findings in the diseased person	Therapeutic strategies using probiotics/symbiotics
Chronic hepatitis B	Reduced SCFA-producers (e.g., Roseburia, Dialister); increased Escherichia–Shigella and Proteobacteria	Restoration of microbial balance via lactobacillus and bifidobacterium strains
Liver cirrhosis	Overgrowth of Enterobacteriaceae; reduced Lachnospiraceae, Ruminococcaceae; decreased SCFA producers	Rebalancing microbiota using synbiotics; targeted probiotics
Hepatocellular crcinoma	Enrichment of Proteobacteria, Rothia; depletion of Bifidobacterium, Roseburia	Prevention in aflatoxin exposure models using probiotic mixtures
Across CLD spectrum	Gradual decrease in SCFA-producing bacteria; increased gram-negative pathogens	General microbiota modulation via diet and probiotics
Acute pancreatitis	↑ Enterococcus, ↓ Bifidobacterium in severe cases; increased IL-6 with dysbiosis	Lactobacillus plantarum reduced necrosis in RCTs; caution due to PROPATRIA trial findings
Chronic pancreatitis	↑ Proteobacteria, ↓ Firmicutes; SIBO in approximately 36% of patients	Symbiotics (e.g., Lactobacillus + FOS); PERT restores Akkermansia muciniphila
Pancreatic cancer	Oral: ↑ Porphyromonas gingivalis; Tumor: ↑ Fusobacterium, Proteobacteria	Probiotics may enhance chemotherapy; antibiotics may reduce gemcitabine-degrading bacteria
Diabetes mellitus	↓ Faecalibacterium and butyrate levels; ↑ LPS-producing taxa	SCFA supplementation; dietary prebiotics

FOS: Fructooligosaccharides; CLD: Chronic liver disease; SCFA: Short-chain fatty acids; RCT: Randomized control trials; SIBO: Small intestinal bacterial overgrowth; LPS: Lipopolysaccharide; PERT: Pancreatic enzyme replacement therapy.

Microbial signatures across hepatic and pancreatic disorders

In chronic liver diseases, there is a consistent decrease in beneficial bacteria such as Firmicutes, Roseburia, and Blautia, alongside an increase in potentially pathogenic taxa including Proteobacteria, E. coli, and Enterococcus. These microbial shifts correlate with disease progression and severity, as reflected by the Child-Pugh classification[40].

In pancreatic diseases, AP is associated with increased Enterococcus and decreased Bifidobacterium, while approximately 36% of patients with CP exhibit SIBO. In pancreatic cancer, a high Firmicutes/Bacteroidetes ratio and the presence of Fusobacterium nucleatum have been linked to increased disease risk[41].

Microbiota as biomarkers in pancreatic and liver cancers

Pancreatic cancer is associated with distinct microbial alterations, including enrichment of Streptococcus, Proteobacteria, and Fusobacterium nucleatum in tumor tissues. These shifts are linked to tumor progression, liver metastasis, and poor prognosis. Conversely, higher abundance of Akkermansia has been associated with better response to neoadjuvant therapy. These microbial patterns are being investigated as potential diagnostic and prognostic biomarkers, as well as therapeutic targets in microbiome-modulating interventions[42].

In HCC, altered GM composition includes increased Veillonella, Dialister, and Fusobacterium, correlating with disease recurrence and severity. Metabolomic shifts, such as reduced stercobilin and elevated triterpenoids, further support diagnostic utility. Certain taxa, such as Clostridium leptum and Bacteroides stercoris, have been linked to favorable prognosis and improved response to immunotherapy. These findings underscore the microbiome’s relevance in HCC progression and therapeutic outcomes[43].

THERAPEUTIC STRATEGIES

Dietary interventions

High-fiber and Mediterranean-style diets have been shown to promote the production of SCFAs by beneficial microbes such as Bifidobacterium and Lactobacillus, thereby strengthening intestinal barrier integrity, reducing systemic inflammation, and modulating hepatic metabolism and autophagy. Nutritional strategies that emphasize increased dietary fiber and reduced saturated fat intake play a foundational role in shaping GM composition and function. Additionally, diets enriched with polyphenols, omega-3 fatty acids, and complex carbohydrates are associated with enhanced microbial diversity and improved metabolic profiles[44,45].

Microbiome-based therapies

Microbiota-targeted therapies are emerging as promising interventions aimed at restoring gut microbial balance and modulating host-microbiota interactions. The administration of beneficial bacterial strains or fermentable fibers, such as probiotics and prebiotics, helps re-establish a favorable microbial profile. Specific strains like Lactobacillus and Bifidobacterium have been shown to reduce intestinal inflammation, enhance barrier integrity, and modulate immune responses, while prebiotics like inulin and fructooligosaccharides selectively promote the growth of SCFA-producing bacteria. FMT introduces a diverse, healthy microbiota from a donor to a recipient, aiming to outcompete dysbiotic species and restore microbial diversity, and has shown success in treating recurrent Clostridioides difficile infection, with ongoing investigations into its use for metabolic and inflammatory conditions. BA modulators, including BA sequestrants, FXR agonists, and dietary strategies that alter enterohepatic circulation, can influence BA synthesis or receptor signaling (FXR, TGR5), thereby reshaping microbial composition and metabolic output. Supplementation with SCFAs such as butyrate, propionate, and acetate may help compensate for microbial deficits, offering anti-inflammatory benefits, strengthening epithelial barriers, and regulating immune signaling. Finally, next-generation microbiome modulators, including engineered probiotics, microbial consortia, and postbiotics, are being developed to deliver precise therapeutic effects, with emerging technologies like CRISPR-edited bacteria and synthetic microbial ecosystems targeting specific pathogenic pathways or metabolite profiles.

KEY CHALLENGES AND FUTURE DIRECTIONS

This study highlights several important avenues for future research, including the need for larger, longitudinal cohorts to validate the progression-linked microbial shifts observed from chronic hepatitis B through cirrhosis to HCC. Further investigations using metabolomics are critical to clarify the role of microbial by-products such as SCFAs, BAs, and LPSs in disease progression. Experimental studies on butyrate or acetate supplementation, particularly in animal models or clinical trials, could help define therapeutic targets. Additionally, greater focus should be placed on exploring the GLPA, as interactions between intestinal microbiota and pancreatic function remain under-investigated and may significantly influence the pathogenesis of both hepatic and pancreatic diseases. Addressing these future directions will be essential for advancing microbiome-based diagnostic and therapeutic strategies for chronic liver disease and its association with pancreatic dysfunction.

CONCLUSION

The GLPA plays a crucial role in maintaining metabolic and immune balance, with the GM acting as a central regulator. Dysbiosis disrupts this axis, contributing to liver and pancreatic diseases through mechanisms such as barrier dysfunction, harmful metabolites, and immune imbalance. While emerging tools like metagenomics offer diagnostic promise, and therapies such as probiotics and dietary interventions show potential, clinical application remains limited. Future research should focus on clarifying microbial mechanisms and standardizing interventions to harness the GLPA for effective, personalized treatment strategies.