Role of gut microbiota in the development of metabolic dysfunction-associated steatotic liver disease in inflammatory bowel disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and inflammatory bowel disease (IBD) are chronic conditions with complex aetiologies, in which environmental factors and interactions between the gut and liver play a key role. Both conditions are characterised by disturbances in the gut microbiota, which can affect local and systemic inflammatory responses. In particular, increased intestinal permeability promotes the translocation of bacterial components into the portal circulation, contributing to the development of inflammation in the liver. There is growing evidence that modulation of the gut microbiota and improved intestinal barrier function may be of therapeutic importance. The purpose of this review is to discuss the pathogenetic mechanisms that link MASLD and IBD, with a particular emphasis on the influence of the microbiota and environmental factors on the development of these diseases.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Inflammatory bowel disease; Gut microbiota; Inflammation; Liver-gut axis; Oxidative stress

Core Tip: Metabolic dysfunction-associated steatotic liver disease (MASLD) in inflammatory bowel disease (IBD) may share a common denominator with the gut microbiota. Through various factors, such as environmental factors, intestinal dysbiosis can occur, disrupting the homeostasis of the intestinal barrier and the entry of, for example, bacterial metabolites that exacerbate inflammation in the body. In the review, we analysed the various pathogenetic mechanisms of MASLD in IBD with an emphasis on the role of the gut microbiota.

INTRODUCTION

The nomenclature of liver disease has evolved since the 1980s, when cases of non-alcoholic steatohepatitis were first described, excluding alcohol as a causative factor. In 2007, the term ‘non-alcoholic fatty liver disease’ (NAFLD) was introduced, followed by ‘metabolic dysfunction-associated fatty liver disease’ in 2020. NAFLD was permanently withdrawn in 2023 after a multicentre Delphi consensus statement was published. Instead, a new term was adopted, ‘metabolic dysfunction-associated steatotic liver disease’ (MASLD), highlighting its association with metabolic disorders[1].

The defining feature of MASLD is the accumulation of excessive triglycerides in the liver (hepatocytes ≥ 5%), which can lead to inflammation and metabolic dysfunction-associated steatohepatitis (MASH), as well as progressive fibrosis[2,3]. The excess and abnormal metabolism of triacylglycerols and diacylglycerols leads to hepatocyte dysfunction[4]. In addition, patients with MASLD have elevated plasma total cholesterol and low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels. These changes have been linked to an increase in the expression of the sterol regulatory element-binding protein 2 transcription factor, excessive activation of which can lead to cholesterol overload in cells and can exacerbate cellular stress. Lipotoxic ceramides also play a significant role in disease progression. Their elevated levels have been linked to both metabolic syndrome and MASLD. The action of ceramides through activation of protein kinase C ζ and protein phosphatase 2A leads to impaired translocation and dephosphorylation of protein kinase B, which exacerbates hepatic steatosis and insulin resistance. Furthermore, insulin resistance in MASLD contributes to increased very-low-density lipoprotein secretion and lipid dysregulation[5]. The inflammatory response, closely associated with hepatocyte distension and fibrosis, increases the risk of cirrhosis and hepatocellular carcinoma[2,3]. MASLD is estimated to occur in approximately 32.4% of the general population, making it the leading cause of liver disease worldwide[3].

Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation in forms such as Crohn’s disease and ulcerative colitis (UC), with systemic effects on liver health. In these diseases, disruption of the intestinal epithelial barrier, particularly loss of function of tight junction proteins and Paneth cell dysfunction, allows pathogenic/inflammatory microbes to enter the portal circulation[6]. This process results in the delivery of lipopolysaccharide (LPS) and secondary bile acid metabolites to the liver. Activation of Toll-like receptors (TLRs) (TLR4, TLR9) in the liver triggers an inflammatory response in both hepatocytes and Kupffer cells, increasing the release of tumour necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-1β[7]. These cytokines activate the cellular oxidative stress, endoplasmic reticulum (ER) stress, and hepatic apoptosis pathways, predisposing to steatosis, inflammation, and fibrosis[8].

Current scientific evidence suggests a frequent co-occurrence of MASLD with IBD. Both MASLD and MASH are observed in 8%-59% of patients with IBD. Interestingly, advanced liver fibrosis is common among these patients, and the presence of metabolic syndrome is considered a significant risk factor[9].

IBD is a group of conditions characterised by chronic and recurrent inflammation of the gastrointestinal tract, including UC and Crohn’s disease. The first descriptions of IBD date back to North America and Europe in the late 18^th century. At that time, an association was observed between the incidence of these conditions and the economic development of the regions[10,11]. IBD most commonly affects young adults under the age of 20 years. However, it is concerning that it is also increasingly being diagnosed in children, with 5% of cases occurring under the age of 5, and 20% under the age of 10[11].

The molecular mechanisms leading to the development of IBD are not yet fully understood[10]. The disease is assumed to develop as a result of an aberrant or disturbed immune response directed against the gut microbiota in genetically predisposed individuals[11]. IBD patients show changes in the composition of the gut microbiota, including a reduction in the number of bacteria responsible for the production of short-chain fatty acids (SCFAs), such as acetate, propionate and butyrate, and indole derivatives[10]. The interaction between host genetic variants and the gut microbiome may also contribute to the development of IBD. The most common genes studied in the context of IBD are NOD2, CARD9, immunoglobulin-like receptor in myeloid cells, IL-23 receptor and ATG16 L1[12].

In recent years, an increasing number of studies have demonstrated that lifestyle factors, including diet, physical activity, and the use of medications and stimulants have a significant impact on the composition and function of the gut microbiota. These changes may play a key role in the pathogenesis of both IBD and MASLD. The gut microbiota influences lipid metabolism, immune function, and intestinal barrier integrity, and its disruption is considered a potential common pathway that links the two diseases.

Understanding the mechanisms that connect MASLD and IBD is essential to improving our understanding of their coexistence and to developing more effective diagnostic and therapeutic strategies. Therefore, this review places particular emphasis on lifestyle-related factors and their influence on the gut microbiota in individuals affected by MASLD and IBD.

PATHOGENESIS OF MASLD IN THE COURSE OF IBD

Zhong et al[9] identified 116 shared differentially expressed genes (SDEGs) in MASH and IBD. Analysis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways revealed the significant involvement of SDEGs in defence responses, apoptosis, cell death, and cytokine and chemokine activities, as well as in the phosphoinositide 3-kinase-protein kinase B, TLR, peroxisome proliferator-activated receptor (PPAR), and Ras-proximate-1 signalling pathways. This confirms the common pathogenesis of these conditions and their interplay. Table 1 provides a brief overview of MASLD and IBD[13-16].

Table 1 Characteristics of metabolic dysfunction-associated steatotic liver disease and inflammatory bowel disease[2,3,9,10,13-16].

Features	MASLD	IBD
Main location[9,14]	Liver	Gastrointestinal tract: UC inflammation of the colonic mucosa (rectum, sigmoid colon, area beyond the sigmoid colon or entire colon up to the caecum); CD inflammation of the terminal ileum and colon
Type of disease[9]	Metabolic, chronic	Autoimmune-inflammatory, chronic
Risk and progression factors[2,3,9,10,15]	Genetics, epigenetic changes, gut microbiota disorders, cardiometabolic factors, endocrinopathies, obesity, insulin resistance, metabolic syndrome, environmental factors including industrialisation	Genetics, epigenetic changes, gut microbiota disorders, immune response, early life antibiotic therapy, environmental factors, including industrialisation
Complications[9,13,14,16]	Liver cirrhosis, hepatocellular carcinoma, circulatory system diseases, type II diabetes, chronic kidney disease	Extraintestinal lesions, including hepatic: Fatty liver, hepatic amyloidosis, sclerosing cholangitis, autoimmune hepatitis, and liver abscess; Colon cancer
Link between IBD and MASLD[9]	MASLD and MASH are often co-occurring in IBD patients (twice as high a risk)

IBD: Inflammatory bowel disease; MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; UC: Ulcerative colitis; CD: Crohn’s disease.

Risk factors for the development of MASLD in patients with IBD are considered to include diet, changes in the composition of the gut microbiota, disease activity and duration, drug treatment used, and previous gastrointestinal surgery. It is possible that a change in diet after surgery, as well as the advanced course of the disease and accompanying increased inflammation, may influence the development of MASLD. Furthermore, surgical resection of the gastrointestinal tract may lead to metabolic dysfunction that promotes lipid accumulation in the liver[17].

Inflammation in the course of MASLD and IBD

In an observational study by Magrì et al[18], patients with IBD and MASLD showed a higher intake of calories and fat compared to patients without MASLD, regardless of disease activity. In contrast, Glassner et al[19] found that older patients with a longer duration of IBD were more likely to develop MASLD, especially if they had risk factors for metabolic syndrome. Interestingly, patients with concomitant MASLD and IBD had fewer classic metabolic risk factors (such as elevated body weight, hypertension, diabetes, dyslipidemia), which may suggest the existence of other mechanisms leading to inflammation, e.g., related to disease activity, that predispose to the development of MASLD. Similarly, in the study by Abenavoli et al[20], patients with IBD-MASLD were significantly older and had a higher body mass index (BMI), waist circumference, and triglyceride levels. They were also more likely to have cardiometabolic conditions. Patients with IBD-MASLD also showed higher IBD activity and a need for more frequent surgical interventions. Other factors, such as a chronic low-grade condition, alterations in the intestinal microbiota, or genetic predisposition, may play an important role in the pathogenesis of MASLD in patients with IBD[21].

In a study by Rotaru et al[21], patients with IBD-MASLD had more severe hepatic steatosis and elevated levels of systemic inflammation. MASLD was also present in lean subjects, with a prevalence of 34.1% in this group, suggesting the existence of a distinct disease-promoting phenotype in IBD patients. Nevertheless, those with MASLD were characterised by a higher BMI and the presence of visceral obesity. Excess visceral fat has been linked to increased secretion of pro-inflammatory cytokines, development of inflammation, and metabolic disorders. It has been shown that visceral fat reduction may be helpful in reducing inflammatory markers and cardiometabolic disorders[22,23]. This seems important because lipid metabolism disorders occur in patients with IBD-MASLD, presenting as increased triglyceride and reduced high-density lipoprotein levels. Importantly, the results of the study by Rotaru et al[21] did not show differences in typical liver markers such as C-reactive protein (CRP), alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase and alkaline phosphatase, which may limit their diagnostic value in lean individuals with MASLD. The use of the Clínica Universidad de Navarra-Body adiposity estimator index in detecting steatosis compared to traditional indices such as fatty liver index and hepatic steatosis index is also considered to be of higher diagnostic value in lean individuals[24]. According to Zhang et al[22], the presence of lean/non-lean MASLD is associated with an increased risk of death in patients with IBD. However, the risk is higher the greater the number of cardiometabolic risk factors and is markedly higher in lean MASLD patients.

The inflammation accompanying active IBD likely plays a key role in the development of MASLD, regardless of the presence of classical metabolic factors. This suggests that MASLD in patients with IBD requires a distinct preventive and diagnostic approach.

Oxidative stress as a common denominator of IBD and MASLD

Elevated oxidative stress markers are observed in patients with IBD and MASLD[25,26]. Mierzwa et al[27] observed increased glutathione-S-transferase activity, higher concentrations of reduced glutathione, malondialdehyde (MDA) and nitrite/nitrate in patients with IBD. At the same time, they observed decreased superoxide dismutase-1 and glutathione peroxidase (GPX) activity. In the active form of IBD, oxidative stress is particularly severe, but even in the remission phase, reduced antioxidant levels are observed. Tratenšek et al[28] found elevated levels of antioxidant enzymes and proteins such as catalase, albumin, transferrin, and paraoxonase in patients with IBD during exacerbation. In patients with UC, they also observed an increase in MDA and total antioxidant capacity, and in Crohn’s disease, increased GPX activity and thiol group levels of sulfhydryl group (R-SH).

There is believed to be a three-way relationship between reactive oxygen species (ROS), the microbiome, and the development of MASLD. In the course of MASLD, dysfunction of the adenosine 5’-monophosphate-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant pathways is observed. Mitochondrial dysfunction and ER stress exacerbate cellular stress. Furthermore, the penetration of LPS and harmful gut-derived metabolites such as N-trimethylamine oxide into the liver activates inflammatory cascades. Impaired defence mechanisms, including the AMPK, Nrf2, and PPAR pathways, are unable to effectively counteract damage, leading to liver disease progression and potentially resulting in multi-organ damage[29].

Inflammation and regulatory T cells/Th17 balance

T17 cells play a key role in the inflammatory response in the development and progression of MASLD and IBD. In the normal intestinal environment, Th17 and regulatory T cells (Treg) remain in dynamic balance, and their disruption may be one of the mechanisms driving the pathogenesis of these diseases[30,31]. There are reports that decreased secondary bile acids in IBD patients may lead to an imbalance between Th17 and Treg lymphocytes as a result of impaired signalling via farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 5 (TGR5). A similar mechanism is observed in MASLD, where intestinal dysbiosis leads to a decrease in secondary bile acids and reduced activation of FXR and TGR5, which promotes increased lipogenesis and inflammatory responses[32]. The development of MASH is also thought to be associated with an excessive Th17 response[33].

Metabolic disturbances resulting from a high-fat diet and the development of inflammation in the gut are associated with increased production of pro-inflammatory cytokines such as IL-6, IL-12, TNF-α and IL-1β. This results in low-grade chronic inflammation, a weak intestinal barrier, and an impaired immune response[34]. Polymorphisms of genes encoding proteins involved in maintaining the integrity of the intestinal barrier, such as MYO9B, signalling pathway proteins, e.g., MAGI2, cell adhesion molecules (e.g., E-cadherin), and mucosal layer-forming proteins (e.g., mucin 3A and mucin 19) represent an important component of the complex pathophysiological landscape shared by IBD and MASLD. These changes may affect the expression of tight junction proteins, increasing susceptibility to the development of IBD, chronic inflammation, and MASLD[32]. As is well known, increased intestinal permeability, in addition to an inadequately balanced and highly processed diet, can also be linked to the presence of medical conditions such as obesity and diabetes. This leads to the penetration of bacterial molecules [pathogen-associated molecular patterns (PAMPs), e.g., LPS] into the portal circulation[35]. LPS activates the TLR4 receptor present on Kupffer cells, which in turn causes the activation of the nuclear transcription factor nuclear factor kappa-B (NF-κB) and the inflammasome[32]. Chronic accumulation of lipids in the liver can lead to lipotoxicity, which promotes inflammation and damage to hepatocytes[33]. At the same time, systemic insulin resistance develops[29].

IL-17 secreted by Th-17 cells exacerbates inflammation by inducing ROS and increasing neutrophil infiltration[36]. Increased secretion of IL-17 is observed in the course of MASLD, which promotes increased expression of pro-inflammatory cytokines and chemokines in the hepatic milieu. This is accompanied by increased recruitment of myeloid cells and T cells, increasing inflammation and promoting disease progression. IL-17 may also act directly on the activation of hepatic stellate cells, leading to increased fibrosis[37].

Thielemann et al[33] showed that people with the IL-17A rs2275913 A/A genotype have higher levels of IL-17A cytokines and are more likely to develop liver fibrosis and progress from MASLD to MASH. In addition, it has been observed that progression of MASLD to MASH is characterised by an increase in IL-17A-producing cells in intrahepatic cluster of differentiation 4 + T cells and a higher Th17/Treg ratio in the peripheral blood[38]. Similar mechanisms are observed in IBD. Prananda et al[39] reported elevated IL-17 Levels in IBD patients, particularly the UC group, where IL-17 Levels correlated with disease activity. In addition to IL-17, Lucaciu et al[40] also showed a correlation between IL-23 Levels and the severity of IBD. In contrast, in the study by Menesy et al[41], IL-17 Levels were not related to disease activity. Interestingly, the levels were higher in patients who smoked cigarettes, suggesting concomitant environmental factors on the severity of the inflammatory response.

Dysregulation of the immune and microbial balance within the gut-liver axis together with associated inflammation may represent a common pathogenetic mechanism in the development of IBD and MASLD.

THE ROLE OF GUT MICROBIOTA IN IBD AND MASLD

Characterisation of the intestinal microbiota

The intestinal microbiota is the totality of microorganisms, consisting mainly of bacteria, but also viruses, fungi, and protozoa. In the large intestine of a healthy adult human, the predominant types are Bacteroidetes and Firmicutes. However, Marchesi et al[42] indicate that at least 10 different types of microorganisms can exert significant effects on the host organism. The correct composition of the intestinal microbiota determines the proper functioning of the intestinal barrier and the maintenance of homeostasis. The commensal intestinal microbiota, as one of the factors, determines the appropriate selective permeability of nutrients necessary for the proper functioning of the body. It also participates in protection against pathogenic microorganisms and in immunity[43]. A normal ‘healthy’ intestinal barrier consists of a layer of mucus (water, glycoproteins mucin), and an outer and inner epithelium, consisting of goblet cells, enterocytes, Paneth cells, microvilli, and enteroendocrine cells, between which there are tight junctions, gap junctions, adherens junctions, and desmosomes[44]. A micro-biotic change in the intestinal tract that reduces the commensal microbiota in favour of the pathogenic one causes intestinal dysbiosis. However, several factors are required for this to occur. Weiss and Hennet[45] point out that these include an inadequate dietary composition, the influence of medications, and the immune system. The result is increased intestinal permeability[46]. It is initially associated with low-grade inflammation, which may later develop into systemic inflammation[47].

Intestinal dysbiosis and IBD

In IBD, Halfvarson et al[48] showed significantly higher fluctuations in the composition of the intestinal microbiome compared to the composition in healthy individuals. The authors also point out that the composition of the gut microbiome of IBD patients was periodically like that of the healthy population and then changed to unfavourable. In their work, Imhann et al[49] also indicate that a high genetic risk for IBD may predispose to a change in the composition of the intestinal microbiota (e.g., reduced Roseburia). Genes such as ATG16 L1, NOD2, and CARD9 are associated with a decrease in acetate to butyrate conversion by Roseburia spp.[49]. In addition, CARD9 and NOD2 may be involved in the proper functioning of neutrophils in the body’s defence against pathogenic microorganisms[50]. Another adverse factor in IBD is the interaction of the intestinal microbiota with the intestinal epithelial barrier. Damage to the mechanical intestinal barrier occurs through a decrease in the proper functioning of tight junction proteins, and in addition, the homeostasis of the chemical barrier is also reduced through a decrease in the mucus layer and its colonisation by pathogenic bacteria. Qiu et al[51] state that immune barrier function can be reduced through the secretion of immunosuppressive proteins by a pathogenic microorganism. Kudelka et al[52] point out that the proper glycosylation process of the intestinal epithelium is fundamental to maintaining the integrity of the intestinal barrier, since epithelial glycans are involved in the delivery of nutrients and therefore show a link to the regulation of the intestinal microbiota. In their study, Franzosa et al[53] focused on the metabolic activity of the gut microbiota in IBD patients. They observed a reduction in the metabolic diversity of the gut microbiota in IBD; in addition, some species and their metabolites may have disturbed mechanistic relationships, which may consequently, for example, reduce the body’s response to oxidative stress. Micro-biotic changes in IBD patients are most often characterized by an increase in Proteobacteria and a decrease in Firmicutes and Bacteroidetes. Quaglio et al[54] indicate that patients with IBD show a decrease in the abundance of butyrate producers, e.g., Roseburia spp. and Faecalibacterium prausnitzii, and an increase in pathogenic microorganisms, e.g., Escherichia coli. Other work also indicates an increase in unfavourable bacteria, e.g., Ruminococcus gnavus and Clostridium bolteae, in the active form of the disease[55].

Intestinal dysbiosis and MASLD

An important role is played by the gut-liver axis (Figure 1), which is functionally and anatomically an interconnected structure that is a two-way ‘communication highway’ between the gut microbiota and the liver. This structure is an important barrier both physically, immunologically and chemically against pathogens[56]. Once pathogens cross the intestinal barrier, they initiate low-grade chronic inflammation. Through lymphoid and vascular barriers, they reach the portal vein, activating Kupffer cells, which flow to the peritumoural area, providing another barrier to intestinal toxins or pathogens[57,58]. Kupffer cells recognise PAMPs and LPS, with increased inflammation, generating the secretion of pro-inflammatory cytokines, e.g., IL-6, TNF-α[59,60]. In the other direction, bile, consisting of bile acids, immunoglobulin A (IgA), bicarbonates, and antimicrobial peptides, can also have an effect on the gut microbiota[61].

Figure 1 Gut-liver axis. A damaged intestinal barrier causes increased intestinal permeability. This, in turn, allows bacteria or their components (e.g., lipopolysaccharide) to pass from the intestine to the portal circulation, contributing to liver inflammation and the progression of metabolic dysfunction-associated steatotic liver disease. In addition, bile acids, produced in the liver and transported to the intestine via the bile ducts, play an important role in the bidirectional communication of the gut-liver axis. MASLD: Metabolic dysfunction-associated steatotic liver disease.

Some of the bile acids are converted by the intestinal microbiota (Eubacterium, Clostridium XIVa and Clostridium XI) into a secondary form[62]. In their study, Yuan et al[63] isolated a potential pathogenic bacterium of MASLD Prevotella copri. Among other things, it affects fatty acid metabolism and immunity. In another paper, Li et al[64] point to an increase in the abundance of Bacteroidetes and a decrease in Prevotella bacteria. Effenberger et al[65] noted a reduction in the abundance of Prevotellaceae, Bacteroidales and Streptococcaceae, among others, in correlation with reduced levels of apelin (one of the adipokines that may correlate with liver damage) in the serum of MASLD patients. An altered Firmicutes/Bacteroidetes ratio can lead to a decrease in the tightness of the intestinal barrier, which consequently promotes the entry of endotoxins into the body[66]. In addition, Proteobacteria may be associated with liver fibrosis[67]. In their article, Yun et al[68] point out that a reduced abundance of Deferribacteriales and Actinomycetales can be observed in patients with MASLD. Zazueta et al[69], however, indicate a lower abundance of Ruminiclostridium-6 and Ruminococcaceae UCG 013 and, in contrast, a higher abundance of Sellimonas. The meta-analysis by Su et al[70] also indicates a decrease in beneficial bacteria (e.g., Coprococcus, Ruminococcaceae) and an increase in pro-inflammatory microorganisms (Escherichia, Fusobacterium). An increase in pathogenic bacteria with a simultaneous decrease in commensal microorganisms may be associated with a disruption of the intestinal barrier, and thus the entry of toxic substances into the body, which may consequently affect the development of MASLD.

Summary of common factors in IBD and MASLD, in the context of the intestinal barrier and the intestinal microbiota

One of the main commonalities in IBD and MASLD is the presence of intestinal dysbiosis, including an increase in Escherichia coli and Proteobacteria, e.g., Klebsiella[71,72]. In another paper, the authors point to a reduction in the number of SCFA producers such as Faecalibacterium prausnitzii, Ruminococcus and Roseburia[73]. By reducing SCFA production, the tightness of the intestinal barrier can be weakened[74]. Intestinal dysbiosis also affects the secretion of mucus and MUC2. Examples of bacteria that negatively affect mucus are Listeria and Salmonella, while those that have a beneficial effect are Clostridium tyrobutyricum and Lactobacillus acidophilus[75]. Another commonality between IBD and MASLD is a reduction in the proper functioning of tight junctions (e.g., a reduction in zonula occludens-1)[76,77]. All abnormalities lead to a ‘leaky gut’ and consequently penetration of endotoxins into the body and increased inflammation (IL-6, TNF-α)[78,79]. Figure 2 shows selected common factors of IBD and MASLD.

Figure 2 Disorders occurring in both inflammatory bowel disease and steatohepatitis associated with metabolic disorders. SCFA: Short-chain fatty acid; LPS: Lipopolysaccharide; IL: Interleukin; TNF: Tumour necrosis factor; IBD: Inflammatory bowel disease; MASLD: Metabolic dysfunction-associated steatotic liver disease; E. coli: Escherichia coli; F. prausnitzii: Faecalibacterium prausnitzii.

EFFECT OF LIFESTYLE ON GUT MICROBIOTA

Diet

Lifestyle, including diet, has an impact on the composition and quantity of the gut microbiota. Complex carbohydrates, specifically dietary fibre metabolised by certain intestinal bacteria, promote the production of SCFAs. The SCFA group includes propionate, acetate, and butyrate. The latter is the main source of energy for intestinal epithelial cells. Martin-Gallausiaux et al[80] indicate that the main producers of butyrate in the gut are the Lachnospiraceae, Ruminococcaceae, and Erysipelotrichaceae. In a paper by García-Montero et al[81], the authors presented the advantages of a Mediterranean diet, based on complex carbohydrates, vegetables, fruits, and poly- and monounsaturated fatty acids. They point out that the composition of the diet influences the normal composition of the intestinal microbiota, thus promoting proper intestinal barrier function and nutrition of the body, and may affect the normal immune response. Perler et al[82] further describe the anti-inflammatory properties of the Mediterranean diet, which also translates into the preservation of intestinal homeostasis. Compounds such as polyphenols and flavonoids can increase the abundance of Bifidobacterium, Enterococcus and Lactobacillus[83]. In addition, care should be taken to ensure a proper supply of minerals (iron, zinc, copper, selenium) because their deficiencies can affect the quantitative change in the composition of the intestinal microbiota. There should also be an adequate supply of vitamins (B group, vitamin C, A, D, E, K)[84]. In contrast, a Western-type diet, rich in total fat, saturated fatty acids, and trans-isomeric unsaturated fatty acids, induces low-grade inflammation. The gut microbiota is qualitatively altered, reducing the number of SCFA producers. A high-fat diet also increases oxidative stress, stimulating stress in the ER, which consequently can disrupt the intestinal barrier homeostasis[85].

Physical activity

Physical activity can affect the gut microbiota both quantitatively and qualitatively. Campaniello et al[86] list a number of potential factors as to why this occurs, including increased SCFA production, decreased intestinal transit time, and increased IgA production[86]. In their paper, Aya et al[87] present that athletes have a higher α-diversity of gut microbiota. However, they also point out that this is probably closely related to their diet. In addition, athletes who practice different sports and at different levels of performance show a different quantitative and qualitative compositions of microorganisms in the gut. In contrast, Wegierska et al[88] indicate that irregular physical exercise, at too-high an intensity, and for prolonged periods without adequate recovery can negatively affect the gut microbiota. Physical exertion not only has an effect on the gut microbiota, but when performed regularly at moderate intensity, it can promote normal intestinal blood flow and maintain normal intestinal barrier function[89]. Exercise can also affect the circulation of bile acids between the intestines and the liver, which can also affect the composition of intestinal microbes[90]. The effects of exercise on the gut microbiota are mainly studied in animal models; in addition, amateur athletes and people performing activities with various diseases are also worth considering in the future[91]. Resistance exercise and aerobic activity effectively change the body composition and reduce body fat. These changes may influence the composition of the intestinal microbiota and the maintenance of normal intestinal barrier homeostasis[92,93].

Sleep and diurnal rhythm

In addition to adequate nutrition and physical activity levels, recovery and maintenance of a normal diurnal rhythm are essential. The composition of the intestinal microbiota itself shows a 10% diurnal variation, mainly in Parabacteroides, Bulleida and Lachnospira[94]. Another study showed diurnal oscillations in Roseburia, Desulfovibrio, Escherichia and Eubacterium[95]. The diurnal rhythm depends on many factors, e.g., genetics, changes in the cycle of light and darkness, and meal schedule[96]. In their work, Sen et al[97] indicate that the vagus nerve, serotonergic system, and immune interactions affect the gut-brain axis, which in turn affects sleep. In the study by Anderson et al[98], the researchers observed that good sleep quality showed a relationship with the proportions of Lentisphaerae and Verrucomicrobia types. Sleep deprivation also affects the activation of the inflammatory response, which, among other things, results in increased permeability of the intestinal barrier. Increased levels of serum zonulin and decreased expression of zonula occludens-1, occludin, Muc-2 and Claudin-1 were demonstrated[99]. Not only do reduced sleep quality and duration affect the gut microbiota, but the gut microbiota has also been shown to affect sleep. Ogawa et al[100] observed in animal models that abnormalities in the gut microbiota can contribute to the duration of the non-rapid eye movement sleep and rapid eye movement sleep phases. The authors indicate that this may be due to an imbalance of neurotransmitters. Wang et al[101] indicate that the gut microbiota may also affect sleep quality via modulation of endocrine conduction, neuronal signalling and bacterial metabolites. Intestinal dysbiosis induced by sleep deprivation can activate the TLR4/NF-κB inflammatory pathway and impair intestinal barrier function[102]. Li et al[103] showed increased abundance of Blautia, Eubacterium hallii and decreased Lachnospira bacteria in patients with insomnia, compared to healthy controls. Finally, the authors showed a correlation between certain bacteria (Blautia, Faecalibacterium) and plasma IL-1β levels in patients with insomnia.

Psychological stress

Psychological stress can impair the function of the hypothalamic-pituitary-adrenal (HPA) axis, thereby altering the composition and quantity of the commensal gut microbiota, leading to changes in microbial metabolites[104]. This is a bidirectional relationship, since the gut microbiota changes throughout the day, which also modulates the diurnal concentrations of corticosterone, which responds to stress on the HPA axis[105]. In addition, Tofani et al[106] indicate that micro-biotic changes in the gut can alter the rhythmicity of stress pathways in the hippocampus and amygdala. Altered diurnal rhythms also occur in disorders such as depression and schizophrenia, which may also be linked to intestinal dysbiosis[107,108]. On the other hand, stressful situations can also have an impact on the state of the gut microbiota. In their work, Lai et al[109] describe that exposure to chronic stress can reduce the abundance of Firmicutes. They also present that there is a dysregulation of the stress response with a depleted microbiome. In their review, Cooke et al[110] propose mechanisms of action that could potentially assist in coping with stress, e.g., improving sleep quality, re-educating inflammation, and including a probiotic in a well-balanced diet. Similarly, Zhang et al[111] present that regulating the gut microbiota can help the body cope with stress. Kaur et al[112] indicate that the gut microbiota can be altered in diseases associated with neurological disorders, specifically a reduction in the number of bacteria involved in the metabolism of tryptophan in the gut. In a systematic review, Ma et al[113] observed that the appearance of stress was associated with an increased abundance of Euryarchaeota, along with a decreased abundance of Verrucomicrobia and Proteobacteria. Chronic psychological stress can also negatively affect the homeostasis of the intestinal barrier. It can reduce the expression of tight junction proteins through its association with excessive intestinal permeability[114].

Other factors modulating the gut microbiota

Another factor that modulates intestinal barrier function is smoking. Bai et al[115] observed that in animal models, cigarette smoke can alter the function of the intestinal barrier and ‘dysbiotically’ alter the composition of the intestinal microbiota. Consequently, this can initiate mitogen-activated protein kinase/extracellular regulated protein kinases signalling in the intestinal epithelium, leading to the promotion of colorectal cancer. Similarly, Fan et al[116] point to the occurrence of intestinal dysbiosis after exposure to cigarette smoke. The authors also describe a potential mechanism for the effects of smoking on the gut microbiota through correlations between tryptophan and tyrosine metabolism. Similar conclusions are drawn by Antinozzi et al[117] in their paper. Another factor is alcohol abuse. Leclercq et al[118] noted that transplanting the gut microbiota from humans who abuse alcohol into mice resulted in behavioural changes and higher stress levels in the animals, which may suggest a broad influence of behavioural changes via gut dysbiosis. In their study in animal models, Yang et al[119] also point to changes in the gut microbiota and metabolic pathways after exposure to alcohol. Chronic exposure to ethanol can lead to NLRP3-dependent hippocampal neuroinflammation through disturbance of intestinal barrier homeostasis[120]. In addition to the factors mentioned above that disrupt the proper functioning and composition of the intestinal microbiota, some medications can also have a negative impact. The authors of some studies have noted that the intestinal microbiota is altered with the use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, or antibiotics[121-124].

Effects of lifestyle on IBD and MASLD

An anti-healthy lifestyle may be one of several components that predispose to the development of both IBD and MASLD. A high-calorie Western-type diet, high in saturated fatty acids, highly processed foods, characterised by low amounts of vegetables, fruits, and whole-grain cereal products, may be a predictor of the development of some diseases, including MASLD and IBD[125,126]. In addition, cigarette smoking and low levels or a lack of physical activity in correlation with genetic factors may be associated with an increased risk of IBD[127]. A moderate level of regular physical activity is also recommended for diagnosed MASLD, the main goal of which is to lower the BMI[128]. In addition, when diagnosed with MASH, Mucinski et al[129] point to a reduction in fat mass and liver damage following the introduction of exercise and diet. Cigarette smoking, through its effects on the gut microbiota and intestinal barrier, has shown potential effects on the predisposition to the development of both MASLD and IBD[130,131].

All the aforementioned factors can affect the composition and quality of the intestinal microbiota and compromise intestinal barrier homeostasis. As a result, they can increase susceptibility to the development of both IBD and MASLD.

FROM GUT TO LIVER: EATING BEHAVIOUR PATTERNS AND NUTRITIONAL RISK IN IBD-ASSOCIATED MASLD

Chronic inflammatory conditions, including IBD, not only cause intestinal inflammation but also profoundly affect eating behaviours[132]. Patients tend to develop restrictive eating habits to reduce gastrointestinal symptoms, both during active and remission periods: Avoiding food, skipping meals, limiting certain food groups, etc. are frequently observed[133]. Avoidant/restrictive food intake disorder (ARFID) is a significant concern among those with IBD[134]. Psychosocial factors such as IBD diagnosis, disease activity, intensity of gastrointestinal symptoms, and gastrointestinal-specific anxiety play a role in the development of ARFID[135].

One of the mechanisms underlying this deterioration in eating behaviours is ‘food literacy’. Low food literacy leads patients to make dietary decisions based on misinformation, which, combined with nutritional deficiencies and psychosocial stress, increases the risk of ARFID and malnutrition. This process progresses in a cyclical model triggered by gastrointestinal symptoms[136].

Eating satisfaction decreases in people with IBD; it has been observed that people avoid eating out during periods of intense symptoms, experience social isolation, and the psychosocial dimension of eating is affected. This situation negatively affects both nutritional diversity and quality of life[137]. Another mechanism that increases the risk of ARFID is food fears caused by gastrointestinal symptoms. In those with more active disease, the development of ARFID is promoted by the expectation of symptoms even though they are not ill. Disease activity stands out as an independent factor in the development of ARFID[135]. Skipping meals and snacking behaviours between meals also play an important role in IBD. Nutritional insufficiency arises from skipping meals, biases against certain foods, and deficits in protein and micronutrients, with 38.6% of patients in remission exhibiting protein consumption below recommended levels[138].

Consumption of ultra-processed food is another factor that increases the risk of both IBD and MASLD. Increased sensitivity to processed foods creates dysbiosis in the gut microbiota, triggering inflammation and gastrointestinal symptoms[139]. Dietary management strategies used in IBD can improve patient nutritional quality, but long-term restrictions can lead to dysbiosis and disturbance of micronutrients[140].

Protein-energy malnutrition due to IBD triggers muscle insulin resistance, which is one of the basic mechanisms of hepatic steatosis[141]. Decreased glucose utilisation in muscle tissue results in increased mobilisation of free fatty acids, favouring the accumulation of triglycerides in the liver. At the same time, conditions such as sarcopenia and muscle proteolysis reduce the buffering function of the liver in lipid metabolism, increasing the ease of developing steatosis[142]. The sarcopenic condition identified in patients with IBD should be regarded as an independent risk factor for MASLD[143].

The anorexia, gastrointestinal symptoms (abdominal pain, diarrhoea, nausea), and inflammation-related appetite suppression seen in the active phases of IBD further restrict energy and nutrient intake. Micronutrient deficiencies, especially vitamin B12, folate, vitamin D, zinc, and iron, are common[143]. These deficiencies have negative effects on hepatic mitochondrial functions, antioxidant defence mechanisms, and cellular redox balance, facilitating lipotoxicity and inflammation in hepatocytes. For example, vitamin D deficiency can increase transforming growth factor-β and inflammatory cytokine expression, which promote both immune dysfunction and liver fibrosis[144].

Malnutrition is not only limited to deficiencies; enteral/parenteral nutrition practices and elimination diets, which are frequently encountered in patients with IBD, can also lead to a disturbance of metabolic balance in the long term[145]. In some individuals, following uniform diets with poor carbohydrate and lipid content can reduce metabolic flexibility, leading to decreased levels of hormones that suppress the lipogenesis pathway[146]. The risk of MASLD is also thought to increase with increased consumption of saturated fat and processed foods[147].

The microbial products (e.g., LPS) that pass to the portal system as a result of intestinal dysbiosis and increased intestinal permeability in IBD increase both systemic inflammation and hepatic inflammatory response[148]. This situation, together with malnutrition, deepens the pathogenesis of MASLD by creating an ‘inflammatory vicious cycle’ in the gut-liver axis. In these individuals, both inflammation and nutritional deficiencies accelerate the pathophysiological process that leads to MASLD[149].

In conclusion, the nutritional deficiencies accompanying IBD are related not only to the gastrointestinal course of the disease but also to the systemic effects on the liver. When factors such as inadequate energy intake, sarcopenia, micronutrient deficiencies, and dysbiosis come together, the risk of developing MASLD in individuals with IBD increases significantly[150]. Therefore, holistic consideration of hepatic evaluation and nutritional support is of great importance in the multidisciplinary management of IBD patients[151].

NUTRITION-MICROBIOTA AXIS IN MASLD PATHOGENESIS

MASLD represents a complex pathology shaped by the interaction of diet composition, eating behaviours, and the gut microbiota. This interaction explains the influence of modern diets, especially high-calorie, processed and low-fibre diets, on the development of MASLD[152].

Epidemiological analyses using the dietary index of gut microbiota (DI-GM) score, which measures the relationship between diet and gut microbiota, show that high-quality diets significantly reduce the risk of MASLD by increasing the diversity of the gut microbiota; each 1-unit increase in the DI-GM score reduces the risk of MASLD by approximately 10% through hypersensitive-CRP and BMI. Eating behaviours, especially excessive saturated fat, processed meat, and high fructose consumption, create dysbiosis in the intestinal microbiota and increase the rates of inflammatory metabolites, triggering the development of MASLD[153-155]. There are also studies showing the positive effects of diet on gut microbiota. In particular, it has been determined that dietary intake of live microorganisms (e.g., fermented milk products, kefir, probiotic-rich foods) reduces the risk of MASLD and leads to improvements in liver enzymes and inflammation markers[156]. Similarly, high-fibre, plant-based diets similar to the Mediterranean diet support both metabolic parameters and liver health by increasing gut microbiota diversity[157]. Dietary modifications such as intermittent fasting are also among the promising methods to reduce inflammation in MASLD by reshaping gut microbiota profiles[158].

In conclusion, the interaction between dietary behaviours and gut microbiota plays a central role in the development of MASLD. Poor dietary habits increase dysbiosis and inflammation, while improved dietary adjustments allow these processes to be kept at tolerable levels. Therefore, a holistic approach that includes eating quality, microorganism intake and intestinal health should be adopted in MASLD management strategies[159].

EATING BEHAVIOURS AS A MICROBIAL MODIFIER: GUT HEALTH IMPLICATIONS IN IBD

IBD profoundly affects the gut microbiota through diet and eating behaviours, with strong implications for disease activity and overall health[160]. The Western-style diet increases dysbiosis by depleting the gut microbiota of nutrients through its high saturated fat, refined sugar, processed foods, and low fibre content. This diet pattern reduces SCFAs levels, such as butyrate and propionate, while promoting the proliferation of pathobiont bacteria[161]. SCFAs maintain epithelial integrity and suppress inflammation by promoting Treg cell differentiation through G protein-coupled receptors (e.g., GPR41/43, GPR109a). The impairment of these mechanisms facilitates increased gut permeability, systemic inflammation, and disease exacerbation[162].

Controlled dietary interventions in IBD patients have shown that diets rich in prebiotics (fibre plant foods), probiotics (fermented dairy products) or omega-3 rapidly provide positive changes in the gut microbiota. This approach resulted in significant decreases in proinflammatory cytokines such as IL-6 and IL-8, leading to an increase in anti-inflammatory SCFA producers such as Roseburia, Faecalibacterium prausnitzii and Bacteroides[161].

Trends in eating behaviours such as restriction, ARFID and food avoidance can lead individuals to long-term low fibre and unbalanced micronutrient intake. A low-fibre diet leads to a reduction in beneficial bacteria such as Bifidobacterium and Lactobacillus and SCFAs that protect the mucus-nerve barrier[162]. Furthermore, low diversity may facilitate pathogenesis, leading to mixed outcomes associated with metabolic syndrome in individuals with IBD[163]. Controlled interventions with diet (e.g., Mediterranean diet) may provide neutral or favourable gut microbiota interactions. However, restrictive diets such as low-FODMAP can lead to a reduction in beneficial species such as Bifidobacterium in the long term; therefore, personalised approaches are essential[164].

In conclusion, eating behaviours in individuals with IBD have important effects on the gut microbiota profile and indirectly on the disease status. When healthy eating behaviours are supported by balanced high fibre, fermented foods and omega-3 diets, an improvement in the gut microbiota is observed, inflammation is reduced, and the epithelial barrier is protected. Therefore, eating behaviour assessments in IBD should be considered as a clinical target that modulates the gut microbiota, not just nutritional status[165].

TREATMENT OF MASLD IN THE CONTEXT OF IBD THERAPY

MASLD and IBD share common risk factors and mechanisms that promote the progression of these diseases. Although the common pathophysiology of these diseases is not yet fully understood, available scientific data make it possible to identify key common points that may explain the development of MASLD in patients with IBD, even in the absence of classical metabolic risk factors.

Dysfunction of the gut-liver axis is considered one of the main pathogenetic mechanisms. Abnormalities in the composition of the gut microbiota and increased intestinal permeability promote translocation of PAMPs, activation of the immune system, and chronic inflammation, which can lead to the development and progression of MASLD in the course of IBD. Therapies targeting the modulation of the gut microbiota can influence bile acid composition and metabolism and restore normal FXR and TGR5 signalling, leading to improved intestinal barrier integrity, normalisation of Treg/Th17 cell ratios, and reduction of inflammation. It is believed that the use of appropriate dietary interventions, supplemented with probiotics and synbiotics, can be an effective strategy to support therapies, through a multidirectional effect on the gut-liver axis and the gut microbiota[166,167].

The use of IL-17 and IL-23 inhibitors could potentially benefit the treatment of MASLD by reducing inflammation and improving metabolic parameters. However, the results of the available studies show inconclusive effects on the liver and, in the case of IL-17 inhibitors, even exacerbations of inflammation in the gut and an increase in fungal infections have been reported[168-171]. Therefore, it is necessary to conduct large, well-designed preclinical and prospective studies to assess the efficacy and safety of these therapies in the course of MASLD/MASH in the group of patients with IBD, but also to search for other therapeutic pathways[168,171].

CONCLUSION

Both IBD and MASLD are chronic diseases linked by environmental factors. Although the pathogenetic components are not fully understood, they show common mechanisms, e.g., oxidative stress and chronic inflammation. In addition, a Western-type diet, low or no physical activity, chronic psychological stress, and sleep and diurnal rhythm disturbances predispose to intestinal dysbiosis and disruption of intestinal barrier homeostasis. Inflammation in the body can increase through increased ‘leaky gut’ via the gut-liver axis and translocation of bacterial metabolites. Nutritional disorders can exacerbate intestinal dysbiosis, promoting the development of diseases, so it is necessary to incorporate lifestyle factors that promote health in patients, if their condition allows.

ACKNOWLEDGEMENTS

We would like to thank Jarmakiewicz A for creating the illustrations.