Review Article

Polyphenols as a Complementary Dietary Strategy in the Management of MASLD

Stella M Honoré^1,2*, Sara S Sánchez¹, Ernesto N Diaz Miranda¹ and Maria C Bazán de Casella³

¹Instituto Superior de Investigaciones Biológicas (INSIBIO, CONICET-UNT), Argentina

²Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán. Chacabuco 461, T4000ILI-San Miguel de Tucumán, Argentina

³Facultad de Medicina, Universidad Nacional de Tucumán. Lamadrid 875, T4000ILI-San Miguel de Tucumán, Argentina

Submission:October 30, 2024;Published:November 11, 2024

*Corresponding author:Stella M Honoré, Instituto de Biología “Dr. Francisco D. Barbieri”, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán. Chacabuco 461, T4000ILI-San Miguel de Tucumán, Tucumán, Argentina

How to cite this article:Honoré S M, Sanchez S S, Diaz Miranda E N, Bazán de Casella M C. Polyphenols as a Natural Complementary Dietary Strategy in the Management of MASLD. Adv Res Gastroentero Hepatol, 2024; 21(1): 556054.DOI: 10.19080/ARGH.2024.21.556054.

Abstract

The alarming worldwide prevalence of non-alcoholic fatty liver disease (NAFLD), recently termed metabolic dysfunction-associated fatty liver disease (MASLD), and its pathophysiological, clinical, and socioeconomic implications have strongly encouraged research in this area in search of effective therapies to combat this disease. Following the recent conditional approval of resmetirom, the importance of a comprehensive treatment involving pharmacotherapy and lifestyle improvement is becoming increasingly evident. Including natural polyphenols in the diet could be a complementary strategy to reduce liver damage and the metabolic burden associated with MASLD.

Keywords:Polyphenols; Pathophysiological; MASLD; Complementary Dietary Strategy

Abbreviations:NAFLD: Non-Alcoholic Fatty Liver Disease; MASLD: Metabolic Dysfunction-Associated Fatty Liver Disease; NASH: Non-Alcoholic Steatohepatitis; THR: Thyroid Hormone Receptor; LPS: Lipopolysaccharides; GLP-1: Glucagon Like Peptide 1

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a global health problem, rapidly escalating in parallel with the rise in prevalence of obesity and metabolic síndrome [1]. Some patients with NAFLD remain clinically stable; others may develop a broad spectrum of liver changes, progressing to non-alcoholic steatohepatitis (NASH), fibrosis, and even degenerating into liver cirrhosis [2]. Although most people with NAFLD do not develop severe liver disease, they are at increased risk of mortality and morbidity due to the association of NAFLD with cardiovascular disease and other chronic pathologies such as type 2 diabetes, chronic kidney disease, sleep apnea, osteoporosis, and certain types of extrahepatic cancers [3]. Therefore, increasing attention has been paid to the fact that NAFLD may also contribute to a significant burden of extrahepatic chronic complications, thus being considered a multisystem disease affecting several extrahepatic organs, requiring a multidisciplinary and integrated-holistic approach [4].Dietary intervention effectively improves intestinal health and ameliorates inflammatory responses associated with NAFLD progression [5]. This review examines the potential benefits of incorporating polyphenols in the treatment of NAFLD based on preclinical and clinical studies. These natural compounds may positively modulate a variety of steps in the pathogenesis of NAFLD through diverse and complementary mechanisms of action. We aim to provide a new angle on the development and use of polyphenols to improve hepatic metabolic disorders.

A new comprehension of steatosis liver disease

To reflect current knowledge about the disease process, international expert panels have extensively reviewed the definition of NAFLD and its differential diagnostic criteria [6]. New nomenclatures for the disease have been proposed that seek to more accurately reflect its pathogenesis and contribute to the stratification of patients for treatment [7]. Introducing a simple and concise set of “positive” diagnostic criteria, the term “fatty liver disease associated with metabolic dysfunction” (MAFLD) was proposed in 2020 [8,9]. This new terminology underscores the critical role of metabolic dysfunction in the development and progression of chronic liver disease and the associated cardiovascular risks. At the same time, it removes the requirement to exclude concomitant liver diseases and reduces the stigma associated with alcohol use. MAFLD allows for identifying individuals at risk and emphasizes the need for management strategies that address both liver disease and its metabolic comorbidities [10]. Using previously collected data; several studies have evaluated the applicability of MAFLD [7]. A good degree of overlap between NAFLD and MAFLD has been demonstrated. However, works have also highlighted differences based on the overall prevalence of metabolic dysfunction and other forms of liver disease in the population studied, reflecting many uncategorized patients [3,10].

To integrate the current understanding of patient heterogeneity and to avoid the stigmatizing terms “fatty,” a new nomenclature was proposed in 2023: metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic-dysfunction associated steatohepatitis (MASH), whose definition and diagnostic criteria are epidemiologically more interchangeable with those of NAFLD or NASH, respectively [11,12]. The new consensus nomenclature encompasses the various causes of steatosis, so it has been relevant for diagnosing, stratification, and treating patients with MASLD [13]. Comparative studies in diverse settings reported a high degree of overlap (more than 99%) between patients identified as MASLD and those with a natural history of NAFLD, highlighting the relevance of this new nomenclature in the field [14,15]. From now on, we will use MASLD as a standardized nomenclature instead of NAFLD. The introduction of new diagnostic criteria for MAFLD/MASLD revealed a global prevalence of 30%, which is continuously increasing, especially in Latin America, Europe, Asia, and North America. These figures are expected to increase significantly in the next 10 years [1,16].

Metabolic dysfunction-associated steatotic liver disease

MASLD is defined as hepatic steatosis together with at least one out of five cardiometabolic risk factors (overweight or obesity, hypertension or dyslipidemia, presence of impaired glucose regulation or type 2 diabetes) and no other discernible cause of steatosis [11,12,13]. MASLD results from complex interactions between multiple genetic, epigenetic, environmental, and conduction factors involved in the development and progression of this disease [2,17]. MASLD encompasses a broad clinical spectrum of liver abnormalities ranging from uncomplicated steatosis to the more severe form of MASH, progressing to cirrhosis and liver cancer [4]. MASH occurs in nearly one-third of MASLD patients and can be distinguished histologically from simple MASLD by histological features such as lobular inflammation and ballooning of hepatocytes [2,18]. MASH is becoming a significant risk factor for progressive liver fibrosis. Progression between stages in patients with simple steatosis has been estimated to occur in an average of 14 years, while in patients with MASH, it may occur in only 7 years [19]. On the other hand, there is convincing evidence that chronic liver inflammation also increases the risk of cirrhosis, hepatocellular carcinoma (HCC), and other complications of MASLD, both within and outside the liver [3]. In addition, the MASH phenotype can be affected by the presence of obesity, metabolic syndrome, and type 2 diabetes (recorded in 90% of patients), which exacerbate lipid imbalance in the liver and systemic inflammation in patients, aggravating their clinical complexity [20].

For years, the “two-hit” theory attempted to explain the pathophysiology of MASLD. It consisted of a first “hit” involving liver fat accumulation and insulin resistance, as well as a second “hit” of other factors such as hepatocyte dysfunction, oxidative stress, endoplasmic reticulum stress, and other lesions, which mark the development and progression of hepatic inflammation (MASH) and fibrosis [21]. However, a better understanding of the complex and multifactorial etiology of chronic liver inflammation and its relationship with low-grade systemic inflammation subsequently gave rise to the “multiple hit” model [2,3,22]. This model amalgamates different genetic, epigenetic, and environmental factors as “hits” that dynamically interact to promote an inflammatory state that characterizes and drives the progression of MASLD. Additional factors, such as intestinal dysbiosis and changes in intestinal permeability, have been integrated into this model [2,22,23]. Now, it is recognized that the progression of MASLD extends beyond the liver, driven by the intricate cross-communication between the liver, brain, and intestinal microbiota, the so-called “gut-brain-liver axis,” where genetics, diet, and interactions between organs influence the development of the disease [24].

Current and future therapeutic approaches

In recent years, a deeper understanding of the critical pathophysiological mechanisms leading to MASLD has contributed to the discovery of new therapeutic agents and the proposal to repurpose already available drugs [25]. Current MASLD therapies focus on four main pathways encompassing the initial dysmetabolic stage, characterized by insulin resistance and hepatic steatosis. The later stages present oxidative stress, apoptosis, inflammation, and liver fibrosis [2,26]. MASLD is a complex, multifaceted disease commonly associated with obesity and type 2 diabetes and their associated metabolic comorbidities [7]. So, the first therapeutic approach has considered antidiabetic drugs such as insulin sensitizers, thiazolidinediones, glucagon like peptide-1 (GLP-1) receptor receptor agonists (tirzepatide, cotadutide, survodutide, semaglutide, liraglutide) and sodium-glucose cotransporter 2 inhibitors (dapagliflozina, empagliflozina, ipragliflozina, luseogliflozina, topogliflozina, canagliflozina anomng others) [6,27,28,29]. All of these agents have demonstrated a general improvement in hepatic steatosis and serum transaminases in patients with MASLD, obesity, or type 2 diabetes, mainly through achieving weight loss and/or glycemic control. Interestingly, new generations of mono GLP-1 receptor agonists contribute to the significant resolution of MASH by promoting body weight loss and improving clinical, biochemical, and histological markers of fatty liver and fibrosis in patients with MASH [27,28]. The therapeutic efficacy of this family of drugs in the treatment of MASLD promises to increase following the recent development of dual or triple receptor agonists. These molecules targeting different critical metabolic pathways of adiposity-induced insulin resistance and pancreatic insulin deficiency [28]. Current approaches also consider the incorporation of current DPP-4 inhibitors (vildagliptin, sitagliptin, omarigliptin) as potential agents for the treatment of MASLD [30].

A second group of drugs seeks to correct the disruption of the lipid metabolism balance in the liver that causes abnormal lipid deposition and the consequent metabolic stress. Agents in this group include the bile acid-farnesoid X receptor axis regulators (obeticholic acid, betulinic acid derived compounds), de novo lipogenesis inhibitors (aramchol), peroxisome proliferatoractivated receptor agonists (pioglitazone, elafibranor, saroglitazar), and fibroblast growth factor 21/19 analogs (deciphering) [5,6,30,31]. The third group of drugs aims to prevent/counteract the effects of lipotoxicity and inflammation, targeting mainly oxidative stress, inflammation, and fibrosis. These drugs include antioxidants such as vitamin E, tumor necrosis factor-α pathway regulators such as emricasan, pentoxifylline, ZSP160, and immune modulators such as cenicriviroc and belapectin [30]. Since continued hepatocellular damage leads to fibrosis, a precursor to MASLD-related morbidity and mortality, antifibrotics such as simtuzumab, GR-MD-02, could be considered essential elements of therapy, especially in high-risk groups [6].

Nowadays, the growing understanding of the role of the intestinal ecosystem in the pathogenesis of MASLD has allowed the emerging development of therapies [2]. As the fourth approach, M-124e and solithromycin are promising agents to target microbiota and/or its metabolic function and alleviate the development or progression of the disease [32]. Recent studies revealed the potential of disulfiram, a drug commonly used to clinically treat chronic alcoholism, to modulate intestinal microbiota and bile acid metabolism and thus improve MASH phenotype in mice and humans. However, common adverse reactions such as pruritus and those related to abnormal lipid metabolism (elevated LDL cholesterol and decreased HDL cholesterol) associated with this drug have limited its current approval [33]. In addition, a clinical pilot study demonstrated the efficacy of phloroglucinol, an analgesic and spasmolytic drug, in improving postprandial glycemic control and altering lipid metabolism, suggesting new potential therapeutic uses in the prevention of MASLD and insulin resistance [34].

Ongoing therapeutic research

Although research is currently addressing different therapeutic targets at all stages of MASLD pathophysiology, particular emphasis has been placed on agents that directly affect fibrogenesis or pre-existing inflammation due to the strong association of advanced liver fibrosis with the risk of mortality and liver transplant-free survival in patients with MASH [35]. The effectiveness of several potential therapeutic agents has been tested or is under investigation in phase 2b and phase 3 trials, showing promising favorable effects on liver histology in selected patients with MASLD/MASH [30]. However, to date, there is no effective and safe pharmacological approach to prevent the progression of MASLD/MASH to cirrhosis formally approved by regulatory agencies. Limited efficacy and/or unfavorable side effect profiles of the drugs under evaluation, difficulties with establishing a precise diagnosis during sequential follow-up, lack of participation in trials, and the need for a long time window to observe significant changes in NASH resolution are some of the factors explaining these difficulties [6]. Furthermore, the complex and heterogeneous nature of MALSD/MASH explains the high variability in treatment response rates, highlighting the need to individualize both the follow-up and management of patients with different phenotypes. The possibility of integrating multiomic approaches to establish future noninvasive biomarkers that provide personalized information in this field was widely suggested [36].

In March 2024, the drug resmetirom (formerly MGL-3196) was conditionally approved by the FDA, demonstrating promising results for treating adults with non-cirrhotic MASH with moderate to advanced fibrosis. Resmetirom is a selective drug for the liver’s thyroid hormone receptor (THR)-β [37]. TR receptor activation displays prominent effects on hepatic lipids and cholesterol metabolism, reducing de novo lipogénesis and cholesterol synthesis and promoting β-oxidation, with anti-inflammatory and antifibrotic effects [38]. In line with these actions resmetirom demonstrated positive effects on hepatic steatosis, inflammation, fibrosis, and biomarkers of liver injury, evidencing relatively low adverse effects. The drug also showed favorable effects on the serum lipid profile, which contributes to reducing cardiovascular risk in treated patients. While verification studies of the clinical benefits of resmetirom for its definitive approval are still ongoing, it has been found to produce positive changes in the structure of the liver of patients after one year of treatment [37]. Thus, resmetirom could provide a specific treatment option for patients for the first time, along with diet and exercise.

Complementary approaches

The effects of Resmetirom and new drugs in development on liver function and metabolic status are encouraging. However, since MASLD is a chronic disease that requires lifelong management, profound lifestyle changes, such as reducing caloric intake and increasing physical activity, are necessary to support pharmacological treatment [5,39]. It is known that a weight loss of ≥7–10% is necessary to reduce hepatic steatosis and necroinflammation in MASLD [39]. In addition to energy restriction, evidence suggests that dietary patterns and composition may critically influence metabolic functions, promoting and aggravating the disease [40]. In this regard, consumption of the “Western diet”, rich in animal proteins, saturated fats, added sugar, and processed foods, has been associated with an increased risk of developing MASLD and hepatocellular carcinoma [5]. In contrast, the “Mediterranean diet” and also other plant-based dietary patterns (vegetarian, vegan diets, dietary approaches associated with hypertension) low in red and processed meats, saturated fats, and refined carbohydrates have been demonstrated to contribute to weight loss with beneficial for the prevention/treatment of metabolic disorders such as MASLD [40]. The possible advantages of paleolithic, ketogenic, and intermittent fasting diets in MASLD require further research [40, 41]. Recent studies indicate that incorporating diets rich in polyphenols may offer protection against chronic diseases, such as obesity, diabetes, some types of cancer, and MASLD [22,42].

The role of polyphenols

Phenolic compounds are natural phytoconstituents with many structures characterized by multiple hydroxylated phenolic rings. They are classified as phenolic acids (as chlorogenic, caffeic acids), flavonoids (as anthocyanins, quercetin, rutin, naringenin, genistein, silymarin, hesperidin), stilbenes (as resveratrol), and lignans [43]. These biologically active compounds can be isolated or extracted mainly from plants, where they are synthesized as secondary metabolites as part of a defense system against different environmental stresses or as signaling molecules [21]. Polyphenols can be found in a wide range of meals, including vegetables, fruits, whole grains, and plant products or plantbased foods [22,24]. The emergence of new methods used in the recovery of plant matrices and technological improvements in the preparation, stability, and bioavailability of phenolics allow their use in the formulation of functional foods and dietary supplements to impact health [44].

These bioactive compounds modulate the microbiota composition and influence metabolic processes, as demonstrated in various cellular and animal models [22,45]. Many reported health benefits are linked to their proven antioxidant, antidiabetic, hypolipidemic, antibiotic, antiviral, antitumor, and immunomodulatory activities [24, 44, 46]. In the gut, polyphenols may interact with other food components, such as starch and fibers, increasing or reducing their bioavailability [47]. Polyphenol molecules that can be absorbed in the small intestine are simple forms, usually aglycones. However, most dietary polyphenols reaching the large intestine are complex forms such as glucosides, esters, or polymers [46,48]. There, bacterial enzymes release them from matrices and transform them into bioavailable metabolites through hydrolysis, reduction, or cleavage reactions prompted by intestinal epithelial cells and the microbiota to facilitate their subsequent absorption. Unmetabolized or no-absorbed polyphenols are excreted in feces [24,46]. In the intestinal wall and/ or in the liver, some polyphenols often undergo glucuronidation, sulfation, or methylation reactions, depending on the structure or type of polyphenol, and finally transported to various internal organs [47]. Although conjugated and unconjugated forms have been found in various body tissues, the precise role of biotransformation in biological activity is unknown.

Dietary polyphenols provide energy to the microbiota, stimulating the growth of beneficial bacteria or inhibiting specific harmful strains. This metabolic prebiotic effect of polyphenols modulates microbiota composition and maintains a healthy profile [49]. Several studies have demonstrated notable intestinal dysbiosis in patients with obesity, type 2 diabetes, or MASLD [26,50,51]. Moreover, changes in the abundance and diversity of gut microbiome may vary throughout the stages of MASLD [26,52]. In particular, a relative abundance of the phylum Proteobacteria and Firmicutes, a decrease in Bacteroidetes, and a loss of commensal bacterial metabolic functions have been described in MASLD. However, a higher abundance of Bacteroides and increased gramnegative bacteria were associated with MASH progression [51,52]. Resveratrol, alone or in combination with quercetin, can restore the abundance of Bacteroidetes and Firmicutes and reduce that of Clostridium XlVb, a microbiota genus that correlates with the severity of the disease [53]. In addition, quercetin supplementation alone improves Firmicutes/Bacteroidetes and Proteobacteria ratio. It also increased the abundance of the genera Sutturella, Allobaculum, and Flavobacterium while reducing Helicobacter Coprobacillus and Desulfovibrio [54]. Chlorogenic acid elevates the abundance of Bifidobacterium and reduces Escherichia coli, demonstrating its prebiotic potential [55]. Different in vivo studies showed that curcumin, naringenin, hesperidin, anthocyanin flavonoids, caffeic acid, and other isolated polyphenols fractions restore microbiota diversity affected by MASLD [56,57,58]. In all cases, changes in microbiota were reported to overlap with improvements in MASLD phenotypes [45,53,56,57,58,59].

As mentioned above, the microbiota can metabolize polyphenols provided by the diet and produce value-added compounds such as short-chain fatty acids (SCFAs), secondary bile acids, amino acids, and choline [57,60]. These metabolites can drive complex neural and hormonal responses that inform the brain and/or liver of physiological changes [24]. Disorders in gut microbiota can lead to changes in metabolic activities, loss of bacterial functional metabolites, and excessive production of toxic compounds (endogenous ethanol, endotoxins, trimethylamine, or ammonia), which disrupt the gut-brain-liver axis, aggravating dysbiosis and MASLD [57].

SCFAs (acetic, propionic, and butyric acids) are produced mainly by Bifidobacteria, Lactobacillus, and Ruminococcin in the gut through the fermentation of dietary fibers. By activating G-protein-coupled receptors, SCFAs play pleiotropic roles in different organs, improving metabolic status and immunity [57, 60]. Loss of SCFAs-producing species in the microbiota has been associated with abnormal lipid accumulation in liver inflammation and fibrosis [45]. Recent studies indicate that chlorogenic acid causes beneficial changes in Ruminococcin (a butyric acid producer), increasing butyric acid levels and affecting body weight [61]. Butyrate is also a potent anti-inflammatory mediator capable of improving MASLD steatosis by expressing GLP-1R in different tissues [60].

Bile acids act as physiological detergents in the intestinal lumen and as signaling molecules targeting different organs to maintain energy balance [62]. The intestinal microbiota plays a crucial role in bile acid metabolism by converting primary bile acids into secondary bile acids, producing beneficial bile salts (such as ursodeoxycholic acid), or facilitating excretion through feces [49]. Bile acids can regulate their own-synthesis and promote metabolic actions by activating the farnesoid X receptor (FXR)/Takeda G protein-coupled receptor 5 (TGR5) [62]. MASLD decreases the abundance of Bacteroides, Lactobacillus, and Clostridium, converting primary bile acids into secondary bile acids, thus modifying the bile acid pool composition [49]. Dysregulation of the bile acid pool in MASLD contributes to increased energy expenditure. It drives a chronic inflammatory state through modulation of FXR/TGR5 in the gut, liver, adipose tissue, and muscle [52]. Administration of anthocyanins from Lycium ruthenicum Murray (black wolfberry) inhibits bacterial bile acid hydrolase activity. It improves the ratio of conjugated to unconjugated bile acids in feces, reducing lipid accumulation in the liver and adipose tissues of obese mice [63]. A similar action of caffeic acid phenethyl ester on bacterial hydrolase increases tauro-β-muricholic acid, reducing fat production in the liver and increasing GLP-1 secretion in the gut [64]. As we can see, polyphenols play an essential role in both the central nervous system and the enteric system by positively modulating the intestinal microbiota and producing SCFAs, bile acids, and other gastrointestinal peptides, such as ghrelin and CCK, that influence the neuronal centers that control appetite and satiety in the brain and glycolipid metabolism in the liver (Figure 1) [24,65].

Tryptophan is an essential dietary component that may influence the development of obesity and MASLD [66]. This amino acid is catabolized in the intestine by the microbiota. Its metabolic products, such as indole and its derivatives, indole acetic acid and indole-3-propionic acid, exert protective functions locally and in the liver [67]. Quercetin and isoquercetin supplementation have been found to increase the abundance of indole-metabolizing bacteria Bifidobacterium, Lactobacillus, and Akkermansiaby, increasing the levels of tryptophan-indole metabolites [68]. Indole is also linked to mucosal homeostasis by promoting barrier maintenance and GLP-1 secretion. On the other hand, indole acetic acid and indole-3-propionic acid have demonstrated antioxidant and anti-inflammatory properties in the gut and liver [67].

Polyphenols play a role in the gut-liver axis, maintaining the integrity and functionality of the intestinal barrier through interactions with the gut microbiota. The mucus layer and tight junctions between enterocytes form an epithelial barrier that prevents pathogens or harmful bacterial products (endotoxins) from entering the circulation while allowing selective intake of various nutrients [69]. Some studies linked increased intestinal permeability (leaky gut) with quantitative and qualitative changes in the gut microbiota of individuals with MASLD [70]. Administration of quercetin and isoquercetin improves mucus-associated defense by balancing the gut microbiome and the production of microbiota-specific metabolites [54,67]. Resveratrol, curcumin, quercetin, naringenin, and chlorogenic acid can also restore epithelial barrier function by upregulating the expression of tight junction proteins claudin, occludin, and zona occludens -1 (ZO-1) thereby modifying the intestinal immune response triggered by altered microbiota [24,45,53]. Consumption of grapevine tea polyphenols and polyphenol-rich extracts of blueberry and loquat appear to have similar protective effects on the intestinal barrier [24].

Polyphenols act as immunomodulatory agents by regulating intestinal microbiota and immune mediators [71]. Intestinal bacterial overgrowth, impaired intestinal barrier, and increased intestinal permeability in MASLD lead to endotoxemia and inflammation [72]. Gut-derived lipopolysaccharides (LPS) are a critical factor in inducing the inflammatory response of liver tissue. Activation of the LPS/TLR4 signaling pathway triggers the release of proinflammatory cytokines, promoting liver injury in MASLD and contributing to systemic inflammation [73]. Some evidence indicates that reduced fecal levels of some specific strains such as Desulfovibrio, Alistipes, Lachnospiraceae_NK4A136_group in animals supplemented with resveratrol may be responsible for the improvement of hepatic steatosis and the reduction of inflammation-mediated by the induction of the LPS/TLR4/NF- κB pathway [74]. Caffeic acid and naringenin also ameliorate LPS-mediated inflammation, normalizing the expression of genes related to lipid metabolism [45,75]. Furthermore, modulation of the microbiota by chlorogenic acid reverses TLR4 activation and the expression of TNF-α and IL-6 in the liver [45,76].

After being absorbed and entering the circulation, polyphenolic compounds affect other organs and tissues, including the liver. Its most potent effects have been observed as aglycone or deconjugates [75]. Numerous polyphenols are reported to activate the PPAR-α/FGF21/AMPK/PGC-1α signaling pathway to reduce intrahepatic lipid deposits by suppressing de novo synthesis and promoting β-oxidation of fatty acids [76, 77,78,78]. Resveratrol can also upregulate Nrf2, which activates endogenous antioxidants, suppresses the formation of reactive oxygen species (ROS), and modulates mitochondrial biogenesis, thus reducing the damage caused by lipoperoxidation [77]. Furthermore, polyphenols can inhibit inflammatory signals mediated by NF-κB, TNF-α, IL- 1b, IL-6, and MCP-1 preventing cell apoptosis and retarding the liver fibrotic process [45,75,78]. Finally, it is important to note that many of the properties attributed to polyphenols have been studied in the context of obesity and/or insulin resistance [57,75]. This suggests that the complementary use of these natural polyphenols may help reduce the cardiometabolic/multisystem risk associated with the onset and progression of MASLD.

Conclusion

Polyphenols are natural bioactive compounds recognized for their wide-ranging health benefits. The mechanisms underlying the beneficial effects of polyphenols in the treatment of MASLD are based not only on the modulation of the intestinal microbiota and intestinal barrier function but also on the manifestation of protective actions against several metabolic disorders. Indeed, polyphenols inhibit intrahepatic lipid accumulation, improve oxidative state, mitigate inflammatory responses, and attenuate fibrotic progression, improving MASLD. Furthermore, polyphenols promote the development of specific strains of bacteria that produce bioactive metabolites such as SCFAs, bile acids, and tryptophan metabolites and stimulate gut-derived hormones (GLP-1, ghrelin, CCK) and leptin with action on different extraintestinal organs. Moreover, they can indirectly modulate signaling pathways associated with oxidative stress in hepatocytes through alterations in bile acid composition. Indeed, polyphenols may improve MALSD through gut-brain-liver cross-talk. The beneficial effects of polyphenols are promising and encourage further studies on the safety and efficacy of these compounds as potential dietary supplements. Furthermore, additional research is needed to demonstrate the role of polyphenols in combination with other medications in the treatment of MASLD.

Acknowledgment

This research was supported by PIUNT 2023 D733 grants to SMH; and PIP 2023 No. 0109 (CONICET, Argentina) grants to SMH and SSS.

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