Response of Akkermansia muciniphila to Bioactive Compounds: Effects on Its Abundance and Activity

Abstract

Introduction: The gut microbiota is vital for human health, and its modulation through dietary and pharmaceutical compounds has gained increasing attention. Among gut microbes, Akkermansia muciniphila has been extensively researched due to its role in maintaining intestinal barrier integrity, regulating energy metabolism, and influencing inflammatory responses. Subject: To analyze and synthesize the available scientific evidence on the influence of various bioactive compounds, including prebiotics, polyphenols, antioxidants, and pharmaceutical agents, on the abundance and activity of A. muciniphila, considering underlying mechanisms, microbial context, and its therapeutic potential for improving metabolic and intestinal health. Methods: A systematic literature review was conducted in accordance with the PRISMA 2020 guidelines. Databases such as PubMed, ScienceDirect, Scopus, Web of Science, SciFinder-n, and Google Scholar were searched for publications from 2004 to 2025. Experimental studies in animal models or humans that evaluated the impact of bioactive compounds on the abundance or activity of A. muciniphila were prioritized. The selection process was managed using the Covidence platform. Results: A total of 78 studies were included in the qualitative synthesis. This review compiles and analyzes experimental evidence on the interaction between A. muciniphila and various bioactive compounds, including prebiotics, antioxidants, flavonoids, and selected pharmaceutical agents. Factors such as the chemical structure of the compounds, microbial environment, underlying mechanisms, production of short-chain fatty acids (SCFAs), and mucin interactions were considered. Compounds such as resistant starch type 2, GOS, 2′-fucosyllactose, quercetin, resveratrol, metformin, and dapagliflozin showed beneficial effects on A. muciniphila through direct or indirect pathways. Discussion: Variability across studies reflects the influence of multiple variables, including compound type, dose, intervention duration, experimental models, and analytical methods. These differences emphasize the need for a contextualized approach when designing microbiota-based interventions. Conclusions: A. muciniphila emerges as a promising therapeutic target for managing metabolic and inflammatory diseases. Further mechanistic and clinical studies are necessary to validate its role and to support the development of personalized microbiota-based treatment interventions.

1. Introduction

The human gut microbiome contains a diverse and active microbial community that interacts with the host to maintain metabolic balance, regulate the immune system, and preserve the integrity of the intestinal barrier [1,2,3]. Changes in this community, known as dysbiosis, have been linked to various metabolic, inflammatory, and neurological disorders [2,4]. Within this intricate ecosystem, Akkermansia muciniphila, a strictly anaerobic, non-motile, and non-spore-forming bacterium, has become a key microorganism due to its ability to break down mucin, influence immune responses, and help produce short-chain fatty acids (SCFAs), mainly acetate and propionate [5,6,7,8]. Since its discovery in 2004 by Derrien and de Vos [5], A. muciniphila has garnered increasing interest and is now seen as a promising candidate for developing next-generation probiotics [6,7].

A decreased abundance of A. muciniphila has been linked to the onset and progression of various metabolic and inflammatory diseases, such as obesity, insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), and inflammatory bowel disorders [6,8,9]. This association has sparked increased interest in developing nutritional and therapeutic strategies to modulate its presence in the gastrointestinal tract, either through direct supplementation (in viable or pasteurized form) or through bioactive compounds that promote its growth and functional activity [9,10,11]. Among the most studied compounds are prebiotics, such as fructooligosaccharides (FOS), inulin, and breast milk oligosaccharides (e.g., 2′-fucosyllactose); polyphenols, including quercetin and resveratrol; and antidiabetic drugs, such as metformin and dapagliflozin. These modulators affect A. muciniphila either directly or indirectly by influencing its abundance, enzymatic activity, or ecological interactions with other members of the gut microbiota [6,12,13,14].

The goal of this systematic review is to examine and synthesize current scientific evidence on how various bioactive compounds affect the abundance and activity of A. muciniphila. It particularly focuses on the underlying mechanisms, the production of important metabolites such as SCFAs, and the potential therapeutic benefits for metabolic and gut health.

2. Materials and Methods

A comprehensive literature search was conducted across multiple databases, including ScienceDirect, PubMed, SciFinder-n, Scopus, Web of Science, and Google Scholar, covering publications from 2004 to 2025. The search strategy utilized Boolean operators (AND, OR) to refine results using key terms such as:

“A. muciniphila AND prebiotics”

“A. muciniphila AND SCFAs”

“Prebiotics AND gut microbiota AND metabolic health”

The review prioritized experimental studies, including animal models and human clinical trials, that reported a measurable and positive impact on the abundance or activity of A. muciniphila. Articles not aligning with the objective of this review or lacking experimental relevance were excluded.

The study selection process followed the PRISMA 2020 guidelines [15], and the review protocol was registered and managed using the Covidence platform. Initial screening was performed based on title and abstract. Relevant articles were then retrieved in full text and evaluated for inclusion based on methodological quality, clarity of results, and alignment with the topic. Duplicate entries and ineligible records were removed prior to the screening process.

From a total of 179 records identified (171 from databases and 8 from registers), 21 duplicate records were removed before screening, leaving 158 records screened by title and abstract. Of these, 59 were excluded, resulting in 99 reports sought for retrieval. Two reports could not be retrieved, and 97 reports were assessed for eligibility. After a full-text evaluation, 12 reports were excluded because they did not match the scope of this review. Ultimately, 87 studies were included in the final qualitative synthesis.

All figures and diagrams in this review were created using BioRender 2025, biorender.com (accessed on 23 July 2025) under an active publication license.

Scheme 1 illustrates the identification, screening, eligibility assessment, and final inclusion of studies in the systematic review, in accordance with PRISMA 2020 guidelines.

3. Results

3.1. Gut Microbiota and Human Health

The human gut microbiota comprises a diverse array of microorganisms involved in digestion, immune regulation, and energy metabolism. Dysbiosis, or alterations in its composition, has been linked to numerous diseases [1], stimulating scientific interest in understanding its role in health.

Strategies to maintain microbiota balance include functional dietary compounds such as probiotics, prebiotics, antioxidants, and polyphenols [12,13]. Among the key microbial species, A. muciniphila, a Gram-negative, strictly anaerobic, non-motile, and non-spore-forming bacterium that inhabits the intestinal mucus layer, has gained attention since its isolation in 2004 by Derrien and de Vos [5]. As a member of Verrucomicrobiota, it represents a next-generation probiotic candidate due to its metabolic and immunomodulatory effects [6,7].

A. muciniphila supports gut health by degrading mucin glycoproteins into SCFAs, particularly acetate and propionate, aiding intestinal barrier integrity and serving as energy sources for colonocytes. In healthy individuals, it accounts for approximately 1–4% of the gut microbiota, while reductions are common in obesity, insulin resistance, and type 2 diabetes, highlighting its therapeutic potential [7].

The abundance of A. muciniphila can be modulated by various bioactive compounds, including polyphenols (e.g., resveratrol, catechins), prebiotics (e.g., inulin, fructooligosaccharides), and resistant starch [2]. These compounds may enhance its growth directly as substrates or indirectly by modifying the gut environment and promoting cross-feeding interactions.

Diet–microbiota interactions are bidirectional. Microbiota composition is influenced by diet, while microbial metabolism transforms bioactive dietary components, affecting their activity and bioavailability [10,13]. For instance, polyphenols from grapes or green tea are metabolized into active forms by gut microorganisms, which simultaneously foster the growth of A. muciniphila and Bifidobacterium spp., positively impacting health [10,13].

Due to its involvement in fermentation, immune modulation, and gut barrier maintenance [3,4], understanding how bioactive compounds affect A. muciniphila may inform nutritional strategies for managing metabolic and intestinal disorders. An overview of the bidirectional interactions between microbiota and bioactive compounds is presented in Figure 1.

3.2. A. muciniphila: Biological and Functional Characteristics

Probiotics are defined as live microorganisms that provide health benefits when consumed in adequate amounts [16], while prebiotics are substrates selectively utilized by beneficial microorganisms [17,18]. The synergy between probiotics, prebiotics, and the gut microbiota promotes positive health effects [8,9,19], with A. muciniphila emerging as a key probiotic candidate [5,8].

Since its identification in 2004, studies have revealed its pivotal role in metabolic health, gut barrier integrity, and immune modulation [2,6]. The chronological milestones highlighting its discovery and functional characterization are presented in Figure 2, emphasizing its significance in microbiota research [5,6,7,11,14,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35].

3.3. Mucin Degradation and Metabolic Role of A. muciniphila

A. muciniphila colonizes the gut early in life, potentially due to breast milk glycans [36,37]. Its abundance ranges from 0% to 4% of the gut microbiota, decreasing with age [6].

Its hallmark function is the degradation of mucin via enzymes such as sialidases and fucosidases, releasing sugars that are utilized by other bacteria including Faecalibacterium prausnitzii and Roseburia inulinivorans [36,38]. Other enzymes (β-N-acetylglucosaminidases, β-galactosidases, sulfatases) release N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc), which A. muciniphila utilizes to produce acetate and propionate, fostering butyrate production through microbial cross-feeding [38,39].

This cross-feeding sustains mucus renewal, supports epithelial integrity, and improves gut morphology, as evidenced by microvilli elongation in neonatal piglet models [30,38,39]. An overview of these processes is illustrated in Figure 3.

These metabolic activities contribute to improved insulin sensitivity, lipid regulation, and energy balance, mitigating obesity-related metabolic disturbances [40,41].

Animal models show that A. muciniphila reduces fat mass, enhances GLP-1/GLP-2 secretion, and strengthens gut barrier function [6,36,42,43], effects partly mediated by outer membrane proteins (e.g., Amuc_1100, Amuc_1409, P9) [36,37,44].

Its depletion is associated with obesity, diabetes, NAFLD, colitis, and neurological disorders like autism and epilepsy [37,45]. Clinical trials with pasteurized A. muciniphila show metabolic benefits, supporting its probiotic potential [36].

Nevertheless, factors influencing its abundance remain unclear. Prebiotics, polyphenols, and drugs (e.g., metformin, dapagliflozin) show potential modulatory effects, but their mechanisms are varied and depend on the context. This work critically reviews the current research to support the rational development of microbiota-centered therapeutic strategies for metabolic and intestinal dysfunction.

3.4. Bioactive Compounds That Modulate A. muciniphila

The interaction of dietary and pharmacological compounds with the gut microbiota has been extensively studied, particularly regarding their ability to modulate the abundance of beneficial bacteria such as A. muciniphila. Among these compounds, many classified as prebiotics have been shown to promote the growth of A. muciniphila. This increase in abundance is often associated with improved mucin availability or shifts in the microbial ecosystem that favor its proliferation. In turn, A. muciniphila may contribute to intestinal health by stimulating mucin turnover, producing SCFAs, and enhancing epithelial barrier function.

3.4.1. Non-Digestible Fibers

Galactooligosaccharides (GOS) are non-digestible oligosaccharides produced by β-galactosidase-catalyzed transgalactosylation and are found in human and bovine milk.

As indigestible food components, GOS can pass through the upper gastrointestinal tract largely intact and reach the colon, where they are fermented by gut microbiota to produce SCFAs, which in turn help regulate the composition and activity of the intestinal microbiota [46].

GOS consumption significantly increases the abundance of A. muciniphila, not through a direct effect, but rather by modulating the intestinal microbial community. Following GOS intervention, a strengthening of the correlation between A. muciniphila and bacteria such as Eubacterium hallii, Roseburia, and Bacteroides has been observed [47].

Although Bacteroides typically compete with A. muciniphila for mucin, [47] suggests that GOS induces a shift in its carbon source, reducing this competition and facilitating the growth of A. muciniphila. Furthermore, the acetate produced by A. muciniphila can be used by other bacteria to form butyrate. The latter effect strengthens the intestinal barrier and mucin production by stimulating MUC gene expression in intestinal cells, as demonstrated in human epithelial cells cultured under glucose deprivation conditions [48]. Together, GOS promotes the intestinal environment and microbial interactions that indirectly benefit A. muciniphila.

Inulin is abundant in chicory root, garlic, onion, and asparagus. It is composed of linear chains of fructose units, generally with a degree of polymerization of 60 or more. β (2→1) bonds connect these units, and at one end, an α-D-glucopyranose molecule is linked by a (1→2) bond. The presence of an anomeric carbon in the β configuration prevents inulin from being digested in the human small intestine; however, it can be gradually broken down by the microbiota of the large intestine [49].

In a study using a mouse model of high-fat diet-induced hepatic steatosis, Pérez-Monter et al. (2022) evaluated the effects of dietary inulin supplementation (10%) over an eight-week period [50]. Male C57BL/6N mice receiving a high-fat diet supplemented with inulin exhibited a significant reduction in hepatic triglyceride accumulation, accompanied by a marked increase in the relative abundance of A. muciniphila, which rose from approximately 10% to 47% within this group over the 8-week intervention, as determined by 16S rRNA sequencing. A concurrent shift in the intestinal enterotype was also observed, characterized by a predominance of the Verrucomicrobia phylum. Furthermore, Western blot analysis revealed increased expression of the tight junction proteins ZO-1 and occludin, indicating a restoration of intestinal epithelial barrier integrity. A critical function that prevents the translocation of bacterial endotoxins, such as lipopolysaccharide (LPS), into the systemic circulation is essential. This barrier reinforcement, reflected by the increased expression of the tight junction proteins ZO-1 and occludin, suggests that inulin supplementation may counteract high-fat diet-induced permeability and associated inflammatory responses [50].

In contrast, the meta-analysis conducted by Tian et al. (2024), which integrated data from six human studies, evaluated the effects of inulin supplementation (16–20 g/day) over periods ranging from 2 to 12 weeks [47]. While one study reported an increase in A. muciniphila abundance, two others found a decrease. These inconsistencies are likely due to heterogeneity in experimental conditions, including participants’ baseline microbiota composition. The dose and duration of inulin intervention, as well as the analytical techniques used, were identified as critical variables influencing outcomes. Despite isolated findings of increased A. muciniphila in one study, inulin did not consistently or significantly enhance its abundance across the meta-analysis. Nevertheless, inulin consistently increased the abundance of other beneficial genera such as Bifidobacterium and Roseburia, which may indirectly influence the gut environment to favor A. muciniphila.

Fructooligosaccharides (FOS) are present in foods such as garlic, raw onions, leeks, asparagus, green bananas, Jerusalem artichokes, chicory root, and cereals like wheat and rye, composed of short chains of fructose units linked to a terminal glucose by β (2→1) bonds. This structure provides resistance to digestion in the small intestine, enabling them to reach the colon intact, where they act as a fermentable substrate for all bacteria present in the microbiota, thereby performing their prebiotic function [51].

In the study by Everard et al. (2011), oligofructose supplementation in obese mice increased the abundance of A. muciniphila in cecal contents by more than 80-fold, as determined by phylogenetic microarray analysis (MITChip), a DNA-based platform designed to detect and quantify hundreds of specific intestinal bacterial groups [52]. This increase within the phylum Verrucomicrobia was attributed explicitly to A. muciniphila and was confirmed by qPCR and 16S rRNA sequencing. Although the final relative abundance remained low, this shift was associated with improved glucose tolerance, reduced low-grade inflammation, enhanced gut barrier integrity, increased leptin sensitivity, and a higher number of intestinal L-cells [52]. The authors did not measure or directly mention SCFAs in their analysis. However, the observed enrichment of SCFA-producing genera, such as Butyricimonas and Barnesiella, suggests a potential increase in SCFA production, which contributes to the reported metabolic improvements.

In contrast, Reid et al. (2016) explored the preventive potential of OFS supplementation in a postnatal overfeeding model using Sprague–Dawley rats. Overnutrition was induced by rearing pups in small litters (SL, 3 pups per dam), and from weaning (P21) to 19 weeks of age, animals received either a standard AIN-93 diet or one enriched with 10% OFS. In SL rats, OFS significantly reduced body fat percentage and postprandial glycemia, aligning these values with those of normal-litter (NL) controls. GLP-1 levels increased in both SL and NL rats with OFS, while PYY increased only in NL. Notably, OFS increased the abundance of A. muciniphila—from 0.53% to 1.65% in SL rats—alongside a significant upregulation of colonic SCFA receptors GPR41 and GPR43. Although SCFAs were not measured, these changes suggest enhanced fermentation activity and gut–host signaling [53].

Together, both studies support the consistent impact of OFS on A. muciniphila abundance and metabolic health, whether applied as a therapeutic or preventive intervention.

Polydextrose (PDX) is frequently incorporated into low-calorie and high-fiber formulations, such as sugar-free baked goods, meal replacement bars, beverages, breakfast cereals, and dairy products like yogurt. Its physicochemical stability and low sweetness make it a versatile ingredient in functional foods designed to improve digestive and metabolic health. It is recognized as a fermentable fiber that can selectively modulate the gut microbiota. PDX is a randomly bonded condensation polymer composed of D-glucose, sorbitol, and citric acid. Commercial polydextrose also contains small amounts of free glucose, sorbitol, citric acid, and 1,6-anhydro-D-glucose (levoglucosan). It is highly branched, with a degree of polymerization ranging from 2 to 110 (averaging about 12 glucose units) and an average molecular weight of approximately 2000 Daltons [54].

In the clinical study by Hooda et al. (2012), PDX supplementation at 21 g/day for 21 days significantly increased the fecal relative abundance of A. muciniphila in healthy adult men compared to both the no-fiber control and the group consuming soluble corn fiber (SCF) (p < 0.05) [55]. This effect was reiterated in the systematic review by Verhoog et al. (2019), which highlighted its clinical relevance given the emerging role of A. muciniphila in metabolic and intestinal health [56]. No significant changes were observed in classical SCFAs (acetate, propionate, and butyrate), although a slight increase in branched-chain fatty acids (BCFAs) was reported. Interestingly, SCF led to higher SCFA concentrations than PDX, which may be due to its simpler structure and its ability to maintain SCFA-producing taxa such as Eubacterium and Lachnospiraceae. In contrast, PDX reduced the abundance of these groups, suggesting that its selective prebiotic effect on A. muciniphila may rely more on its complex molecular structure than on enhanced saccharolytic fermentation.

Resistant starch type 2 (RS2) is composed of native starch granules characterized by a compact crystalline structure that resists enzymatic digestion in the small intestine (dietary fiber). This resistance primarily results from the dense packing of amylose and amylopectin within the granules, which limits enzyme accessibility [57].

In a study by Maier et al. (2017), 39 insulin-resistant adults participated in a crossover dietary intervention involving high and low intake of resistant starch type 2 (RS2), with multi-omics analyses conducted on fecal samples. A. muciniphila was reported to increase in relative abundance following the high-RS2 diet, yet no quantification was provided, and no functional roles or mechanistic insights were explored. SCFAs were measured and showed a slight increase in butyrate and propionate, attributed to classical butyrate producers such as Faecalibacterium and Roseburia. Still, no direct association with A. muciniphila was identified [58].

In contrast, Tachon et al. (2013) conducted a 10-week dietary intervention in aged male C57BL/6J mice fed diets containing 0%, 18%, or 36% RS2 derived from high-amylose maize (HAM-RS2) [59]. The control diet consisted entirely of amylopectin (0% RS), a fully digestible starch that does not reach the colon. In that study, A. muciniphila abundance increased by 35.1-fold in mice receiving 36% RS2 compared to controls (p < 0.05), and this increase was positively correlated with higher gastrointestinal tract weight, elevated proglucagon expression, and increased post-fasting food intake. Although SCFAs were not measured, the authors hypothesized that mucin fermentation by A. muciniphila may lead to propionate production, potentially mediating the observed physiological effects. Thus, while both studies observed increases in A. muciniphila with RS2 supplementation, only the murine model demonstrated a strong quantitative response, suggesting potential metabolic implications. This evidence has been incorporated into the review by Y. Zhang et al. (2022), which highlights the role of RS2 as a modulator of gut microbiota, with the ability to enrich key synbiotic bacteria such as A. muciniphila [60].

Xylooligosaccharides (XOS) are present in bamboo shoots and corn cobs. They are nondigestible oligosaccharides composed of 2 to 10 xylose units linked by β-1,4-glycosidic bonds. Because they resist digestive enzymes, they reach the colon intact, where beneficial bacteria selectively ferment them [61].

In a study by J. Wang et al. (2025), XOS significantly increases the abundance of A. muciniphila in mice with gestational diabetes mellitus (GDM), but only in the presence of a functional intestinal microbiota [62]. Under pseudo-germ-free (PGF) conditions—where most of the gut microbiota was depleted with antibiotics—XOS failed to increase A. muciniphila, indicating that its effect is indirect and depends on the presence of other microbes capable of metabolizing XOS into substrates usable by A. muciniphila. This was further supported by in vitro experiments, where A. muciniphila did not grow when cultured with XOS alone. Moreover, the combination of XOS and A. muciniphila improved several metabolic and inflammatory parameters, including increased expression of ZO-1 and occludin, as well as modulation of the NKG2D/NKG2DL immune signaling pathway. Taken together, these findings support the hypothesis that XOS may exert more robust effects when used as part of a synbiotic strategy, particularly in the context of microbiota dysbiosis. This inference is based on the observation that its ability to increase A. muciniphila was abolished under pseudo-germ-free (PGF) conditions, and that its combination with the bacterium improved metabolic and immunological parameters, despite not enhancing its abundance.

3.4.2. Plant-Derived Bioactive Compounds

Wild blueberry extract (WBE), obtained from Vaccinium myrtillus L. residues, is rich in phenolic compounds, particularly anthocyanins with potent antioxidant properties. These phenolic compounds can be recovered using clean technologies, such as supercritical CO₂ or pressurized liquids, thereby avoiding toxic solvents and preserving health-promoting effects [63].

The WBE did not directly stimulate the growth of A. muciniphila, even though it contained oligomeric proanthocyanidins (PACs). In contrast, the F2 fraction alone induced a 2.5-fold increase in A. muciniphila abundance, likely due to the absence of interfering compounds present in WBE. The presence of anthocyanins and polymeric PACs in the full extract may have promoted the growth of competing bacterial taxa, such as Ruminococcaceae and Peptostreptococcaceae, potentially inhibiting A. muciniphila. Therefore, the prebiotic effect appears to be specific to oligomeric PACs and may be suppressed in complex mixtures, such as the whole extract [64]. This suggests that fractionation of polyphenol-rich sources may enhance selectivity toward beneficial taxa such as A. muciniphila by minimizing microbial competition and favoring ecological niches required for their expansion. Such targeted enrichment strategies could be critical for optimizing gut microbiota-based interventions in metabolic disorders.

Polyphenols are natural compounds synthesized exclusively by plants and characterized by multiple phenolic structures. Polyphenols play a crucial role in plant defense mechanisms and are abundant in various foods, including fruits (such as grapes and apples), vegetables (like onions), red wine, and green tea. These compounds exhibit antioxidant properties and have been associated with potential health benefits, including modulation of oxidative stress and inflammation [65].

The study by Van Buiten et al. (2024) demonstrated that grape polyphenol extract (GPE) significantly increased the relative abundance of A. muciniphila (468.11%) in lean mice compared with baseline levels, in association with a sustained reduction in intestinal reactive oxygen species (ROS) [10]. This high percentage likely reflects the initially low basal levels of A. muciniphila, meaning that even a little absolute increase resulted in a substantial proportional change when GPE was administered orally. Unlike the antioxidants β-carotene and ascorbic acid, only GPE produced this effect, probably due to its low bioavailability, which enables localized antioxidant action within the intestinal lumen. These findings suggest a direct link between the relative abundance of A. muciniphila and the intestinal redox environment, highlighting a potential therapeutic target for reversing dysbiosis and improving metabolic function [10].

However, when analyzing clinical and human studies, Tian et al. (2024) did not observe a consistent effect of polyphenols on A. muciniphila abundance. This inconsistency may be attributed to variations in the types of polyphenols used (e.g., red-fleshed apple vs. grape pomace), differences in participants’ baseline gut microbiota, small sample sizes (n = 25 and n = 29), and uncontrolled dietary habits. Moreover, neither study reported significant changes in microbial functional pathways related to SCFA metabolism, suggesting a limited systemic effect under the tested conditions [47].

Quercetin is a low-molecular-weight flavonoid that belongs to the class of phenolic phytochemicals, commonly found in the human diet (broccoli, citrus fruits, blueberries, blackberries, parsley, and spinach). It exhibits potent antioxidant capacity, capable of scavenging ROS, reactive nitrogen species (RNS), and reactive chlorine species (ROC), acting as a reducing agent by chelating transition-metal ions [66].

Juárez-Fernández et al. (2021) demonstrated that daily oral supplementation with A. muciniphila (2 × 10⁸ CFU in 10% cysteine-supplemented skim milk) elicited beneficial effects in rats previously fed a high-fat diet (HFD), including reduced epididymal white adipose tissue, decreased hepatic triglyceride content, and downregulation of key lipogenic genes such as CEBPA and DGAT2. However, these effects were significantly enhanced when A. muciniphila was coadministered with quercetin (37.5 mg/kg/day), forming a synbiotic intervention. Only the combined treatment reversed early hepatic steatosis, normalized insulin resistance (HOMA-IR), and significantly suppressed proinflammatory markers like IL-6 and TLR-2. Moreover, changes in SCFAs and the bile acid (BA) pool—specifically, increased levels of unconjugated hydrophilic BAs such as omega-muricholic acid (ωMCA) and ursodeoxycholic acid (UDCA)—were observed exclusively with the synbiotic, not with A. muciniphila alone. These results indicate that while A. muciniphila alone improves lipid metabolism, its full modulatory effect on the gut–liver axis and bile acid signaling requires coadministration with quercetin [67].

Resveratrol is found in red grapes (particularly in the skin), red wine, peanuts, pistachios, blueberries, mulberries, dark chocolate, and cocoa powder. It is a stilbenoid polyphenol composed of two phenolic rings linked by an ethylene bridge, forming trans-3,5,4′-trihydroxystilbene. Resveratrol has been studied for its potential therapeutic effects, including antioxidant, anti-inflammatory, cardioprotective, neuroprotective, and anticancer properties. It has shown promise in modulating various molecular pathways, such as SIRT1 activation, which is associated with aging and metabolic regulation [68].

In a study by Alrafas et al. (2019), short-term oral administration of resveratrol (100 mg/kg/day for 5 days) in BALB/c mice with TNBS-induced colitis effectively reversed inflammation-associated dysbiosis, notably restoring the abundance of A. muciniphila, which had been markedly depleted [69]. This microbial shift was accompanied by a significant increase in i-butyric acid, a SCFA with well-established anti-inflammatory properties. Moreover, resveratrol modulated the immune landscape by promoting anti-inflammatory T cell populations (CD4⁺FOXP3⁺ and CD4⁺IL-10⁺) and reducing proinflammatory subsets (Th1 and Th17). Crucially, fecal microbiota transplantation (FMT) from resveratrol-treated donors conferred protection against colitis in antibiotic-pretreated recipients, demonstrating that the observed effects were microbiota-dependent and not solely attributable to direct host interactions [69].

Complementing these findings, Chen et al. (2020) investigated the effects of chronic resveratrol supplementation (100 mg/kg/day for 12 weeks) in C57BL/6J mice fed a high-fat diet (HFD), a model of metabolic inflammation. Resveratrol significantly increased the relative abundance of A. muciniphila, as confirmed by 16S rRNA sequencing and LEfSe analysis [70]. This increase was associated with improvements in gut barrier function—evidenced by restored expression of tight junction proteins (ZO-1, occludin, claudin-1)—and reductions in systemic inflammation, endotoxemia (plasma LPS), and insulin resistance. Although SCFAs were not directly quantified, the authors note the known capacity of A. muciniphila to produce acetate and propionate, suggesting a possible link between microbial enrichment and mucosal recovery. Notably, resveratrol did not merely reverse HFD-induced dysbiosis but induced a distinct microbial profile, marked by higher Verrucomicrobia and suppression of pro-inflammatory genera such as Bilophila and Ruminococcus [67].

Together, these studies underscore the microbiota-modulating potential of resveratrol across different pathological contexts—acute inflammation and chronic metabolic stress. While Alrafas et al. provide causal evidence of immune modulation through microbiota transfer, Chen et al. highlight the capacity of resveratrol to promote A. muciniphila expansion and intestinal barrier restoration [69,70].

Rhubarb (Rheum rhabarbarum) is a perennial herbaceous plant in the Polygonaceae family. It is widely cultivated for its edible stalks, which are rich in bioactive compounds, including anthraquinones, stilbenes, and flavonoids. These compounds confer various pharmacological properties, including antioxidant, anti-inflammatory, antimicrobial, and anticancer activity [71].

Rhubarb, traditionally utilized for its medicinal properties, has been shown to significantly increase the abundance of A. muciniphila in models of diet-induced obesity, according to a study cited by Abbasi et al. (2024) [6]. This effect was accompanied by improvements in liver inflammation and intestinal homeostasis. Despite its low fiber content, it is suggested that anthraquinone compounds in rhubarb are responsible for this microbial modulation. Therefore, Abbasi et al. indicate that future research will evaluate the use of purified anthraquinones to confirm their role as specific regulators of the gut microbiota and enhancers of A. muciniphila.

3.4.3. Human Milk Oligosaccharides

The prebiotic 2-Fucosyllactose (2′-FL) is one of the most abundant oligosaccharides in breast milk and has shown a positive effect on the abundance of A. muciniphila. It is a fucosylated trisaccharide composed of L-fucose, D-galactose, and D-glucose units. Additionally, it is the most abundant human milk oligosaccharide (HMO) in the milk of secretor mothers, constituting approximately 30% of total HMOs [72].

In a recent study, Ge et al. (2024) demonstrated that A. muciniphila can directly metabolize 2′-FL as its sole carbon source under in vitro conditions, resulting in increased biomass and the production of SCFAs, primarily butyrate and propionate [73]. In the in vivo model, mice treated with high doses of 2′-FL also showed a significant increase in the abundance of A. muciniphila, along with higher fecal levels of SCFAs. However, the authors clarify that this increase in SCFAs might be due to a general modulation of the gut microbiome rather than the exclusive action of A. muciniphila. Furthermore, they emphasize the need to validate these effects in clinical studies to confirm whether the benefits observed in vitro and in vivo in animal models can be extrapolated to the human context. These findings reinforce the potential of 2′-FL as a selective prebiotic, capable of enriching beneficial bacteria associated with metabolic homeostasis and intestinal health.

3.4.4. Drugs

Dapagliflozin is a synthetic glucoside consisting of a D-glucose moiety linked through a carbon–carbon bond to a substituted aromatic ring. Dapagliflozin has been approved for treating type 2 diabetes mellitus, heart failure with reduced ejection fraction (HFrEF), and chronic kidney disease (CKD) due to its ability to lower blood glucose by promoting urinary glucose excretion and offering cardio- and nephroprotective effects [74]. In a mouse model of type 2 diabetes, Lee et al. (2018) evaluated the effects of treatment with dapagliflozin sodium-glucose cotransporter 2 (SGLT2) inhibitors on gut microbiota composition using 16S rRNA gene sequencing [75]. The results indicated that diabetic mice had a significant decrease in A. muciniphila abundance compared to the controls; however, after eight weeks of dapagliflozin treatment, a trend toward an increased abundance of this species was noted.

Furthermore, positive correlations were identified between A. muciniphila abundance and vascular function, along with negative correlations with arterial stiffness, suggesting a potential beneficial role in the drug’s vascular effects. Although the study does not definitively determine the mechanism by which dapagliflozin promotes the growth of A. muciniphila, the authors propose that it could be due to a reduction in intestinal inflammation and an increase in mucin secretion, a substrate exclusive to this bacterium. However, the study did not evaluate the production of SCFAs, so it cannot be established whether these metabolites are involved in the observed effects.

Metformin is a biguanide antidiabetic agent that lowers blood glucose levels by inhibiting hepatic gluconeogenesis, decreasing intestinal glucose absorption, and enhancing peripheral glucose uptake and utilization. It is considered the first-line pharmacological treatment for type 2 diabetes mellitus due to its efficacy and safety profile [76]. Several studies have demonstrated that metformin, in addition to its classic antidiabetic action, increases the abundance of A. muciniphila in the intestine. According to Bu et al. (2020), this effect is observed both in mice fed a high-fat diet and in ex vivo fecal cultures, and it is associated with improved glucose tolerance and reduced intestinal inflammation [45]. Consistently, Abbasi et al. (2024) reported that metformin positively modulates the intestinal microbiota, specifically favoring A. muciniphila, which could contribute to its action on intestinal barrier integrity and the reduction of metabolic endotoxemia [6]. Both authors agree that this microbial effect represents a significant additional mechanism contributing to the metabolic benefits of metformin.

Table 1. Summary of Experimental Evidence on the Effects of Bioactive Compounds on A. muciniphila.

Bioactive Compounds	Interaction with A. muciniphila	SCFAs	Experimental Model	Reference
Non-digestible Fibers
Galacto-oligosaccharides (GOS)	↑ Increase in A. muciniphila abundance compared to the placebo group.	↑ Acetate and indirectly, butyrate production.	Meta-analysis of 821 human stool samples collected from 451 participants in 4 countries. For the study of GOS, n = 94, 5 g per day were administered for 3 weeks.	[47]
Inulin	Inconsistent effect across the three reported studies: A. muciniphila abundance ↑ in one study, but ↓ in the other two.	An analysis of the SCFAs produced is not reported.	Meta-analysis of 821 human stool samples collected from 451 participants in 4 countries. For the inulin intervention, three human studies (n = 303) were included, using doses of 16–20 g/day for 2–12 weeks.	[47]
Inulin	↑ Abundance from 10% to 47% of relative abundance in high-fat diet groups.	Increased activity of the propionate metabolism pathway, associated with inulin consumption (predicted by PICRUSt analysis).	C57BL/6N mice (n = 40) divided into 4 groups (n = 10): control or high-fat diet (HFD) (45% kcal) supplemented with cellulose or inulin (10%) for 8 weeks. Assessed biochemical parameters, liver histology, fecal microbiota (16S rRNA), tight junction proteins (ZO-1, occludin, TLR4), and bacterial metabolic pathways (PICRUSt).	[50]
Oligofructose (FOS)	↑ A. muciniphila abundance from 0.001% to 0.089% in cecal content compared to control.	Not measured; enrichment of SCFAs-producing genera (Butyricimonas, Barnesiella) was observed, but SCFAs levels were not quantified.	C57BL/6 ob/ob mice and HFD-induced obese C57BL/6J mice were treated with oligofructose: 5 weeks in diet (ob/ob) or 8 weeks in drinking water (0.3 g/mouse/day, HFD). Outcomes included microbiota profiling (qPCR, 16S rRNA pyrosequencing, MITChip), glucose tolerance, lipid metabolism, gut barrier integrity (LPS, FITC-dextran, ZO-1/occludin), gene expression (GLP-1, IL-1, LPL, ACC), L-cell number, and leptin sensitivity.	[52]
Oligofructose (FOS)	↑ A. muciniphila from 0.53% to 1.65% (SL) and 0.29% to 0.57% (NL). SL rats showed higher abundance than NL, regardless of diet.	SCFAs were not measured directly; their production is inferred from OFS fermentation. OFS diet ↑ colonic expression of SCFA receptors GPR41 and GPR43 (p < 0.03), regardless of litter size.	Male Sprague–Dawley rats were reared in small (SL, 3 pups) or normal litters (NL, 12 pups), then fed either standard AIN-93 diet or AIN-93 supplemented with 10% oligofructose (w/w) from weaning (P21) to week 19. Outcomes included body composition, glucose tolerance, gut hormones, gene expression, and microbiota.	[53]
Polydextrose	↑ A. muciniphila in relative abundance with polydextrose (no-fiber control: 1.08% → polydextrose: 3.54%; soluble corn fiber: 0.41%).	Fecal SCFAs (acetate, propionate, butyrate) were higher with SCF than with PDX (p < 0.05), despite increased F. prausnitzii with PDX. Authors note that fecal levels do not reflect actual SCFA production due to rapid colonic absorption.	Fecal microbiota composition was an alyzed by 16S rRNA gene pyrosequencing after 21 days of fiber supplementation (21 g/day of polydextrose, soluble corn fiber, or no fiber) in a randomized crossover study with healthy adult men (n = 20). SCFAs were measured in fecal samples using gas chromatography.	[55,56]
Resistant starch type 2 (HAM-RS2, high amylose corn)	↑ Relative abundance after the high-resistant starch diet compared to both the low-RS and baseline diets. Its functions were not analyzed, and no mechanisms were discussed in the study.	SCFAs showed a slight increase in butyrate and propionate after the high-RS diet. This was linked to butyrate-producing genera, but not directly to A. muciniphila, despite its increased abundance.	Crossover study with 39 insulin-resistant adults. Participants consumed high (48–66 g/day) and low (3–4 g/day) RS2 diets for 2 weeks each, with a washout in between. Fecal samples were analyzed by 16S rRNA, metaproteomics, and FT-ICR-MS; SCFAs quantified by UHPLC-MS.	[58]
Resistant starch type 2 (HAM-RS2, high amylose maize)	↑ Relative abundance (35.1-fold) in mice fed 36% HAM-RS2 compared to controls (p < 0.05; control diet contained 0% RS and 100% amylopectin).	Not quantified. Authors hypothesize propionate production by A. muciniphila as a possible mechanism, but no SCFA data were reported.	Aged male C57BL/6J mice (18–20 months; n = 6 per group) were fed diets with 0%, 18%, or 36% HAM-RS2 for 10 weeks. Cecal microbiota analyzed by 16S rRNA gene pyrosequencing (V1–V3 regions). Proglucagon expression measured by RT-qPCR. SCFAs were not measured.	[59]
Xylo-oligosaccharides (XOS)	↑ A. muciniphila abundance only when administered XOS alone, in vivo, and in the presence of a functional gut microbiota. This effect is lost in the pseudo-germ-free (PGF) model and is not enhanced—indeed, it may be reversed—when combined with direct administration of A. muciniphila.	No SCFAs analysis was reported.	C57BL/6J female mice (n = 225) were fed AIN-93 or HFD diets. After 4 weeks, HFD-fed mice were divided into 9 groups (n ≥ 19) with combinations of GDM (induced by STZ), XOS (500 mg/kg), A. muciniphila (4 × 108 CFU), and/or antibiotics (PGF model). Interventions began on gestation day 8. On day 18, fasting blood glucose and body weight were measured. After sacrifice, blood, tissues, feces, and cecal contents were collected for further analysis, including bacterial quantification and DNA extraction.	[62]
Plant-Derived Bioactive Compounds
Wild blueberry extract (WBE)	The total extract (WBE) did not stimulate A. muciniphila. However, the F2 fraction (PAC oligomers) increased its abundance 2.5-fold, as confirmed by qPCR.	SCFAs were not directly measured in this study.	Male C57BL/6J mice were fed a high-fat, high-sucrose (HFHS) diet for 8 weeks and were orally supplemented by gavage with either the wild blueberry extract (WBE, 200 mg/kg), or one of its polyphenolic fractions: F1 (anthocyanins and phenolic acids, 32 mg/kg), F2 (oligomeric PACs, 53 mg/kg), or F3 (polymeric PACs, 37 mg/kg), in doses equivalent to their natural proportion in the WBE	[64]
Grape polyphenol Extract (GPE)	↑ 468% vs. baseline (day 0); this large increase reflects a proportional rise from a low initial abundance.	No direct changes in SCFAs were reported. Sustained reduction of ROS in the gut.	Lean C57BL/6J mice (n = 5/group) were assigned to four groups: control (vehicle), ascorbic acid, β-carotene, or GPE. All treatments were administered daily by oral gavage (360 mg/kg) for 14 days. Fecal samples were analyzed by qPCR and ABTS assay; gastrointestinal ROS were assessed by NIRF imaging, and metabolic status by OGTT.	[10]
Polyphenols (red-fleshed apple andpolyphenols grape-pomace)	No significant change in A. muciniphila abundance was observed in either polyphenol intervention.	No significant changes observed; no SCFA-related pathway alterations reported.	Meta-analysis of 821 human stool samples collected from 451 participants in 4 countries. For polyphenol studies, human intervention trials were conducted: apple supplementation for 5 weeks and grape pomace supplementation for 6 weeks. Fecal microbiota was analyzed by 16S rRNA sequencing and processed with QIIME2 and PICRUSt2.	[47]
Quercetin	↑ Relative abundance of A. muciniphila in rats previously fed a high-fat diet (HFD) and supplemented with the bacterium (alone or with quercetin), compared to non-supplemented groups.	There was no direct effect on SCFAs. The increase in SCFAs was attributed to dietary intervention, not to quercetin.	Twenty-one-day-old male Wistar rats were fed a HFD for 6 weeks to induce early obesity and NAFLD, then received a control diet (10% fat) for 3 weeks, supplemented with or without quercetin (37.5 mg/kg/day in diet), A. muciniphila (2 × 108 CFU/day by oral gavage), or both.	[67]
Resveratrol	↑ A. muciniphila abundance (qPCR; p < 0.001)—restored after resveratrol treatment, following colitis-induced depletion.	In both healthy and colitis mice, it caused a significant ↑ of i-butyrate and acetate, in the TNBS + Resveratrol group.	BALB/c mice with TNBS-induced colitis were administered oral resveratrol (100 mg/kg/day) for 5 days. The microbiota was assessed by 16S rRNA sequencing, SCFAs by chromatography, and T cell subpopulations by flow cytometry.	[69]
Resveratrol	↑ A. muciniphila relative abundance (p < 0.05 vs. HFD and ND). The genus Akkermansia (phylum Verrucomicrobia) was significantly enriched in the HFD + Resveratrol group, as determined by 16S rRNA sequencing and LEfSe analysis.	SCFAs Not directly quantified in this study.	C57BL/6J mice (n = 15) were divided into: ND (normal diet), HFD for 20 weeks), and HFD + RES (HFD plus oral resveratrol, 100 mg/kg/day, for 12 weeks). Metabolic, inflammatory, and intestinal permeability markers (ZO-1, occludin, claudin-1) were assessed. Gut microbiota was analyzed via 16S rRNA sequencing (Illumina MiSeq, QIIME, LEfSe). SCFAs were not directly measured. ANOVA + Tukey test; p < 0.05 was considered significant.	[70]
Rhubarb	The abundance of A. muciniphila increased to 38.9% of total fecal microorganisms in DIO mice (vs. 9.4% on standard diet) after 17 days of supplementation.	No effects on SCFAs were specified. A decrease in Firmicutes and improvements in liver inflammation, oxidative stress, and intestinal homeostasis were reported.	DIO mice fed the AIN93M diet were supplemented with rhubarb extract for 17 days. The microbiota was assessed by 16S rRNA pyrosequencing.	[6]
Human Milk Oligosaccharides
2′-fucosyllactose (2′-FL)	↑ abundance between 13 and 18%, significantly greater than in the control group.	↑ Butyrate, propionate, isovalerate, valerate, caproate, and 4-methylvalerate.	In vitro: A. muciniphila cultured with 2′-FL for 72 h. In vivo: C57BL/6J mice (3 weeks old) treated for 14 days with 2.0 g/kg (low dose) or 6.0 g/kg (high dose) of 2′-FL by gavage. Microbiota analysis by 16S rRNA sequencing.	[73]
Drugs
Dapagliflozin	Trend towards increased abundance in treated diabetic mice.	No studies reported on 49 s, improved vascular function (↓ arterial stiffness, ↑ endothelial dilation).	C57BLKS mice (type 2 diabetes model), males, 8 weeks of treatment with a diet supplemented with dapagliflozin (60 mg/kg diet; 0.006%).	[75]
Metformin	↑ The abundance of A. muciniphila in HFD-fed mice. This effect is associated with improved glucose tolerance and reduced inflammation.	It improved intestinal barrier integrity, reduced LPS absorption, decreased inflammation, and maintained intestinal homeostasis. No direct effects on SCFA levels were reported.	Mice were fed on a high-fat diet (HFD); metformin was administered orally and validated in fecal cultures in BHI medium.	[6,45]

Note: The arrow symbols indicate direction of change: ↑ for increase, ↓ for decrease compared to the control group.

summarizes key experimental findings linking specific compounds to changes in A. muciniphila abundance and associated physiological effects.

4. Discussion

This review highlights the influence of various prebiotic and bioactive compounds on the abundance and activity of A. muciniphila, with an emphasis on the diversity of mechanisms, experimental models, and outcomes reported. Compounds such as GOS and 2′-FL have been shown to stimulate A. muciniphila through both direct metabolic support and indirect ecological modulation. GOS promotes beneficial microbial interactions that reduce mucin competition [30], while 2′-FL can serve as a direct carbon source, enhancing bacterial growth and increasing SCFA production, particularly butyrate and propionate [73].

In contrast, the effects of plant-derived compounds such as GPE, quercetin, and rhubarb seem to operate through modulation of the intestinal environment rather than fermentation. GPE, for instance, helps lower intestinal oxidative stress, creating a more favorable niche for strict anaerobes like A. muciniphila [39]. Additionally, the combination of quercetin and A. muciniphila has shown synergistic effects, suggesting that certain polyphenols may enhance colonization and activity when administered in conjunction with this bacterium [67].

Other compounds, including XOS and polydextrose, demonstrate context-dependent effects that rely on the existing microbial community. The increase in A. muciniphila abundance observed with XOS was only evident in the presence of a functional microbiota, suggesting that intermediary metabolites generated by other bacteria play a role [37]. Meanwhile, polydextrose has been shown to produce significant increases in A. muciniphila in humans, without substantial changes in classical SCFA profiles, indicating a potentially specific action linked to its structure and fermentation kinetics [55,56].

RS2 is one of the few compounds studied in both human and animal models that has consistently shown a positive impact on the relative abundance of A. muciniphila, often accompanied by metabolic improvements [58,59]. These results support the inclusion of RS2 in dietary interventions, especially for individuals with insulin resistance. Likewise, therapeutic agents such as metformin, dapagliflozin, and resveratrol have also been associated with increases in A. muciniphila, alongside improved gut barrier function and reduced inflammatory markers [45,69,75]. These observations suggest that modulating this bacterium could contribute to the overall clinical benefits of such compounds and may offer opportunities for synergistic strategies involving both pharmaceuticals and prebiotics.

Despite the growing body of positive evidence, outcomes are not always consistent across studies. These discrepancies can be attributed to key methodological variables, which complicate interpretation and limit comparability.

First, the chemical structure and origin of the bioactive compounds play a pivotal role. For instance, while resveratrol and ellagic acid have been shown to promote A. muciniphila growth in mice [77,78], quercetin has produced variable effects depending on the dose and host model [79]. Similarly, inulin-type fructans with different degrees of polymerization influence fermentability and microbial selectivity in distinct ways [80].

Intervention efficacy also depends on dose and duration, as high-concentration or prolonged treatments tend to yield more pronounced effects, while short-term studies often report minimal changes. For example, Everard et al. (2013) observed a significant increase in A. muciniphila following four weeks of inulin supplementation in obese mice, whereas shorter interventions such as those in Cani et al. (2008) showed limited impact [21,81].

The experimental model used is another critical factor. Rodent models provide controlled conditions, but differ substantially from human physiology and microbiota composition. Human trials, such as the study by Depommier et al. (2019), show promise, but are influenced by individual variability in diet, lifestyle, and baseline microbial composition [82].

Finally, variation in microbiota analysis techniques, including 16S rRNA region selection, sequencing depth, and bioinformatics pipelines, can affect the detection and quantification of A. muciniphila, making standardization essential to improve reproducibility [83].

A. muciniphila participates in the modulation of SCFA production through multiple mechanisms. Its mucin-degrading activity leads to the release of oligosaccharides and amino acids, which are subsequently utilized by other commensal bacteria, such as Faecalibacterium prausnitzii and Roseburia spp., which are key producers of butyrate. Although A. muciniphila itself primarily produces acetate and propionate, its trophic interactions enhance butyrate production in the gut via cross-feeding networks.

• Acetate: A. muciniphila produces acetate through the fermentation of mucin-derived sugars. Acetate acts as a substrate for peripheral tissues and is also involved in cholesterol metabolism and lipogenesis. Furthermore, acetate can serve as a precursor for butyrate synthesis by other colonic microbes.
• Propionate: Propionate is generated via the succinate pathway in A. muciniphila. This SCFA contributes to gluconeogenesis in the liver and has been associated with satiety regulation and improved insulin sensitivity.
• Butyrate: Although not directly synthesized by A. muciniphila, its activity supports butyrate producers by supplying fermentation intermediates. Butyrate is essential for colonic epithelial health, anti-inflammatory responses, and maintaining the integrity of the gut barrier—effects indirectly reinforced by the presence of A. muciniphila.

This intricate metabolic network is critical to the health-promoting effects observed with A. muciniphila, particularly in populations with obesity, type 2 diabetes, or inflammatory bowel diseases. The restoration of SCFA profiles through A. muciniphila-mediated modulation may help re-establish gut homeostasis in these target groups.

In summary, the ability of prebiotics and other bioactive compounds to modulate A. muciniphila depends not only on their chemical properties, but also on the host environment, microbial context, experimental design, and analytical approach. While some compounds may exert direct effects on this bacterium, many of the observed benefits appear to arise from indirect pathways, including cross-feeding, ecological shifts, or improvements in the intestinal environment. These findings highlight the importance of considering the microbiota as a dynamic ecosystem when designing effective strategies to target A. muciniphila for therapeutic purposes.

The schematic highlights the intricate relationship between specific compounds and their health effects mediated by A. muciniphila. Figure 4 shows how nutrients, microbial metabolites, and pharmacological agents can influence the host’s metabolic and immune pathways by modulating A. muciniphila, emphasizing its growing importance in gut microbiota–host interactions and the regulation of systemic health.

The figure illustrates the interaction between A. muciniphila and different classes of modulators—including prebiotics (e.g., inulin, resistant starch, polydextrose), plant-derived polyphenols (e.g., quercetin, resveratrol), and pharmaceutical drugs (e.g., metformin, dapagliflozin). These compounds influence bacterial abundance and activity, as well as SCFA production, with potential implications for intestinal and metabolic health.

5. Conclusions

Improving metabolic and intestinal health through the selective modulation of A. muciniphila represents a promising therapeutic approach. The findings of this review indicate that the impact of dietary and pharmacological compounds on this bacterium does not follow a uniform pattern; rather, it depends on both the chemical structure of the compound and the microbial environment in which it acts. Compounds such as RS2, metformin, resveratrol, dapagliflozin, polydextrose, blueberry extract, rhubarb, quercetin, 2′-FL, and various polyphenols have demonstrated the ability to modulate the abundance and activity of A. muciniphila, either directly or indirectly.

These findings reflect the complexity of interactions between the gut microbiota and bioactive compounds, highlighting the potential of A. muciniphila as a microbial target for the development of innovative, microbiota-based therapeutic strategies.

6. Perspectives

The findings reviewed reinforce the potential of A. muciniphila as a promising therapeutic target for managing various metabolic and inflammatory disorders. Moving forward, it is essential to characterize further the compounds capable of modulating its growth and activity, as well as to identify key metabolites produced during its interactions with the host.

The rational selection of specific prebiotics, pharmaceutical agents, or synergistic combinations that enhance A. muciniphila could lead to the development of more effective and safer microbiota-targeted interventions. Additionally, the use of A. muciniphila or its bioactive components as a next-generation probiotic represents a valuable opportunity for the design of novel functional therapies.

Future research should focus on validating these strategies through well-designed, large-scale clinical trials to ensure their safety, efficacy, and applicability in real-world healthcare settings. Integrating mechanistic studies with clinical evidence will be key to unlocking the full therapeutic potential of A. muciniphila in personalized nutrition and microbiome-based medicine.