From gut microbial ecology to lipid homeostasis: Decoding the role of gut microbiota in dyslipidemia pathogenesis and intervention

Abstract

Dyslipidemia, a complex disorder characterized by systemic lipid profile abnormalities, affects more than half of adults globally and constitutes a major modifiable risk factor for atherosclerotic cardiovascular disease. Mounting evidence has established the gut microbiota (GM) as a pivotal metabolic modulator that is correlated with atherogenic lipid profiles through dietary biotransformation, immunometabolic regulation, and bioactive metabolite signaling. However, the host-microbe interactions that drive dyslipidemia pathogenesis involve complex gene-environment crosstalk spanning epigenetic modifications to circadian entrainment. Mechanistically, GM perturbations disrupt lipid homeostasis via lipopolysaccharide-triggered hepatic very low-density lipoprotein overproduction, short-chain fatty acid-G protein-coupled receptor 43/41-mediated adipocyte lipolysis, bile acid-farnesoid X receptor/Takeda G protein-coupled receptor 5 axis dysfunction altering cholesterol flux, microbial β-oxidation intermediates impairing mitochondrial energetics, and host-microbiota non-coding RNA crosstalk regulating lipogenic genes. This comprehensive review systematically examines three critical dimensions, including bidirectional GM-lipid axis interactions, molecular cascades bridging microbial ecology to metabolic dysfunction, and translational applications of GM modulation through precision probiotics, structure-specific prebiotics, and a metabolically optimized fecal microbiota transplantation protocol. Notwithstanding these advances, critical gaps persist in establishing causal microbial taxa-pathway relationships and optimal intervention timing. Future directions require longitudinal multi-omic studies, gnotobiotic models for mechanistic validation, and machine learning-driven personalized microbiota profiling. This synthesis provides a framework for developing microbiota-centric strategies targeting dyslipidemia pathophysiology, with implications for precision dyslipidemia management and next-generation cardiovascular disease prevention.

Key Words: Dyslipidemia; Lipid metabolism; Gut microbiota; Dietary patterns; Circadian rhythms; Probiotics; Prebiotics; Fecal microbiota transplantation

Core Tip: Dyslipidemia’s multifactorial pathogenesis involves gene-environment-microbiota crosstalk, with gut microbiota (GM) emerging as a master regulator of lipid homeostasis through lipopolysaccharide-induced very low-density lipoprotein overproduction, short-chain fatty acid-G protein-coupled receptor signaling, bile acid-farnesoid X receptor/Takeda G protein-coupled receptor 5 axis modulation, and microbiota-host non-coding RNA crosstalk. This review delineates GM-dyslipidemia interactions, molecular mechanisms, and interventions such as probiotics, prebiotics and fecal microbiota transplantation. Key challenges involve establishing causal GM-lipid pathway links and optimal intervention timing. Advancing precision therapies require longitudinal multi-omics integration coupled with gnotobiotic validation models, ultimately enabling machine learning-driven prediction of personalized microbial signatures for targeted cardiovascular prevention.

INTRODUCTION

Lipid metabolism governs fundamental biological processes, including lipid assimilation, lipoprotein trafficking, and steroid hormone synthesis. Dyslipidemia is a pathological state characterized by elevated triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL) cholesterol (LDL-C) levels, and/or reduced high-density lipoprotein cholesterol (HDL-C) levels. In > 50% of the global adult population, this disorder accounts for approximately 33% of the annual ischemic heart disease mortality and is frequently comorbid with obesity and metabolic syndrome (MetS)[1]. The persistent residual cardiovascular risk in statin-treated patients underscores the urgent need for innovative therapeutic paradigms[1].

The gut microbiota (GM), an evolutionarily conserved ecosystem harboring trillions of microorganisms, has recently been recognized as a master conductor of lipid metabolism[1]. Phylogenetic analyses revealed Firmicutes and Bacteroidetes as the dominant phyla in healthy adults, with developmental trajectory studies demonstrating stage-specific colonization patterns: Neonatal dominance of Enterobacteriaceae and Staphylococcus transitions to Bifidobacterium enrichment until weaning, ultimately maturing into a geography- and diet-modulated steady state[2]. Enterotype classification (e.g., Bacteroides- vs Prevotella-dominant clusters) further correlates with metabolic phenotypes, whereas dyslipidemia-associated dysbiosis manifests as reduced α-diversity and altered Firmicutes/Bacteroidetes (F/B) ratios, particularly Bacteroides depletion, impairing cholesterol catabolism[3,4].

In addition to their taxonomic composition, the GM exerts systemic endocrine regulation through bioactive metabolites that interact with host physiology, including pro-inflammatory lipopolysaccharide (LPS)[1], short-chain fatty acids (SCFAs) that modulate hepatic lipogenesis[5], trimethylamine/trimethylamine-N-oxide (TMAO), which influences reverse cholesterol transport (RCT)[6,7], secondary bile acids (BAs) that regulate farnesoid X receptor (FXR)/Takeda G protein-coupled receptor 5 (TGR5) signaling[8], and cross-kingdom non-coding RNA (ncRNA) communication. Notably, emerging studies have demonstrated bidirectional crosstalk between the GM and circadian rhythms in the regulation of lipid metabolism[9-12]. Specifically, circadian disruption induces GM dysbiosis characterized by the loss of rhythmic taxa, altered BA rhythms, and impaired SCFA cycling, whereas high-fat diets (HFDs) suppress microbial oscillations as well. Causal relationships are evidenced by the resistance of germ-free (GF) mice to diet-induced dyslipidemia and the ability of fecal microbiota transplantation (FMT) to transfer atherogenic phenotypes[13]. These findings underscore the dual role of the GM as both a metabolic modulator and a therapeutic target[1,14]. While 16S rRNA sequencing establishes taxonomic associations, integrated multi-omics (metatranscriptomics-metaproteomics-metabolomics) now decodes functional microbial contributions to lipid dysregulation[15,16]. However, certain critical challenges persist: (1) Causality delineation: Overreliance on observational human studies; (2) Confounder control: Host genetics, diet, and medications masking microbial signals; and (3) Therapeutic translation: Strain-specific effects and microbiota engineering safety.

This review focuses on bidirectional GM-lipid axis interactions, molecular mechanisms linking microbial metabolites to lipidogenic pathways, and emerging interventions spanning precision probiotics, prebiotics, and metabolically optimized FMT. By bridging microbial ecology with host pathophysiology, we propose a roadmap for developing microbiota-centric strategies that complement conventional therapies, thereby addressing unmet needs in residual cardiovascular risk management through targeted microbial reprogramming.

FACTORS INFLUENCING DYSLIPIDEMIA AND GM

The GM is as a dynamically balanced supraorganism shaped by host-environmental co-dependencies, with its taxonomic architecture and metabolic output governed by host genetics, developmental stage, dietary patterns, lifestyle factors, pharmacological exposures, and ecological memory from prior microbial perturbations (Figure 1)[15,17]. Crucially, these confounders exhibit hierarchical interactions, necessitating multivariate adjustment in study designs to isolate authentic microbiota-dyslipidemia associations. This paradigm-shifting discovery centers on the GM’s mediation of obesity-dyslipidemia crosstalk. Central adiposity (waist-to-hip ratio > 0.9 in men/0.85 in women), independent of body mass index (BMI), elevates dyslipidemia risk, potentially through adipose-derived inflammatory cytokines that impair lipid homeostasis; however, the GM actively modulates this pathophysiology via the diet-microbiota-adipose axis, transgenerational metabolic memory, and ecological resilience loss[18]. Notably, the disease specificity of these microbial alterations remains enigmatic, e.g., causal vs compensatory; thus, resolution requires longitudinal multi-omics cohorts tracking GM trajectories from dyslipidemia initiation through progression.

Figure 1 Host-environment co-dependencies shaping the gut microbiota-lipid metabolism axis. The gut microbiota function as a dynamic meta-organism whose composition and metabolic activity are differentially regulated by host genetic factors and environmental modulators, including lifestyle factors, dietary patterns, pharmacological exposures, and circadian rhythms, which are also potent regulators of lipid metabolism.

Dietary modulation of the GM and lipid homeostasis

Dietary patterns exert profound enterotype-specific influences on the gut microbial architecture and metabolic function. Chronic consumption of high-fat/Low-fiber diets favors Bacteroides-dominant ecosystems optimized for mucin degradation and saturated fatty acid (SFA) metabolism, whereas fiber-rich regimens promote Prevotella-enriched consortia specialized in complex polysaccharide fermentation[19]. This nutritional program demonstrates temporal stratification: Short-term dietary interventions (e.g., 5-day animal-based protocols) induce transient blooms of bile-tolerant genera (Alistipes, Bilophila, Bacteroides) accompanied by depletion of fiber-utilizing taxa, yet these shifts largely revert within several days of intervention cessation[20]. However, nutritional modifications during critical developmental windows (prenatal to early postnatal stages) can persistently reshape the microbial community[21]. This restructuring occurs through epigenetic imprinting mechanisms affecting both the host intestinal epithelia and the resident microbiota[21].

HFDs and their multifaceted impact on the GM and lipid metabolism: HFDs function as dual metabolic regulators, serving both as essential nutritional substrates and potent disruptors of lipid homeostasis. While dietary lipids constitute fundamental components of the cellular architecture and signaling networks, chronic overconsumption of SFAs and trans fatty acids and cholesterol directly perturbs systemic lipid homeostasis, establishing a causal link to dyslipidemia through microbiota-mediated and independent pathways[22,23]. The GM emerges as a central biological transducer in this process, orchestrating bidirectional crosstalk between dietary lipid intake and host metabolic regulation. Sustained HFD exposure drives substantial ecological restructuring of the GM ecosystem, characterized by a marked reduction in microbial diversity alongside selective enrichment of bile-tolerant taxa and depletion of fiber-fermenting consortia[20]. Functional metagenomic analyses revealed that this compositional shift precipitated a metabolic transition from carbohydrate fermentation dominance to proteolytic metabolism dominance, whereas the results of the GF mouse experiments confirmed that this transformation worsened HFD-induced adiposity in the context of dysbiosis microbiota transplantation[24].

The intestinal barrier is profoundly affected by HFD-induced microbial dysregulation. Through coordinated mechanisms involving depletion of butyrogenic Bifidobacterium populations, expansion of sulfate-reducing taxa, and proliferation of endotoxin-producing Enterobacteriaceae, HFDs instigate a cascade of epithelial dysfunction[25]. These alterations synergistically compromise intestinal barrier integrity, as evidenced by the downregulation of tight junction proteins [including occluding and zonula occludens-1 (ZO-1)] and elevated systemic LPS levels, establishing a pro-inflammatory milieu conductive to metabolic endotoxemia[26]. Microbial signature analysis further revealed specific taxon-phenotype correlations, with Lactobacillus abundance inversely correlated and Oscillobacter positively associated with intestinal hyperpermeability in HFD-fed models[26].

Dietary lipid composition critically influences microbial interactions and metabolic effects. Studies have shown that lard-based SFA diets promote pro-inflammatory Bilophila wadsworthia; in contrast, marine omega-3 polyunsaturated fatty acids enrich beneficial taxa such as Lactobacillus, Bacteroides, Akkermansia, and Coprococcus, while increasing fecal butyrate and isovalerate levels[27]. Modern dietary imbalances in omega-6/omega-3 ratios disrupt these protective mechanisms, although microbial biotransformation of polyunsaturated fatty acids offers compensatory pathways[22]. For example, GM-mediated conversion of linoleic acid to 10-hydroxy-cis-12-octadecenoic acid activates G protein-coupled receptor (GPR) 40/120 signaling, stimulating glucagon-like peptide-1 (GLP-1) secretion, enhancing gut motility and reducing lipid absorption, whose effects are transmissible via FMT[22].

Emerging nutritional interventions leverage lipid structure-specific microbial modulation. Camellia seed oil, which is rich in monounsaturated fatty acids, provides dual benefits by enriching beneficial GM taxa (Dubosiella, Lactobacillus, and Alistipes). It also improves lipid profiles by inhibiting mammalian target of rapamycin signaling, a key regulator of lipid metabolism through sterol regulatory element-binding protein 1 activation[28,29]. Similarly, sea buckthorn juice and algal-derived fibers ameliorate hyperlipidemia and adiposity by selectively promoting beneficial taxa and SCFA producers[24,30]. These findings collectively underscore the therapeutic potential of structure-guided dietary strategies targeting the GM-lipid metabolism axis.

Insights from Mediterranean and plant-based dietary patterns: The Mediterranean diet (MD) is characterized by high intake of plant-based foods (fruits, vegetables, nuts, and legumes), extra-virgin olive oil, and moderate wine consumption, with minimal animal products. Long-term MD adherence (> 5 years) shows unparalleled cardiovascular protection reducing cardiovascular disease incidence in cohort studies[31,32]. Beyond direct nutrient-mediated benefits, MD cultivates a cardioprotective GM signature through an enrichment of butyrogenic Faecalibacterium prausnitzii and Roseburia, and suppression of pro-inflammatory species Ruminococcus gnavus and Collinsella aerofaciens[33,34]. This microbial ecology drives metabolic benefits by increasing fecal SCFA levels and decreasing atherogenic TMAO production[21,34]. Randomized trials confirm that MD-induced reduction in TC and LDL-C strongly correlate with improved microbial gene richness and BA pool remodeling[21,34].

Plant-based dietary models, particularly strict vegan regimens, induce Prevotella-dominant enterotypes associated with leanness and enhanced SCFA production[35]. Fiber subtype specificity governs microbial modulation: Insoluble wheat bran selectively enriches Lactobacillus and Bifidobacterium, whereas resistant starch from whole grains promotes Eubacterium rectale and Roseburia while suppressing Clostridium and Enterococcus[36,37]. Paradoxically, excessive fructose intake in plant-heavy diets may counteract these benefits, inducing GM dysbiosis and impairing intestinal barrier function, ultimately triggering hepatic Kupffer cell activation and inflammation.

Central to these dietary patterns is microbiota-accessible carbohydrate (MAC) availability. Western diets with chronic MAC deprivation drive transgenerational loss of Bacteroidales and Clostridiales, creating ecological voids resistant to short-term fiber intervention[18]. Strikingly, combinatorial MAC restoration with targeted missing-taxa supplementation achieves certain degree of recovery of GM ecological balance compared to traditional diets, highlighting the therapeutic potential of precision microbial rehabilitation[18]. These findings position dietary fiber not merely as a microbial substrate but as an ecological engineering tool for GM reprogramming.

Obesity as a critical modulator of GM and lipid metabolism

Host weight stability exerts profound regulatory effects on gut microbial ecosystems, with weight fluctuations demonstrating greater impacts on microbial composition than temporal variations alone[38]. In individuals with stable weights and lifestyles, the GM profiles show remarkable stability over time[38]. These microbial communities remain consistent for more than 3 months and potentially up to five years, indicating that the host metabolic state is a key determinant of microbial ecology[38]. This interdependence holds clinical significance in obesity, which disrupts lipid metabolism through multiple pathways. Key dysregulation features include hepatic very LDL (VLDL) overproduction, impaired lipoprotein lipase (LPL) activity, LDL receptor downregulation, reduced HDL-C levels, and dysfunctional lipid transport via cholesteryl ester transferase protein/phospholipid transfer protein axis alterations[39].

Obesity is closely linked to GM dysbiosis, which is characterized by reduced microbial diversity and taxonomic shifts, including depletion of beneficial genera (Bacteroides, Prevotella, Lactobacillus, Bifidobacterium, Akkermansia) and expansion of pro-inflammatory taxa (Clostridium, Staphylococcus, and Escherichia)[40-42]. A key feature of this dysbiosis is an elevated F/B ratio, which contributes to obesity progression by disrupting energy homeostasis, promoting fat storage, modulating appetite, and inducing chronic low-grade inflammation[43]. Cross-species evidence supports the F/B ratio as a conserved obesity signature, with metabolically compromised individuals (e.g., obese women) showing positive correlations between the F/B ratio and atherogenic lipids (TC, LDL-C), as well as inverse associations with fecal SCFA[41,44]. Fecal transplantation studies further confirmed the causal role of the GM in adiposity regulation, demonstrating that obesity-associated microbiota can transfer metabolic dysfunction, affecting GM harvest efficiency and fermentative capacity, as well as promoting chronic inflammation[41,44]. Weight loss interventions (e.g., caloric restriction and bariatric surgery) partially reverse obesity-associated dysbiosis, typically reducing Firmicutes while increasing Bacteroidetes[45]. However, the diagnostic utility of F/B ratio remains inconsistent due to heterogeneous study designs, population-specific variables, and clinical confounders (e.g., obesity severity and intervention duration). Despite these discrepancies, MetS is consistently associated with elevated F/B ratios across multiple studies[42,44], suggesting its potential as a context-dependent biomarker. Therapeutic strategies targeting GM modulation, such as probiotics, prebiotics, and FMT, may help restore a balanced F/B ratio and mitigate obesity-related metabolic dysfunction[43].

The GM actively modulates adipose biology through diet-microbe-host crosstalk, functioning as an environmental amplifier during the multifactorial pathogenesis of obesity. Current evidence reveals three key mechanisms, including LPS-mediated inflammation, SCFA signaling, and BA axis regulation. The development of targeted microbiota therapies for obesity-related dyslipidemia will require standardized multi-omics approaches to clarify these complex interactions.

Medications as modulators of GM and metabolic health

Antibiotics as a double-edged sword: While indispensable for infection control, antibiotics induce profound GM perturbations through biodiversity loss and selection of resistant pathogens[46]. Early-life exposure to antibiotics exerts particularly durable effects, disrupting microbial colonization patterns and increasing lifelong risks of obesity and metabolic dysfunction, while these developmental programming effects are synergistically exacerbated by concurrent HFD co-exposure[47,48]. Cumulative antibiotic courses progressively deplete low-abundance taxa and impair microbial functions that are essential for lipid metabolism, with subtherapeutic antibiotic exposure recapitulating obesity-associated GM profiles characterized by Firmicutes enrichment and Bacteroidetes depletion[46]. These shifts correlate with enhanced energy harvest and adipogenesis, positioning antibiotics as inadvertent metabolic disruptors necessitating judicious clinical use[49].

Metformin as a microbiota-mediated metabolic regulator: The first-line antidiabetic agent metformin demonstrates GM-dependent lipid modulation through selective enrichment of beneficial Akkermansia and functional enhancement of butyrate synthesis and carbohydrate metabolism[50,51]. Clinical trials reveal metformin-herbal combinations increasing Blautia and Faecalibacterium abundances alongside lipid profile improvement in dyslipidemic diabetics[50], paralleled by rodent studies showing metformin counteracts HFD-induced dysbiosis[52]. FMT from metformin-treated donors improve glucose tolerance in GF mice, mechanistically linked to altered fatty acid metabolism and antimicrobial activity[53].

Statins lowering cholesterol with microbial implications: Statins, while primarily acting via HMG-CoA reductase inhibition to lower LDL-C, exhibit microbiota-mediated pleiotropic effects[16,54-56]: (1) Microbial secondary BAs modulate simvastatin bioavailability and LDL-C reduction efficacy; (2) Pregnane X receptor signaling mediates statin-induced restoration of microbial diversity and BA metabolic modulation; and (3) Bacteroidetes elevation and Faecalibacterium reduction correlate with statin-mediated metabolic improvements. Rodent models further demonstrate statins alter butyrate-producing taxa and inflammatory pathways, suggesting GM modulation contributes to both therapeutic and adverse effects[57].

Current evidence positions medications as potent GM modulators with cascading metabolic consequences. Critical knowledge gaps persist in understanding precise drug-microbiota interaction mechanisms, individual response heterogeneity, and direct microbial contributions to therapeutic outcomes. While microbial profiling holds promise for personalized pharmacotherapy, clinical translation requires mechanistic validation through standardized multi-omics approaches[39]. Prioritizing these investigations will enable harnessing GM’s therapeutic potential in dyslipidemia management.

Circadian rhythms and the GM: A bidirectional regulatory axis in metabolic health

Circadian rhythms are regulated by hypothalamic suprachiasmatic nucleus-driven transcriptional-translational feedback loops. These rhythms coordinate physiological processes from thermoregulation to lipid homeostasis through core clock genes, such as circadian locomotor output cycles kaput and brain and muscle-ARNT-like 1, which form heterodimers that activate period and cryptochrome[10,58]. These endogenous 24-hour oscillations synchronize peripheral tissues (e.g., liver, adipose, and gastrointestinal tracts) with environmental light-dark cycles, precisely regulating nutrient absorption dynamics and microbial metabolic activity[58,59]. Clinical studies have identified circadian misalignment (e.g., shift work) as an independent risk factor for dyslipidemia and obesity[11,12]. The risk associated with hypercaloric diets, while chronotherapies such as time-restricted feeding, shows metabolic benefits even under HFD conditions[11,12].

The GM engages in reciprocal regulation with the host circadian system through synchronized diurnal oscillations in composition and function[9]. Disruption of host rhythms via sleep deprivation, erratic feeding, or genetic clock disruption induces GM dysbiosis characterized by depletion of beneficial taxa and expansion of pro-inflammatory genera[10,60,61]. Conversely, over 20% of microbial genes show intrinsic rhythmicity, which is directly modulated by host-derived circadian signals[11,12,60]. Specific taxa (e.g., Lactobacillus and Klebsiella) program host metabolism through hepatic gene regulation and systemic metabolite fluxes (e.g., SCFAs and secondary BAs)[11,12,60].

Environmental perturbations exert profound effects on this circadian-microbiota axis: Chronic HFD exposure abolishes microbial rhythmicity, elevates F/B ratios, suppresses Verrucomicrobia and dysregulates hepatic clock gene expression, whereas antibiotic-induced eradication of oscillating microbiota exacerbates circadian disruption, manifesting as metabolic dysfunction (e.g., adiposity and glucose intolerance)[10,61]. Genetic evidence from brain and muscle-ARNT-like 1 knockout mice confirms the indispensability of the host circadian machinery, demonstrating the complete loss of microbial and metabolic rhythms irrespective of dietary input[11,59]. This bidirectional dysregulation establishes a self-reinforcing cycle: GM dysbiosis amplifies host metabolic disturbances (e.g., insulin resistance and dyslipidemia), whereas circadian dysfunction perpetuates microbial instability, clinically presenting as atherogenic lipid profiles, progressive weight gain and hepatic steatosis[11,59].

The evolutionary conservation of this axis underscores temporal synchrony as a prerequisite for metabolic health. Therapeutic strategies targeting circadian-microbiota crosstalk, including timed feeding protocols and microbial metabolite supplementation, have the potential to restore host-microbial rhythmicity, offering novel mechanistic avenues for metabolic disease management. The preservation of circadian integrity through chrononutrition and microbiota-directed interventions may thus constitute a critical frontier in combating global metabolic disorder epidemics[12].

MECHANISTIC OVERVIEW OF SYETEMIC LIPID REGULATION AND GM CROSSTALK

The liver operates as the metabolic command center governing systemic lipid homeostasis through an intricate balance of de novo lipogenesis converting excess carbohydrates to fatty acids, VLDL assembly, TG transport, and mitochondrial β-oxidation regulating fatty acid catabolism (Figure 2)[62-64]. These coordinated pathways normally distribute fatty acids into structural components (phospholipids and cholesterol easters) and signaling molecules. Dyslipidemia develops when this balance is disrupted, manifesting in excessive fatty acid synthesis, diminished catabolic capacity, and impaired peripheral lipid clearance, ultimately resulting in the production of atherogenic lipoproteins[65,66].

Figure 2 Schematic illustration of gut microbiota and lipid metabolism interactions. Different pathways have been proposed for the influences of gut microbiota (GM) on systemic lipid metabolism. The liver operates as the metabolic command center governing systemic lipid homeostasis through an intricate balance of de novo lipogenesis converting excess carbohydrates to fatty acids, very low-density lipoprotein assembly, triglyceride transport, and mitochondrial β-oxidation regulating fatty acid catabolism. Parallel to hepatic regulation, GM engages in systemic lipid modulation through bidirectional molecular dialogues. Microbial structural components such as lipopolysaccharide translocate across the intestinal barrier, activating host pattern recognition receptors including toll-like receptors. These interactions trigger pro-inflammatory or immunomodulatory cascades. Concurrently, GM-derived metabolites such as short-chain fatty acids and bile acids exert multifaceted regulatory effects, and molecular mechanisms of short-chain fatty acids center on G protein-coupled receptor networks, with interactions stimulating anorexigenic hormone secretion, while trimethylamine N-oxide exacerbates atherosclerosis through foam cell formation. SCFAs: Short-chain fatty acids; PC: Phosphatidylcholine; BAs: Bile acids; GPR: G protein-coupled receptor; TMA: Trimethylamine; FXR: Farnesoid X receptor; LPS: Lipopolysaccharide; GLP-1: Glucagon-like peptide-1; PYY: Peptide YY; FGF: Fibroblast growth factor; TLR: Toll-like receptor; NF-κB: Nuclear factor-kappa B; PPAR: Peroxisome proliferator-activated receptor; NDL: De novo lipogenesis; TMAO: Trimethylamine N-oxide; FMO3: Flavin monooxygenase 3; CYP7A1: Cholesterol 7α-hydroxylase; FAs: Fatty acids; VLDL: Very low-density lipoprotein; TG: Triglyceride; LDL: Low-density lipoprotein; HDL: High-density lipoprotein.

Parallel to hepatic regulation, the GM engages in systemic lipid modulation through bidirectional molecular dialogues. Microbial structural components such as LPS and extracellular polysaccharides translocate across the intestinal barrier, activating host pattern recognition receptors, including membrane-bound toll-like receptors (TLRs) (e.g., TLR2/4/5) on intestinal epithelial surfaces and endosomal TLR3/7/9 in immune cells[67]. These interactions trigger pro-inflammatory or immunomodulatory cascades that perturb hepatic LDL receptor recycling and HDL maturation. Concurrently, GM-derived metabolites exert multifaceted regulatory effects: SCFAs and BAs increase hepatic fatty acid oxidation, VLDL secretion, and cholesterol flux, whereas TMAO exacerbates atherosclerosis through foam cell formation[67]. A third layer of regulation emerges through microbial extracellular vesicles (EVs), which traverse the gut-liver axis via systemic circulation. These nanoscale carriers deliver bioactive cargo, such as microbial microRNAs (miRNAs) and proteins, to local intestinal cells and distant organs, including hepatocytes, where they epigenetically reprogram lipidogenic genes and post-translationally modify metabolic enzymes, thereby reshaping lipid flux[68,69]. This tripartite communication system, encompassing structural component signaling, metabolite-driven regulation, and EV-mediated genetic reprogramming, establishes the GM as a master regulator of systemic lipid homeostasis, with dysbiotic perturbations directly contributing to dyslipidemia pathogenesis.

Insights into gram-negative opportunistic bacteria in the pathogenesis of dyslipidemia

Gram-negative opportunistic bacteria and their endotoxin byproducts constitute an important pathophysiological axis in metabolic dysregulation, with LPS emerging as a potent mediator linking GM dysbiosis to dyslipidemia. Under physiological conditions, LPS remains sequestered within the intestinal lumen by zonulin-1/occluding-mediated tight junction integrity[70]. HFDs, circadian disruption, or microbial imbalance impair gut barrier function, allowing the translocation of LPS into the circulation, a condition called metabolic endotoxemia[60]. This elevates plasma LPS levels several-fold, activating pattern recognition receptors (e.g., TLR-4, CD14, and nucleotide-binding oligomerization domain 1) on macrophages and dendritic cells[60]. This initiates a self-perpetuating inflammatory cascade: Nuclear factor-kappa B activation downregulates intestinal tight junction proteins while inducing fasting-induced adipose factor (FIAF), an endogenous LPL inhibitor that promotes ectopic lipid deposition in adipose and muscle tissues[71]. Preclinical models have demonstrated that LPS-mediated metabolic dysregulation occurs through coordinated pathways[72]. Chronic LPS administration in mice recapitulates the atherogenic lipid triad, specifically elevated TG levels, increased LDL-C levels, and reduced HDL-C levels, via TLR2/4-dependent mechanisms that impair hepatic VLDL clearance and suppress adipose LPL activity[73].

Clinical investigations corroborate these preclinical findings, revealing elevated abundances of endotoxin-producing bacteria and circulating LPS levels in obese individuals, which strongly correlate with atherogenic lipid profiles and chronic low-grade inflammation[74,75]. Fei and Zhao[76] reported that a traditional whole-grain Chinese diet with prebiotics reduced the abundance of Enterobacter (a potent endotoxin producer) from 35% to undetectable levels in an obese diabetic patient. This intervention resulted in dramatic metabolic improvements, including 51.4 kg weight loss (from 174.8 kg baseline), better lipid profiles, and reduced endotoxemia[76]. GF mice colonized with the patient’s isolated Enterobacter cloacae B29 strain developed HFD-dependent metabolic dysfunction characterized by elevated serum LPS, adipose inflammation, and dyslipidemia, effects that are absent in chow-fed counterparts[76].

These findings establish a mechanistic paradigm in which endotoxin-producing bacteria drive dyslipidemia through barrier disruption followed by metabolic endotoxemia, TLR-induced systemic inflammation, and FIAF-mediated lipid partitioning[76]. Future research must delineate strain-specific endotoxin production kinetics and develop targeted strategies to disrupt this pathophysiological axis, potentially through precision dietary interventions or anti-endotoxin therapies.

GM-derived SCFAs: Multifunctional metabolic regulators

SCFAs, the major microbial fermentation products of non-digestible carbohydrates (e.g., pectin, hemicelluloses, and galactose-oligosaccharides), are predominantly acetate (60%), propionate (20%) and butyrate (20%)[77,78]. SCFA synthesis is fiber dependent, with daily production ranging from 400 to 800 mmol, and is influenced primarily by the quantity and composition of dietary fiber (e.g., β-glucan in oat bran and resistant starch in legumes yield the highest output)[77]. In vitro fermentation of ileostomy effluent confirmed the presence of 120-420 mmol acetate per day, validating fermentation efficiency[79]. In addition, an estimated 50-60 g/day of fermentable carbohydrates generate 500-600 mmol of SCFAs[80]. SCFA concentrations exhibit significant spatial and metabolic gradients along the gastrointestinal tract and systemic circulation. In sudden-death autopsies, luminal SCFA levels were 10-fold higher in the cecum (131 mmol/kg) than in the ileum (13 mmol/kg), with regional variations in the colon: Ascending (123 mmol/kg), transverse (117 mmol/kg), descending (80 mmol/kg), and sigmoid colon (100 mmol/kg)[77]. These differences reflect progressive microbial fermentation and absorption along the intestinal tract. In addition, a steep concentration gradient exists from the intestinal lumen and portal circulation to the peripheral blood, resulting in varying levels of cellular exposure to SCFAs, dictating SCFA bioavailability[81]. Colonocytes metabolize the majority of luminal SCFAs for energy, and surplus SCFAs enter the hepatic portal vein where concentrations (375 μmol/L) are 5-fold higher than those in the peripheral blood (79 μmol/L), confirming gut-derived production[80]. Hepatic extraction further reduces SCFA levels to 148 μmol/L (39% of portal blood), reflecting first-pass metabolism[82]. Specifically, during major upper abdominal surgery, acetate reaches the highest peripheral concentration (19-160 μmol/L), followed by propionate (1-13 μmol/L) and butyrate (1-12 μmol/L), reflecting differential absorption and hepatic processing[83,84]. Moreover, resistant starch supplementation (30 g/day) elevates postprandial acetate (up to 280 μmol/L) and propionate (13 μmol/L) levels, demonstrating diet-dependent modulation of SCFA bioavailability[85]. Most importantly, GM taxonomic profiling revealed distinct production patterns: Bacteroidetes preferentially generate acetate and propionate, whereas Firmicutes are key butyrate producers[86]. At the genus level, acetate production is associated with Streptococcus, Prevotella, Bifidobacterium, Clostridium and Akkermansia muciniphila; propionate synthesis with Bacteroides, Salmonella, Dialister, Veillonella, Roseburia, Coprococcus, and Blautia; and butyrate with the Lachnospiraceae and Ruminococcaceae families[87,88].

SCFAs regulate host metabolism through three interconnected mechanisms[88-90]. At the local colonic level, SCFAs serve as essential energy substrates for epithelial cells, while butyrate specifically enhances intestinal barrier integrity through the modulation of tight junctions and mucus production. Systemically, the portal circulation distributes SCFAs to peripheral tissues, where they profoundly influence hepatic TG metabolism, cholesterol metabolism, and adipocyte lipogenesis. Additionally, SCFAs function as endocrine signaling molecules, regulating appetite and energy expenditure through free fatty acid receptor (FFAR)-mediated pathways. The biological effects of SCFAs are mediated primarily through GPRs, particularly FFAR2 (GPR43) and FFAR3 (GPR41). These SCFA-sensing receptors are widely distributed across enteroendocrine cells, adipocytes, sympathetic ganglia, and immune cells, underscoring their systemic signaling potential[91].

Each major SCFA has distinct metabolic fates and physiological roles: Acetate, which constitutes the largest proportion of SCFAs, undergoes peripheral oxidation, participates in adipocyte lipogenesis, or may be converted to butyrate by the GM[92]; butyrate preferentially serves as the primary energy source for colonocytes while simultaneously enhancing barrier function and suppressing local inflammation[93]; and propionate uniquely stimulates intestinal gluconeogenesis and promotes the secretion of anorexigenic hormones [GLP-1/2, peptide YY (PYY), leptin][44,91,94], while also exerting anti-adipogenic effects through visceral fat reduction[5].

The regulatory effects of SCFAs on lipid metabolism are particularly noteworthy[95]. Acetate and propionate collectively suppress endogenous lipolytic activity, with propionate additionally modulating circulating lipid levels through increased LPL expression[96,97]. These coordinated actions contribute to reduced plasma lipid concentrations and body weight regulation. In addition to their effects on lipid mobilization, SCFAs significantly influence adipocyte development. Experimental studies have demonstrated that propionate and acetate stimulate preadipocyte differentiation through the upregulation of FFAR2 and proliferator-activated receptor-gamma (PPARγ) pathways via GPR41/43 activation[98-100]. Furthermore, SCFAs impact cholesterol homeostasis through multiple mechanisms, including the facilitation of hepatic cholesterol uptake (by acetate, propionate, and butyrate) and the direct suppression of cholesterol biosynthesis (specifically by propionate)[101-103], processes that involve BA synthesis and microbial coprostanol conversion[104]. Notably, the majority of current research has focused on butyrate, which is typically present at undetectable or very low concentrations in the body, unlike acetate and propionate[91].

The metabolic impacts of SCFAs exhibit context-dependent characteristics[1]. While collectively contributing more than 10% of daily caloric requirements and generally improving lipid profiles, excessive acetate production may paradoxically elevate plasma TG and promote obesity through ghrelin-mediated hyperphagia[105,106]. The F/B ratio, often proposed as a microbial metabolic indicator, demonstrates species-specific complexity[78]. Murine models (ob/ob and GF mice) associate an elevated F/B ratio with increased SCFA production and energy harvest[107], whereas human studies present conflicting associations, with some reporting no differences between obese and lean individuals[108] and others demonstrating inverse correlations in overweight cohorts[109]. These discrepancies highlight the necessity for population-specific interpretation of microbial metrics and caution against oversimplification of GM-host metabolic interactions.

As master regulators of intestinal integrity, neuroendocrine signaling, and systemic lipid homeostasis, SCFAs represent promising therapeutic targets. However, their dualistic effects require precise modulation of concentration gradients, compositional ratios, and tissue-specific receptor activation patterns[91]. Translating these insights requires elucidating temporal dynamics and individualized responses to SCFA-mediated metabolic regulation.

TMAO: Linking the GM to metabolic dysregulation

The GM-derived metabolite TMAO has emerged as a pivotal mediator of cardiovascular pathology, counterbalancing the cardioprotective effects of SCFAs through distinct pro-atherogenic mechanisms. This pathogenic cascade begins when the GM metabolizes dietary phosphatidylcholine and L-carnitine into trimethylamine, after which hepatic flavin monooxygenase 3 (FMO3) then oxidizes trimethylamine to form TMAO[6,7]. Isotopic tracing confirmed that most circulating TMAO is derived from this microbial pathway. At the molecular level, TMAO exacerbates atherosclerosis through coordinated disruption of cholesterol homeostasis[6,110]: (1) Suppression of RCT, impairing cholesterol efflux from peripheral tissues; (2) Inhibition of BA transporter expression, reducing cholesterol catabolism; and (3) Potentiation of foam cell formation through macrophage scavenger receptor (CD36, SR-A1)-dependent uptake of oxidized LDL.

Preclinical models conclusively establish the causal role of TMAO: Chronic administration in mice elevates circulating atherogenic lipids[111], whereas FMO3 silencing enhances RCT and cholesterol clearance[112]. Clinical cohort studies corroborate these findings, demonstrating that individuals with combined high plasma L-carnitine and elevated TMAO levels exhibit increased cardiovascular risk, surpassing traditional LDL-C risk stratification[6]. Dietary regulation through vegetarian regimens mitigates TMAO production from L-carnitine through microbial composition modulation, highlighting microbiota-targeted nutritional interventions as viable preventative strategies[6,113].

Despite mechanistic clarity, therapeutic translation faces substantial barriers. While GF- and antibiotic-treated models abolish trimethylamine production[6], clinical trials reveal paradoxical outcomes: Broad-spectrum antibiotics reduce TMAO levels but concurrently induce microbial diversity loss and enrich antibiotic resistance genes without improving cardiovascular endpoints[19,114]. Precision targeting of trimethylamine-producing taxa remains technically challenging owing to functional redundancy across microbial consortia[113]. These limitations underscore the urgent need for the development of non-antibiotic approaches, such as competitive inhibition of microbial trimethylamine lyases or pharmacological FMO3 antagonism, to disrupt the TMAO axis while preserving the commensal ecology.

BAs as microbe-modulated metabolic regulators

BAs exemplify the GM’s capacity to generate metabolically beneficial compounds through structural modification of host-derived molecules[39]. Initiated by hepatic cytochrome P450-mediated conversion of cholesterol into primary BAs, cholic acid and chenodeoxycholic acid, this pathway serves dual roles in cholesterol catabolism and systemic metabolic regulation[115,116]. Following conjugation with glycine/taurine and biliary secretion, 90%-95% of primary BAs undergo efficient ileal reabsorption via apical sodium-dependent BA transporter-mediated enterohepatic circulation[117]. The residual 5% reaching the colon become substrates for microbial transformation through three sequential enzymatic processes, including bile salt hydrolase-catalyzed deconjugation, 7α-dehydroxylase-mediated generation of secondary BAs such as deoxycholic acid from cholic acid and lithocholic acid from chenodeoxycholic acid, and epimerization yielding tertiary BAs like ursodeoxycholic acid[115,117]. This microbial diversification creates a bioactive BA pool functioning as endocrine regulators through nuclear and membrane receptor networks, modulating energy expenditure, glucose homeostasis, and cholesterol balance[8,115].

The nuclear receptor (FXR, NR1H4) serves as the central coordinator of BA signaling, orchestrating tissue-specific metabolic responses. Hepatic FXR activation suppresses sterol regulatory element-binding protein 1c-driven lipogenesis and VLDL-C production, while increasing PPARα-mediated fatty acid oxidation and HDL-C synthesis[118]. Intestinal FXR stimulates fibroblast growth factor 15/19 secretion, which through hepatic fibroblast growth factor receptor 4/β-Klotho receptor complexes inhibits cholesterol 7α-hydroxylase, establishing a negative feedback loop regulating BA synthesis[119]. Notably, FXR exhibits pleiotropic microbial crosstalk, suppressing FMO3 to inhibit TMAO production while shaping the gut microbial composition[7]. The membrane G protein-coupled BA receptor 1 (TGR5) complements FXR signaling, with secondary BA-mediated TGR5 activation stimulating GLP-1 secretion and improving glucose tolerance[120]. Furthermore, BAs additionally engage diverse receptor systems including sphingosine-1-phosphate receptor 2, epidermal growth factor receptor, pregnane X receptor, and vitamin D receptor, enabling integrated metabolic and immune regulation[19,121].

This bidirectional BA-microbiota axis creates a self-regulating metabolic circuit[122]: Microbial BA transformation determines receptor activation states, while BAs reciprocally modulate microbial ecology through bacteriostatic effects[10,123,124]; besides, microbial BA transformations directly influence host lipid metabolism, as evidenced by FXR-mediated suppression of TMAO-producing taxa[7]. This circuit maintains metabolic homeostasis but presents therapeutic opportunities through FXR modulators (e.g., glycine-beta-muricholic acid)[125], TGR5 agonists, and probiotic intervention[126]. However, interspecies differences in BA metabolism necessitate caution when translating preclinical findings, particularly given murine-specific BA species like β-muricholic acid[125].

Regulation of fatty acid oxidation by the GM

Emerging evidence has established the GM as a pivotal regulator of systemic fatty acid metabolism through the dynamic modulation of energy harvesting and oxidative pathways. SFAs, recognized drivers of adipogenesis and hepatic steatosis, exert their metabolic effects in part by reshaping the GM composition to favor lipogenic pathways. The metabolic impact of the GM is further evidenced by GF mouse models, which exhibit resistance to diet-induced obesity through synergistic mechanisms, including increased hepatic β-oxidation and suppressed lipid storage via reduced LPL activity[127]. This protective phenotype arises from the ability of the GM to suppress adenosine monophosphate-activated protein kinase (AMPK) signaling, a key regulator of mitochondrial biogenesis and fatty acid catabolism, in skeletal muscle and liver. Microbial suppression of AMPK phosphorylation inhibits fatty acid transport into mitochondria and promotes ectopic lipid accumulation in adipose and hepatic tissues[128]. Concurrently, GM-mediated downregulation of FIAF, an endogenous LPL inhibitor, enhances adipocyte LPL activity, driving TG hydrolysis and white adipose tissue expansion[127]. Compared with lean donor recipients, GF mice receiving microbiota from obese donors develop significantly greater adiposity, accompanied by significant reductions in skeletal muscle AMPK activity and hepatic β-oxidation capacity[71,107]. These findings collectively demonstrate the ability of the GM to reprogram host energy partitioning, optimizing caloric harvest through the suppression of fatty acid oxidation and the potentiation of lipid anabolism. The intricate interplay between microbial ecology and fatty acid metabolism underscores the role of the GM as a metabolic rheostat, balancing energy expenditure and storage through molecular crosstalk involving AMPK-FIAF-LPL axis modulation. Therapeutic targeting of these pathways may offer novel strategies for MetS management.

NcRNAs as integrative mediators of host-microbiota metabolic crosstalk

NcRNAs have emerged as pivotal regulators of metabolic homeostasis, orchestrating complex host-microbiota interactions through epigenetic reprogramming and post-transcriptional gene silencing[129]. Within this regulatory landscape, miRNAs, long ncRNAs (lncRNAs), and circular RNAs (circRNAs) serve as molecular conduits bridging microbial ecology with host physiology. Bidirectional crosstalk occurs through two principal pathways: (1) GM regulate host ncRNAs that control intestinal barrier function and lipid metabolism; and (2) Host ncRNAs conversely shape microbial composition and activity, forming a regulatory loop important in metabolic disease[130-133]. The complexity of this interplay is amplified by microbial induction of epigenetic modifications such as m6A methylation, which intersect with ncRNA dynamics to drive metabolic dysregulation[134].

As about 22 nucleotide post-transcriptional silencers, miRNAs occupy a central position in host-microbe communications[135]. Intestinal epithelial cells secrete miRNAs into the lumen, where they are internalized by microbial cells via endocytosis, selectively modulating the bacterial gene expression through targeted mRNA degradation[136,137]. Conversely, GM-derived EVs deliver microbial miRNAs and metabolites that reprogram host barrier integrity and cholesterol metabolism[136,138]. For example, fecal miR-10b, miR-26, miR-27a/b, miR-30c, miR-33a/b, miR-106b, and miR-144 target genes govern RCT[132,139], whereas miR-122 downregulation is correlated with reduced plasma cholesterol and TG levels[140]. Microbial metabolites further refine this axis: Indole-3-propionic acid attenuate atherosclerosis by upregulating ATP-binding cassette transporter A1 expression through miR-142-5p inhibition, thereby enhancing macrophage RCT[141]; whereas protocatechuic acid inhibits miR-10b to increase ATP-binding cassette transporter A1/G1 expression[142]. In obesity, GM-driven ethanolamine metabolism defects increase miR-101a-3p expression via ARID3a activation, destabilizing ZO-1 mRNA and impairing intestinal barrier function[143], a phenotype reversible by Lactobacillus rhamnosus HL-200 through ARID3a/miR-101a/ZO-1 axis normalization[143]. Probiotic interventions, such as Lactobacillus fermentum/salivarius, further demonstrate therapeutic potential by upregulating barrier-protective miRNAs (miR-143/miR-150/miR-155/223)[144].

LncRNAs (> 200 nt) extend this regulatory paradigm through chromatin remodeling, transcriptional interference, and miRNA sponging[145,146]. GM metabolites dynamically modulate lncRNA networks. For instance, deoxycholic acid upregulates macrophage lncRNA 57RIK via sphingosine-1-phosphate receptor 2, potentiating caspase-4/11-dependent pyroptosis upon LPS stimulation[147]. Conversely, Roseburia intestinalis flagellin induces intestinal lncRNA HIF1A-AS2, suppressing nuclear factor-kappa B/c-Jun N-terminal kinase signaling and reducing colonic inflammation[148]. Microbial suppression of intestinal lncRNA Snhg9 reprograms lipid metabolism via PPARγ activation, altering systemic lipid absorption and storage in mice[149-151]. Such findings position lncRNAs as versatile mediators of microbial influence on host metabolism. CircRNAs further diversify this network through covalently closed loop structures that sequester miRNAs or scaffold metabolic enzymes[152,153]. Notably, GM-derived EVs function as essential interkingdom signaling mediators by delivering functional nucleic acids to host cells, thereby post-transcriptionally modulating gene expression in recipient cells. This vesicle-mediated genetic regulation mechanism establish a novel paradigm whereby commensal microorganisms directly orchestrate host physiological homeostasis at the molecular level[154,155].

The ncRNA-microbiota axis presents novel therapeutic opportunities. MiRNA-based strategies, such as mimics or anti-miRNA oligonucleotides, could correct dysregulated pathways in metabolic diseases, while lncRNA/circRNA modulation offers novel avenues for precision intervention. Moreover, fecal ncRNA profiling show promise as non-invasive biomarkers for dysbiosis-associated metabolic disorders[134]. However, interspecies differences in ncRNA conservation and tissue-specific expression patterns complicate this therapeutic translation. Future research must delineate spatiotemporal dynamics of microbial RNA transfer mechanisms and develop organoid-based models to accelerate clinical translation of ncRNA-targeted metabolic therapies.

THERAPEUTIC MODULATION OF GM IN DYSLIPIDEMIA MANAGEMENT

The GM has emerged as both a pathogenic mediator and therapeutic target in dyslipidemia management, with conventional interventions exerting profound yet bidirectional effects on microbial ecology (Figure 3). Lifestyle modifications, including caloric restriction and aerobic exercise, induce consistent shifts towards Bacteroides-Prevotella-dominant enterotypes while suppressing sulfate-reducing Enterobacteriaceae and Clostridium histolyticum/lituseburense populations, which are strongly correlated with restored microbial gene richness and improved lipid profiles[25]. In refractory obesity, bariatric surgery, such as Roux-en-Y gastric by-pass, drives dramatic microbial restructuring, expanding the anti-inflammatory Faecalibacterium prausnitzii and carbohydrate-fermenting Gammaproteobacteria while suppressing energy-harvesting methanogens[156]. These changes increase satiety hormone secretion (PYY, GLP-1) through microbial γ-aminobutyric acid/SCFA-mediated enteroendocrine activation[157]. Notably, the therapeutic potential of GM modulation is critically contingent on intervention timing. Early-life microbial exposure confers durable metabolic protection even against HFD-induced dyslipidemia by increasing brown adipose thermogenesis and suppressing hepatic lipogenesis, effects that attenuate post-adolescence but remain accessible during gestational microbial reprogramming windows[158]. Current strategies employ probiotics (Lactobacillus and Bifidobacterium strains) and prebiotics (inulin and resistant starches) to restore RCT and inhibit macrophage CD36-mediated foam cell formation[159]. However, efficacy requires precise reconstitution of depleted taxa and metabolic pathways rather than broad taxonomic changes, necessitating mechanistic validation of strain-specific effects through gnotobiotic models and metabolic profiling[46].

Figure 3 Therapeutic strategies targeting gut microbiota for dyslipidemia. The gut microbiota (GM) has emerged as a therapeutic target in dyslipidemia management. Lifestyle modifications, including caloric restriction and aerobic exercise, induce beneficial GM shifts, which are strongly correlated with restored microbial gene richness and improved lipid profiles. Current GM-targeting strategies employ probiotics (e.g., Lactobacillus and Bifidobacterium strains), prebiotics (e.g., inulin and resistant starches), and fecal microbiota transplantation. While, future synergistic design integrating probiotics, prebiotics or fecal microbiota transplantation with lifestyle intervention and pharmacotherapies may amplify strain-specific effects. FMT: Fecal microbiota transplantation.

Probiotics as precision modulators of metabolic homeostasis

Probiotics, defined by the Food and Agricultural Organization/World Health Organization as live microorganisms conferring health benefits when administered in adequate amounts, exert targeted effects on the gut microbial ecology and host metabolism through strain-specific mechanisms[160-163]. Clinical and preclinical studies have validated their therapeutic potential in dyslipidemia, with Lactobacillus and Bifidobacterium species demonstrating multifaceted benefits: Restoring intestinal barrier integrity, reducing adiposity, and attenuating systemic inflammation[164]. Meta-analyses further confirmed its lipid-modulating efficacy, showing that probiotic supplementation significantly lowered TC, LDL-C, and TG levels, particularly in younger individuals with elevated baseline BMIs[165].

Therapeutic outcomes potentially depend on strain specificity. Among the Lactobacillus strains, Lactobacillus rhamnosus CGMCC1.3724 induces sex-dependent weight loss in obese females[166], whereas GG improves dyslipidemia via GM restoration in murine models[167]. Cholesterol-lowering effects are pronounced in Lactobacillus plantarum strains: CECT7527-CECT7529 reduce TC and LDL-C levels in hypercholesterolemic humans[168], and CAI6/SC4 decreases serum TC levels in dyslipidemic mice[169], whereas their combination with Lactobacillus curvatus further reduces both serum and hepatic lipid accumulation in HFD-fed mice through conjugated linoleic acid production, leptin/fatty acid synthetase regulation, enhanced fatty acid oxidation, and angiopoietin like-4-mediated LPL inhibition[169,170]. Akkermansia muciniphila, which constitutes 1%-4% of the healthy colonic microbiota, represents a paradigm-shifting therapeutic candidate[171,172]. Its oral administration enhances intestinal barrier integrity, improves insulin sensitivity, and reduces visceral adiposity in both rodent models and human trials[55,173,174], with Akkermansia muciniphila-derived EVs recapitulating these benefits by reversing diet-induced cholesterol dysregulation and adipose inflammation[175,176]. Novel candidates, such as Alistipes (SCFA producers)[177] and Bacillus (cholesterol lowering via microbial richness modulation)[178], further expand the probiotic therapeutic options.

Polybiotic formulations demonstrate enhanced efficacy through synergistic interactions[165]. The 8-strain VSL#3 consortium (Streptococcus thermophilus, multiple Bifidobacterium and Lactobacillus strains) improved BMI and adiposity metrics[179], whereas Probio-X, enriched which Bifidobacterium animalis and Lactobacillus plantarum, effectively improved the serum lipid profile[180]. Similarly, Lactobacillus curvatus HY7601/Lactobacillus plantarum KY1032 combinations specifically lower serum TG in hypertriglyceridemic subjects[181], and Lactobacillus plantarum 9–41-A plus Lactobacillus fermentum M1-16 preferentially reduces TC levels in hypercholesterolemic models[182]. Compared with single-strain interventions, these formulations enhance the production of beneficial metabolites, such as SCFAs, and promote GLP-1 secretion, amplifying lipid-lowering effects[179,180].

Despite promising results, therapeutic variability persists due to confounding factors, including host genetics, baseline microbiota composition, and treatment duration. While probiotics modulate lipid metabolism, current evidence precludes their use as monotherapy for metabolic disorders, and only considers them as adjunctive therapies, leveraging GM modulation to support metabolic health without displacing pharmacological interventions[66,165]. Key challenges require solution include standardization of strain-specific dosing regimens, mechanistic dissection of host-microbe molecular crosstalk, and development of phenotype-guided formulations using metagenomics-metabolomics integration. Addressing these barriers will enable transition from empirical supplementation to precision probiotics targeting dyslipidemia pathophysiology through defined microbial effector networks.

Prebiotics as microbial modulators of host metabolism

Prebiotics, defined as non-digestible substrates selectively utilized by host microorganisms to confer health benefits, reshape gut microbial ecology through targeted nutritional supplementation. This class of compounds, including inulin, fructans, and galacto-oligosaccharides, serves as fermentable substrates for commensal bacteria, with inulin/fructans, naturally abundant in wheat, fruits, and vegetables, promoting beneficial taxa enrichment, and galacto-oligosaccharides exhibiting potent bifidogenic and butyrogenic properties[183]. In addition to taxonomic modulation, prebiotics amplify microbial metabolite production, strengthen intestinal barrier integrity, and regulate gut motility, positioning them as multifaceted tools for metabolic intervention[183]. Specifically, the therapeutic efficacy of prebiotics stems from their capacity to reconfigure microbial networks, reducing Firmicutes abundance while enriching Bacteroides, Bifidobacteria, Bifidobacterium, Lactobacillus, Prevotella, and Roseburia, a profile associated with improved insulin sensitivity and lipid metabolism[183-185]. At the neuroendocrine level, prebiotics stimulate anorexigenic hormone secretion (PYY and GLP-1) while suppressing ghrelin, collectively strengthening intestinal barrier integrity, regulating energy balance, reducing visceral adiposity, and attenuating chronic low-grade inflammation[184,185].

Emerging plant-derived prebiotics demonstrate targeted lipid modulation. Peanut skin extract exerts dose-dependent anti-dyslipidemic and anti-inflammatory effects in atherosclerotic mouse models, by enriching beneficial Roseburia, Rothia, Parabacteroides, and Akkermansia, and suppressing pro-inflammatory Bilophila and Alistipes[186]. Similarly, Dendrobium officinale elevate Akkermansia and Bifidobacterium, increase acetate/taurine production, lowering LDL-C and VLDL-C levels in HFD-fed mice, effects partially transmissible via FMT[187]. Moreover, barley-derived β-glucan demonstrates lipid-lowering efficacy correlating with increased Faecalibacterium, Bifidobacterium, Ruminococcaceae, and Lachnospira abundances[188]. Clinical meta-analyses confirm prebiotic/synbiotic interventions reduce TC and LDL-C in overweight dyslipidemic individuals, though TG modulation remains inconsistent[189,190]. Notably, the purified polysaccharide from alkali extraction and molecular sieve purification (PNS2A) from Phyllostachys nigra roots demonstrated significant hypoglycemic and anti-obesity effects by improving insulin sensitivity, modulating GM composition (increasing Lactococcus while reducing Escherichia-Shigella and Clostridia_UCG-014), and altering microbial metabolic pathways related to glycolipid metabolism (e.g., enriching toluene degradation I and II, and citrate transport pathways while suppressing lipogenesis)[191].

Current limitations include non-specific microbial modulation and interindividual variability in baseline microbiota and metabolic status[113]. Future formulations may combine prebiotics with targeted probiotics (e.g., Akkermansia muciniphila) to amplify strain-specific effects. While prebiotics demonstrate robust lipid-modulating capacity, clinical translation require resolving several critical challenges, including dose optimization across ethnicities, biomarker-driven algorithms matching prebiotic types to microbial signatures, and synergistic design integrating prebiotics with probiotics/pharmacotherapies. Advancements in multi-omics-guided intervention will enable transition from empirical to precision microbial therapeutics for metabolic disorders.

FMT: Therapeutic potential and challenges

FMT has revolutionized the treatment of recurrent or refractory Clostridioides difficile infection, achieving > 90% efficacy regardless of the administration modality (colonoscopic, nasogastric, or oral capsules), by reconstituting donor-like microbial communities with ecological stability[192-195]. Encapsulated formulations such as SER-109, a purified preparation of Firmicutes spores, have demonstrated non-inferior efficacy compared with traditional invasive methods while increasing patient compliance[196,197]. Since SER-109 exemplifies the promise of microbiome therapeutics, SER-109 might regulate host metabolism by regulating the GM composition; however, its metabolic applications require rigorous validation, and future studies should prioritize this topic[193]. In addition to refractory Clostridioides difficile infection, FMT shows exploratory promise in inflammatory bowel disease and metabolic disorders, although broader application necessitates standardized donor screening protocols, optimized preparation methods, and rigorous long-term safety monitoring for antibiotic resistance gene transfer risks[198].

Preclinical models illuminate the capacity of FMT to transfer metabolic phenotypes[1]: GF mice receiving conventional microbiota exhibit 60% increased adiposity and elevated hepatic de novo lipogenesis despite reduced food intake[71]. However, human trials have revealed only transient effects; lean donor FMT transiently increases butyrate-producing taxa in obese MetS recipients, but microbial profiles and metabolic parameters revert to baseline within 18 weeks[199]. Notably, multiple clinical trials reported no significant effects on body weight, resting energy expenditure, or enteroendocrine hormone levels, despite the observed increases in beneficial taxa such as Bifidobacterium pseudolongum and acetate production[199-201]. This dichotomy underscores the resilience of recipient microbial ecosystems and the need for adjunctive strategies. Combining FMT with lifestyle interventions (e.g., dietary modifications and physical activity) improves microbial engraftment, increasing beneficial taxa (e.g., Lactobacillus and Bifidobacterium) and enhancing lipid metabolism (e.g., lower TC and LDL-C)[202,203]. These benefits correlate with PPARα activation (α-hydroxy-3-methylvalerate), which reduces inflammation in both intermuscular and subcutaneous adipose tissue[202,203]. For example, GM modulation through dietary intervention and FMT significantly improved metabolic parameters, including blood glucose levels, lipid profiles, and blood pressure, in type 2 diabetic patients, with FMT inducing faster microbial shifts than diet alone. The abundance of beneficial bacteria (e.g., Bifidobacterium) increased and correlated negatively with glycemic/Lipid indices, whereas the abundance of sulfate-reducing bacteria (Bilophila, Desulfovibrio) decreased and was positively associated with hyperglycemia, suggesting that GM restructuring is a key mediator of metabolic improvement. The combined approach (diet plus FMT) accelerated weight loss and glycemic control, with a notable transition from Bacteroides- to Prevotella-dominant microbiota, suggesting a promising therapeutic strategy for type 2 diabetic and comorbid metabolic disorders[204]. These findings position FMT as both a therapeutic modality and a discovery platform for host-microbe metabolic crosstalk.

While current clinical trials have not consistently demonstrated the efficacy of FMT in individuals with obesity or MetS, baseline GM diversity may predict treatment responsiveness[199]. Successful microbial engraftment requires the resolution of three critical factors: (1) Engraftment variability: For example, conspecific strains exhibit superior colonization capacity compared with novel species; (2) Protocol standardization: There are persistent debates on fresh vs frozen preparations and no consensus on universal donor criteria; and (3) Safety optimization: Extended-spectrum beta-lactamase-producing Escherichia coli transmission risk demands improved pathogen screening[194,205-207]. Future research must prioritize large-scale trials assessing long-term engraftment stability and metabolic sequelae[1], and mechanistically optimize protocols through refined dosing strategies, engineered formulation or timed interventions synchronized to circadian metabolite rhythms[194,205,206]. Addressing engraftment dynamics and safety concerns through precision microbial ecology engineering will unlock its full potential in dyslipidemia management.

CONCLUSION

Decades of multidisciplinary research have unequivocally established the GM as a potent regulator of lipid metabolism, operating at the nexus of genetic predisposition, dietary patterns, and environmental exposures[1]. While multi-omics studies delineate characteristic dysbiotic signatures in dyslipidemia, critical knowledge gaps persist in distinguishing causal microbial taxa from epiphenomenal bystanders[25,39]. Current GM-targeted interventions, although mechanistically promising, face translational roadblocks: Probiotics/prebiotics transiently enrich beneficial taxa such as Bifidobacterium and Lactobacillus but fail to durably remodel microbial networks, whereas FMT results in variable engraftment and a lack of metabolic endpoint consistency[208,209].

Three paradigm-shifting opportunities have emerged: (1) Precision microbial consortia: Engineered assemblages combining several beneficial taxa to target atherogenic pathways; (2) Chronotherapeutic delivery: Time-restricted administration synchronized to host circadian metabolite oscillations; and (3) Artificial intelligence-driven personalization: Machine learning integration of metagenomic, lipidomic, and clinical data to predict individualized microbial therapy responses. Notably, personalized GM modulation must account for host genetic polymorphisms, baseline microbial ecology, and geographical variations while addressing ethical challenges in donor screening, long-term safety monitoring, and equitable access to microbiota-based therapies[210]. Realizing these potential demands requires coordinated efforts across microbiology, bioengineering, and computational biology to overcome ecological complexity and host-microbe reciprocity. Next-generation microbial therapeutics may ultimately bridge the gap between mechanistic promise and clinical reality in dyslipidemia management.