Gut microbiota-multi-organ axis and neuroinflammatory network: A potential integrative hub in aging and age-related diseases

Abstract

Population aging has emerged as a major global public health challenge. Increasing evidence suggests that the gut microbiota may serve as an important interface linking environmental exposures, host metabolism, and systemic health, and may be associated with aging and age-related diseases. Through multi-organ axes, including the gut-liver axis and gut-brain axis, the gut microbiota has been implicated in metabolic reprogramming, immune regulation, and neuroinflammation. This article summarizes current evidence on how the gut microbiota may influence aging through these multi-organ axes. We discuss the gut-liver axis as a potential metabolic conduit, the gut-brain axis as a candidate neuroimmune communication pathway, and neuroinflammation as a possible integrative link between peripheral disturbances and central nervous system dysfunction. Emerging observations suggest that aging may be characterized by nonlinear microbiota trajectories and functional enrichment in lipid metabolism pathways. Furthermore, we discuss the therapeutic potential of targeting microbial metabolism and highlight the unique advantages of traditional Chinese medicine in modulating gut microbiota through multi-component and multi-target mechanisms - while acknowledging that much of this evidence remains preliminary. Finally, we outline a conceptual framework for precision anti-aging strategies integrating microbiome science, multi-organ axis networks, and environmental factors, with the understanding that this framework is hypothesis-generating rather than clinically definitive.

Key Words: Gut microbiota; Aging; Gut-liver axis; Gut-brain axis; Neuroinflammation; Multi-organ axis; Traditional Chinese medicine

Core Tip: Recent studies have observed functional remodeling of gut microbiota during aging, particularly enhanced lipid metabolism pathways. This article discusses the gut-liver axis and gut-brain axis as potential bridges linking microbial alterations to host aging, with neuroinflammation potentially acting as an integrative hub. Targeting the “microbiota-multi-organ axis-neuroinflammation” network may provide potential directions for future research on healthy aging.

INTRODUCTION

Population aging has emerged as one of the most pressing public health challenges globally. Age-related disorders, including sarcopenia, cognitive decline, metabolic dysregulation, and cardiovascular and cerebrovascular diseases, not only profoundly diminish the quality of life in older adults but also impose a substantial socioeconomic burden. According to the China Cardiovascular Health and Disease Report 2024, the disease burden attributed to stroke accounts for over 25% of the total disease burden in China, a figure projected to escalate with the accelerating aging population[1]. Ischemic stroke, the predominant subtype, exhibits an age-standardized incidence rate of 135.8 per 100000 and a prevalence rate of 1018.8 per 100000[2], characterized by high morbidity, disability, mortality, and recurrence rates. Concurrently, sarcopenia, an age-related syndrome of progressive muscle loss, affects an estimated 9.8% of community-dwelling older adults in China[3], with prevalence soaring to 41% in nursing home populations[4]. Based on these prevalence rates, the total number of affected individuals in China is substantial and represents a significant public health challenge.

In recent years, a growing body of evidence suggests that the gut microbiota may act as an important interface linking environmental exposure, host metabolism, and systemic health, may contribute to the aging process[5,6]. The gut microbiota is not merely involved in nutrient digestion and absorption but actively engages in bidirectional communication with multiple host organ systems through its metabolites - such as short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and bile acids - forming a multi-organ axis network encompassing the “gut-liver axis”, “gut-brain axis”, and “gut-muscle axis”[7,8]. Dysbiosis of this network, characterized by gut microbial imbalance and consequent multi-system disturbances, is now recognized as a core mechanism driving aging and the pathogenesis of associated diseases.

Ischemic stroke has traditionally been understood as neuronal ischemia and necrosis resulting from focal cerebral vascular occlusion. However, modern systems biology research is catalyzing a fundamental shift in this perspective. Accumulating evidence suggests that ischemic stroke has been proposed to involve a systemic immune and metabolic cascade triggered by cerebral ischemia, although most evidence derives from acute disease models rather than normative aging studies, involving complex interactions across multiple organs[9,10]. The onset of cerebral ischemia frequently precipitates systemic effects, rapidly activating widespread immune-inflammatory and metabolic dysregulation. These systemic responses form a deleterious feedback loop with the focal brain injury, collectively determining the ultimate prognosis[9]. It is increasingly apparent that the “vessel-centric” therapeutic model inadequately addresses the systemic pathophysiological disturbances - consistent with a systems biology view - that are ignited by the initial “vascular event”. Expanding the therapeutic focus to encompass the systemic pathological network following ischemic stroke has therefore become an urgent necessity and a frontier direction for improving long-term outcomes.

Parallel to this, research on sarcopenia has undergone a similar paradigm shift. The recent emergence of the “gut-muscle axis” theory offers a novel perspective on the molecular mechanisms underlying sarcopenia, though current evidence is predominantly derived from disease or aged animal models. Chronic systemic inflammation, driven by gut microbial aging and immune-metabolic dysregulation, is recognized both as a “hallmark of aging” and a critical link in gut-muscle axis imbalance[11,12]. Building on this, the “aging microbiota-immune-metabolic network” hypothesis has been proposed, connecting the dynamic interplay between gut microbial senescence and macrophage immune-metabolic dysregulation, thereby enriching the conceptual framework of the traditional gut-muscle axis[13].

Notably, the inflammatory response following stroke constitutes a complex network involving multiple cell types and factors. For years, neuroprotective agents targeting single molecules have been translated into clinical practice with limited success. For instance, nerinetide, a novel peptide drug designed to inhibit excitotoxicity by targeting the postsynaptic density protein 95 protein, generated significant promise based on compelling preclinical data. However, subsequent large, rigorously designed randomized controlled trials - particularly those published in The Lancet in 2020[14] and 2025[15] - failed to meet their primary efficacy endpoints. A subsequent pooled analysis published in The Lancet Neurology in 2025 further clarified that, despite multidimensional exploratory analyses, multiple trials did not achieve their pre-specified primary outcomes[16]. This series of negative findings strongly suggests inherent limitations in the clinical translation of single-target neuroprotective strategies for improving outcomes in ischemic stroke, underscoring an urgent need for systemic intervention strategies that transcend single-target approaches.

This review aims to systematically elucidate the mechanistic network through which the gut microbiota may contribute to aging and related diseases via multi-organ axes. We will specifically focus on the role of the gut-liver axis in metabolic reprogramming, the critical involvement of the gut-brain axis in cognitive decline, and the function of the neuroinflammatory network as a central nexus connecting peripheral disturbances with central nervous system injury. Building on this foundation, we will further explore the unique value of the holistic regulatory philosophy inherent in traditional Chinese medicine (TCM) for microbiota-based interventions. Finally, we will discuss the prospects for a new paradigm in anti-aging research - one centered on the microbiome, integrating multi-organ axis networks, and developing precision, systems-level intervention strategies.

Scope and caveats

Throughout this review, we draw on evidence from both normative aging studies and age-related diseases (including stroke, sarcopenia, Alzheimer’s disease, and metabolic dysfunction). Readers should note that mechanisms validated in disease contexts may not fully recapitulate those operating in healthy aging. Where disease-specific evidence is cited to support aging-relevant mechanisms, we attempt to indicate this explicitly; however, the distinction is not always clear in the primary literature, and extrapolations should be interpreted with appropriate caution.

FROM LINEAR DECLINE TO ECOLOGICAL REMODELING: A PARADIGM SHIFT IN MICROBIOME AGING RESEARCH

Beyond diversity: The discovery of nonlinear trajectories

Prior research has often emphasized a decline in microbial alpha diversity during aging[17]. For instance, Claesson et al[17] demonstrated in a study of the Irish elderly population that gut microbiota diversity was significantly reduced in older individuals compared to younger cohorts, a shift closely associated with health status, living environment (community vs long-term care facilities), and dietary patterns. However, recent longitudinal and cross-sectional population analyses indicate that age-related microbial changes are dynamic and co-shaped by host health status, diet, and environmental factors[18,19].

This evolving understanding has led to the proposal of the “gut microbiota aging trajectory” concept, confirming that the progression of microbial aging correlates with physiological age and is intricately linked to the onset of metabolic diseases[20]. This finding suggests that aging is not merely a process of microbial “impoverishment” but rather a dynamic, phased ecological reconstruction. Research by O’Toole and Jeffery[19] supports this view, highlighting that microbial shifts during aging exhibit significant inter-individual heterogeneity and are more closely associated with health span than with chronological age.

It is crucial to emphasize that detailed cohort characterization - including age stratification within the elderly population, sex distribution, metabolic comorbidities, dietary patterns, and physical activity levels - may be important for strengthening causal inference in microbiome-aging research[18,19]. Future studies should prioritize rigorous control for and stratified analysis of these confounding factors to more precisely delineate the patterns of microbial change associated with aging.

From taxonomy to functional profiling: The central role of lipid metabolism pathways

The application of functional enrichment analysis techniques is shifting the research focus from merely identifying “who is changing” towards understanding “what they are doing”. A growing body of evidence indicates that age-related dysbiosis involves not only shifts in the abundance of specific taxa but, more critically, a reprogramming of the overall metabolic capacity of the microbial community[21]. For instance, Biagi et al[22], in their study of the gut microbiota in centenarians, observed that functional changes related to inflammatory regulation were particularly prominent among the age-associated microbial alterations.

Of particular note, the functional enrichment of lipid metabolism pathways has emerged as a core feature of age-related dysbiosis. Recent research has revealed a selective expansion of lipid metabolism pathways within the aging microbial community, notably the enrichment of genes involved in fatty acid oxidation[23]. This finding offers a conceptual perspective and may inform future research on for developing anti-aging interventions that target microbial metabolic functions.

THE GUT-LIVER AXIS: A METABOLIC BRIDGE CONNECTING MICROBIAL METABOLISM TO HOST AGING

Anatomical and functional basis of the gut-liver axis

The gut-liver axis has been proposed as a core conduit through which microbial metabolites, bile acids, and inflammatory mediators influence hepatic metabolism and systemic aging processes[24]. The anatomical proximity of the intestine and liver, connected via the portal vein system, dictates that gut-derived products directly access the liver, modulating the metabolic function and inflammatory state of hepatocytes. This unique anatomical relationship underscores the pivotal role of the gut-liver axis in microbiota-host crosstalk.

As a central metabolic organ, the liver’s functional status profoundly impacts systemic metabolic homeostasis. Hepatic metabolic dysfunction, particularly in lipid metabolism and insulin sensitivity, has been widely reported in metabolic disease contexts and may overlap with aging-related changes[25]. These age-related hepatic changes may not only be a direct consequence of the aging process but can also accelerate aging in other organ systems by perturbing overall systemic metabolism.

Tripathi et al[24] provided a comprehensive review of the interplay between the gut-liver axis and the microbiome, highlighting that gut dysbiosis contributes to the pathogenesis and progression of liver diseases through multiple mechanisms. These include compromising intestinal barrier integrity, promoting the translocation of bacteria and their products, and modulating bile acid metabolism. Such mechanisms are likely amplified in the context of aging, potentially establishing a deleterious feedback loop.

TMAO: A key metabolic mediator of the gut-liver axis

TMAO, a gut microbiota-derived metabolite, may serve as a molecular link between intestinal ecology and systemic metabolic status. Dietary nutrients such as choline and L-carnitine are metabolized by specific gut bacteria including members of the genera Anaerococcus and Clostridium to produce trimethylamine. Trimethylamine absorbed via the portal circulation subsequently undergoes oxidation in the liver, catalyzed by flavin-containing monooxygenase 3, to generate TMAO[26]. Consequently, the composition and functional capacity of the gut microbiota directly dictate TMAO production, with dysbiosis representing a primary driver of elevated circulating TMAO levels.

A substantial body of evidence implicates TMAO in the pathophysiology of aging and age-related diseases through multiple mechanisms. Zhu et al[27], in a study published in Cell, demonstrated that TMAO directly enhances platelet hyperreactivity, thereby increasing thrombosis potential, providing direct mechanistic evidence linking TMAO to cardiovascular events. Clinical research by Haghikia et al[28] revealed that plasma TMAO levels in patients with ischemic stroke are positively correlated with the activation status of pro-inflammatory monocytes in peripheral blood, suggesting a role for TMAO in stroke pathology via pro-inflammatory effects. Furthermore, large-scale clinical cohort studies have consistently shown that elevated baseline plasma TMAO levels are significantly associated with an increased risk of future cardiovascular events and ischemic stroke[29,30].

Within the field of aging research, TMAO has garnered significant attention. Multiple studies indicate that circulating TMAO levels increase with age and are associated with the risk of various age-related conditions, including atherosclerosis, cognitive decline, and renal dysfunction[31,32]. Collectively, these findings suggest that TMAO may serve as a molecular mediator linking gut dysbiosis to host aging processes, although causal evidence in humans remains incomplete.

Interventional evidence targeting microbial lipid metabolism

Building upon the observed enhancement of lipid metabolism features in the aged microbiota, researchers have employed trimetazidine, a fatty acid oxidation inhibitor, as an interventional strategy. This approach resulted in a partial reversal of gut microbial dysbiosis and concurrent inhibition of hepatic β-oxidation enzymes, including the hydroxyacyl-hydroxyacyl-coenzyme A dehydrogenase trifunctional multienzyme complex subunit beta[23]. These findings construct a coherent logical chain linking aging to cellular senescence, whereby advancing age is linked to enhanced lipid metabolic capacity of the gut microbiota, which in turn is associated with excessive fatty acid oxidation in the host liver, ultimately resulting in the accumulation of cellular senescence markers.

Trimetazidine, a clinically established anti-anginal agent, conventionally exerts its therapeutic effects by inhibiting fatty acid oxidation and promoting glucose oxidation. This research unveils a potential novel application for the drug: Mitigating aspects of aging through modulation of the microbiota-gut-liver axis. This discovery not only offers new insights for drug repurposing but also suggests a rationale for further exploring the therapeutic potential of targeting microbial metabolic functions as an anti-aging strategy.

Notably, corroborating evidence from analogous research supports the potential of targeting microbial metabolism to mitigate age-related disease risk. For instance, structurally similar pecan polyphenols have been shown to ameliorate atherosclerosis in mice by modulating the gut microbiota and subsequently inhibiting flavin-containing monooxygenase 3, thereby reducing TMAO levels[33]. Although focused on a specific disease model, this finding may provide indirect support for the broader concept that microbiota-targeted metabolic interventions could be a viable strategy for addressing age-related pathologies.

Unresolved questions and future directions

Although the findings presented above support a plausible mechanistic framework -whereby an age-related functional shift in the microbiota towards enhanced lipid metabolism may promote hepatic fatty acid oxidation and cellular senescence - several critical questions remain unanswered. First, the specific microbial taxa or metabolites directly responsible for modulating hepatic hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta expression have yet to be identified. Second, given that fatty acid oxidation inhibitors directly suppress oxidation in hepatocytes, it is necessary to delineate liver-specific pharmacological effects from microbiota-mediated mechanisms. Third, the generalizability of this mechanism across the human aging process requires validation through multi-center, large-scale cohort studies.

Future investigations should employ methodologies such as gnotobiotic animal models, fecal microbiota transplantation, and targeted metabolomics to provide further mechanistic validation[34]. Concurrently, integrating multi-omics technologies to systematically dissect the complete regulatory network of “microbial signatures-metabolites-host responses” during aging will establish a more robust theoretical foundation for developing anti-aging interventions targeting the gut-liver axis.

THE GUT-BRAIN AXIS: A CRITICAL PATHWAY LINKING MICROBIOTA TO COGNITIVE AGING

Conceptual and mechanistic foundations of the gut-brain axis

The gut-brain axis is increasingly recognized as a pathway connecting microbiota composition to cognitive aging and neurodegenerative processes[5,6]. The gut microbiota engages in bidirectional communication with the central nervous system through multiple mechanisms, including the production of neuroactive compounds such as SCFAs, gamma-aminobutyric acid, and serotonin precursors, as well as modulation of systemic and neuroinflammatory responses, regulation of blood-brain barrier (BBB) integrity, and influence over neuroendocrine signaling[35,36].

A comprehensive review by Cryan et al[5] published in Physiological Reviews synthesized the progress in gut-brain axis research, highlighting that the gut microbiota influences brain function and behavior through neural, immune, and endocrine pathways. Dysregulation of this bidirectional communication system - termed “microbiota-gut-brain axis” disruption - has been implicated in the pathogenesis of various neurological disorders, including anxiety, depression, autism spectrum disorder, Parkinson’s disease, and Alzheimer’s disease[37,38].

Microbiota-mediated regulation of the BBB and microglia

Experimental evidence suggests that the gut microbiota may modulate BBB permeability[39] and microglial maturation[40], providing a mechanistic basis for microbiota-driven neuroinflammation. Braniste et al[39] demonstrated that germ-free mice exhibit significantly increased BBB permeability, a phenotype that could be partially reversed through fecal microbiota transplantation, indicating a critical role for the gut microbiota in maintaining BBB integrity. This finding holds substantial clinical relevance, as BBB disruption represents an early event in the pathogenesis of various neurological disorders, facilitating the entry of blood-borne harmful substances into the brain parenchyma and triggering neuroinflammatory responses.

Erny et al[40] further elucidated that the host microbiota continuously is implicated in microglial maturation and function within the central nervous system, thereby influencing the magnitude and nature of neuroinflammatory responses. Their study revealed that microglia from germ-free mice display an immature phenotype, characterized by an altered gene expression profile and impaired responsiveness to immune challenges. Notably, supplementation with SCFAs - major metabolites derived from the microbiota - partially reversed these alterations, underscoring the critical role of microbial metabolites in shaping microglial function.

Age-related dysbiosis and neuroinflammation

Aging-associated gut dysbiosis is frequently accompanied by systemic low-grade inflammation, a state that may compromise endothelial tight junctions and potentiate neuroinflammatory cascades[39,41]. This chronic, low-grade inflammatory state can compromise the BBB, activate microglia, and trigger neuroinflammation, thereby contributing to the pathogenesis and progression of cerebral small vessel disease, cognitive impairment, and Alzheimer’s disease.

Vogt et al[38] investigated the gut microbiota composition in patients with Alzheimer’s disease and observed significant alterations in microbial diversity and composition. Notably, changes in the abundance of specific genera, such as Bacteroides, correlated with levels of Alzheimer’s disease biomarkers in the cerebrospinal fluid. This finding may provide clinical evidence supporting the involvement of the microbiota-gut-brain axis in neurodegenerative diseases. Whether these alterations are specific to Alzheimer's disease or reflect general aging processes remains to be determined.

Within the context of ischemic stroke, research by Singh et al[42] further elucidated that gut dysbiosis can influence post-stroke neuroinflammatory responses and the extent of brain injury through modulation of intestinal γδ T cells. This study directly demonstrated a critical role for the gut microbiota in regulating neuroinflammation following stroke, thereby providing an experimental rationale for targeting the gut-brain axis to improve stroke outcomes.

FROM GUT-LIVER TO GUT-BRAIN: INTEGRATION AND INTERPLAY OF MULTI-ORGAN AXES

The gut-liver and gut-brain axes do not operate in isolation; rather, they interact through multiple mechanisms, forming an integrated multi-organ regulatory network. For instance, the liver, as a central metabolic hub, modulates the composition of circulating metabolites, which can subsequently influence BBB integrity and the cerebral microenvironment. Conversely, the central nervous system is implicated in intestinal function, including gut microbiota composition and intestinal barrier integrity, via the autonomic nervous system and neuroendocrine pathways[43].

This interplay among multi-organ axes becomes particularly pronounced in the context of aging. Age-related multisystem functional decline simultaneously affects both the gut-liver and gut-brain axes, and dysfunction in one axis can amplify impairments in the other through their reciprocal interactions, potentially establishing a vicious cycle. Therefore, a systems biology perspective that holistically considers the “microbiota-multi-organ axis” network may be important for comprehending the complexity of aging and for developing effective intervention strategies. To better distinguish between varying levels of evidence, we summarize key mechanisms according to their strength of evidence in Table 1.

Table 1 Evidence grading of microbiota–multi-organ axis mechanisms in aging.

Mechanism	Description	Evidence level	Evidence type
Gut-brain axis	Microbiota influences BBB and microglia	Strong	Animal + human
TMAO	Associated with cardiovascular risk	Moderate	Cohort + experimental
HADHB pathway	Microbiota-liver FAO link	Limited	Animal
TCM-microbiota	Multi-target modulation	Speculative	Preclinical

BBB: Blood-brain barrier; TMAO: Trimethylamine N-oxide; HADHB: Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta; FAO: Fatty acid oxidation; TCM: Traditional Chinese medicine.

THE NEUROINFLAMMATORY NETWORK: A CENTRAL NEXUS LINKING PERIPHERAL DISTURBANCES TO CENTRAL NERVOUS SYSTEM INJURY

Gut microbiota dysbiosis and neuroinflammation following ischemic stroke

Following cerebral ischemia, acute intestinal stress is rapidly induced through neuroendocrine and immune pathways[44], leading to an abrupt disruption of the gut microbial ecosystem. Both clinical and animal studies have demonstrated that post-stroke, the intestinal environment undergoes significant shifts, characterized by an explosive proliferation of opportunistic pathogens such as Enterobacteriaceae, accompanied by a reduction in beneficial bacteria[45]. Concurrently, intestinal mucosal permeability increases[10]. The compromise of both the mechanical and immune barriers of the intestine facilitates the translocation of microbiota-derived harmful substances, notably lipopolysaccharides (LPS), into the circulation.

These translocated microbial products act as potent inflammatory triggers, activating the systemic immune system and instigating a pronounced systemic inflammatory response[46]. Translocated bacterial products, along with inflammatory signals emanating from the gut itself - functioning as an immune organ - activate peripheral immune cells[47]. These activated cells can then migrate to the brain, where they interact with resident microglia and astrocytes. This interaction collectively serves to propel the initial acute inflammation forward, transitioning it into a sustained and amplified neuroinflammatory network[9,48,49].

Pro-inflammatory mechanisms of TMAO

In the cascade linking intestinal disturbances to systemic inflammation and subsequent neuroinflammation, TMAO has garnered significant attention as a key mediator connecting gut dysbiosis to post-stroke inflammation. The study by Haghikia et al[28] not only established a correlation between TMAO levels and the activation of pro-inflammatory monocytes in stroke patients but also demonstrated through cell culture experiments that TMAO directly promotes monocyte differentiation towards a pro-inflammatory phenotype. Animal studies have further elucidated that TMAO can activate the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome, promoting the release of inflammatory cytokines such as interleukin (IL)-1β and IL-18, thereby enhancing the inflammatory phenotype of macrophages and exacerbating inflammatory responses within the vascular and nervous systems[50,51].

Research by Boini et al[50] revealed that TMAO induces endothelial cell inflammation through activation of the reactive oxygen species/thioredoxin-interacting protein/NLRP3 inflammasome pathway. Corroborating this, Chen et al[51], in a study published in the Journal of Lipid Research, provided further evidence that TMAO promotes macrophage foam cell formation and the expression of inflammatory cytokines, offering new insights into the inflammatory mechanisms by which TMAO contributes to atherosclerosis. Collectively, these findings suggest that TMAO may be a mediator through which gut dysbiosis is associated with systemic inflammation. Consequently, targeting the “gut microbiota-TMAO metabolism-neuroinflammation” axis represents a hypothesis that warrants testing for the systemic regulation of ischemic stroke.

Immune-metabolic dysregulation in sarcopenia

Research on sarcopenia may provide another important perspective for understanding the neuroinflammatory network. Macrophages are critical immune cells responsible for maintaining homeostasis and facilitating repair and regeneration in skeletal muscle. Within the aging microenvironment, macrophages undergo significant metabolic reprogramming: Pro-inflammatory M1 macrophages predominantly rely on glycolysis, whereas anti-inflammatory M2 macrophages utilize oxidative phosphorylation as their primary energy source[52]. Studies indicate that the tricarboxylic acid cycle is inhibited in M1 macrophages, with energy metabolism shifting towards glycolysis; in contrast, M2 macrophages maintain an intact tricarboxylic acid cycle and predominantly employ oxidative phosphorylation, which better supports their anti-inflammatory functions[53]. Aging disrupts the balance of macrophage polarization, leading to M1 predominance. These hyperactive M1 macrophages release pro-inflammatory cytokines, directly damaging muscle cells and accelerating muscle atrophy by perpetuating local chronic inflammation[54].

Recent investigations have revealed that in sarcopenic mouse models, the proportion of pro-inflammatory macrophages is significantly elevated in skeletal muscle tissue, accompanied by a reduction in the anti-inflammatory subset. This shift correlates with increased expression of pro-inflammatory cytokines such as tumor necrosis factor α, IL-6, and IL-1β, as well as decreased levels of anti-inflammatory cytokines including IL-10 and transforming growth factor β, alongside enhanced glycolytic flux and reduced oxidative phosphorylation[55]. Furthermore, within the aged microenvironment, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway and the NLRP3 inflammasome pathway are hyperactivated in macrophages, potentiating pro-inflammatory responses, altering metabolic profiles, exacerbating muscle inflammatory damage, and impairing regenerative capacity[54,56]. These findings collectively suggest that macrophage immuno-metabolism may be involved in the pathophysiology of sarcopenia and may represent a potential target for further investigation.

The interplay network between microbiota aging and immune-metabolism

Gut microbiota aging and immune-metabolic dysregulation are not independent processes; rather, they form a complex interactive network that synergistically is associated with the pathogenesis and progression of age-related diseases[57,58]. Gut dysbiosis generates inflammatory signals, such as LPS. These signals enter the circulation and induce monocyte release from the bone marrow via the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathway. Monocytes subsequently migrate to peripheral tissues, including skeletal muscle, where they differentiate into macrophages. Within the senescent microenvironment and under sustained inflammatory stimulation, these newly recruited macrophages are predisposed to polarize towards a pro-inflammatory M1 phenotype. This shift is accompanied by hyperactivation of the JAK-STAT signaling pathway and the NLRP3 inflammasome. Consequently, macrophage immunosenescence accelerates, and their metabolic profile shifts towards pro-inflammatory glycolysis. In turn, these immuno-senescent macrophages release inflammatory cytokines. These cytokines directly damage cells, exacerbating tissue atrophy. They also compromise intestinal barrier integrity by releasing inflammatory mediators. This disruption further alters gut microbiota composition and metabolism, perpetuating dysbiosis and establishing a vicious cycle[56,58].

A comprehensive review by Michaudel and Sokol[59] published in Cell Metabolism systematically elucidated how the gut microbiota modulates immune cell metabolism through its metabolites. The review highlighted that SCFAs, particularly butyrate, can reshape macrophage metabolic profiles, shifting them from pro-inflammatory glycolysis towards anti-inflammatory oxidative phosphorylation, thereby exerting immunomodulatory effects. This finding may provide a conceptual framework for understanding the intricate “microbiota-immune-metabolism” interplay, though direct evidence in the context of aging is still emerging.

Neuroinflammation as a potential integrative hub of multi-organ axes

Synthesizing the evidence presented above, neuroinflammation can be conceptualized as a convergent hub integrating the interactions of multiple organ axes. Pro-inflammatory mediators originating from the gut-liver axis, such as TMAO and LPS, can enter the brain via the systemic circulation and directly activate microglia. Concurrently, dysregulation of the gut-brain axis can lead to abnormal neurotransmitter metabolism, perturbing neuroimmune homeostasis. Furthermore, autonomic nervous system dysfunction can alter intestinal function, exacerbating microbial dysbiosis and disrupting the intestinal barrier, thereby perpetuating a deleterious “gut-brain” feedback loop.

Consequently, targeting the neuroinflammatory network as a therapeutic strategy necessitates a systems-level understanding of its interplay with these multi-organ axes, rather than viewing cerebral inflammatory processes in isolation. This integrative perspective may provide a theoretical foundation for developing microbiota-based systemic intervention strategies and offers a conceptual entry point for elucidating the modern biological basis of the systems thinking principle inherent in TCM.

The conceptual framework of the neuroinflammatory network integrates peripheral immune activation, central neuroimmune responses, and multi-organ axis interactions, thereby offering a unified paradigm for understanding the systemic nature of age-related diseases. We propose that future research should move beyond the traditional single-disease perspective and instead regard neuroinflammation as a common pathological hub shared among various age-related conditions, including post-stroke cognitive impairment, Alzheimer’s disease, Parkinson’s disease, and sarcopenia. This suggests that interventions targeting neuroinflammation may confer broad-spectrum protective effects across multiple disorders. However, the spatiotemporal characteristics, cell-type specificity, and molecular mechanisms of neuroinflammation are likely to differ among these diseases, necessitating fine-resolution dissection using advanced technologies such as single-cell sequencing and spatial transcriptomics. Moreover, current interventions for neuroinflammation have largely focused on anti-inflammatory agents, yet their clinical efficacy remains limited - potentially because such approaches fail to simultaneously address upstream drivers, including gut dysbiosis and metabolic imbalance. Consequently, top-down systemic interventions, such as modulating the gut microbiota or improving intestinal barrier function, may prove more effective than directly suppressing inflammation alone.

To comprehensively illustrate the central role of the neuroinflammatory network in integrating signals from multiple organ axes during aging, we present a schematic diagram summarizing the key components and interactions (Figure 1).

Figure 1 Schematic diagram of the gut microbiota-multi-organ axis network in aging and age-related diseases. TMAO: Trimethylamine N-oxide; LPS: Lipopolysaccharide; TMA: Trimethylamine; FMO3: Flavin-containing monooxygenase 3; SCFAs: Short-chain fatty acids; BBB: Blood-brain barrier; NLPR3: Nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3; NF-κB: Nuclear factor kappa B; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; AD: Alzheimer’s disease; TFHL: Total flavonoids from hawthorn leaves.

However, this integrative role remains largely hypothetical and requires further validation across different aging contexts. The extent to which neuroinflammation serves as a true “hub” vs a correlate of multi-organ dysregulation is not yet established, and causal inference is limited by the predominantly cross-sectional nature of available human studies.

PHILOSOPHICAL ALIGNMENT: HOLISM MEETS COMPLEX SYSTEMS

The intricate complexity of microbiota-host interactions resonates profoundly with the holistic philosophy underpinning TCM[60,61]. The core TCM tenets of systems thinking and syndrome differentiation demonstrate a natural conceptual affinity with intervention strategies that target the gut ecosystem as a complex adaptive system. TCM formulas, through their multi-component and multi-target synergistic actions, modulate the overall functional status of the host organism. This systems-level regulatory mode - characterized by multi-component, multi-target, and multi-pathway interactions - is particularly well-suited for intervening in complex physiological processes like aging, where numerous etiological factors intertwine.

Accumulating evidence suggests that TCM compounds may function as prebiotic substrates or undergo biotransformation by the gut microbiota into bioactive metabolites, thereby modulating key host pathways such as the bile acid pool, tryptophan metabolism, and inflammatory signaling networks[60,61]. This multi-component, multi-target regulatory paradigm may be especially pertinent for addressing the systemic nature of aging.

Treating from the spleen: Theoretical foundation of the spleen-stomach-gut-brain connection

TCM has long emphasized the spleen and stomach as the “foundation of acquired constitution” and the “source of qi and blood biochemistry”. This theoretical framework extends beyond mere digestion and absorption to encompass the systemic regulation of qi movement, the distribution of essential nutrients, and the overall functional status of the body. Within the diagnostic and therapeutic framework for stroke, the principle of “treating from the spleen” represents a distinctive and important academic concept. The Yellow Emperor’s Inner Classic contains early descriptions of the spleen governing transportation and transformation while serving as a guardian of the body, suggesting a close relationship between spleen-stomach function and both host defense and metabolic homeostasis[62]. During the Jin-Yuan dynasties, Li Dongyuan proposed that “internal injury to the spleen and stomach gives rise to all diseases”, emphasizing that spleen-stomach weakness can lead to qi and blood deficiency, phlegm-damp retention, and blood stasis - precisely the core pathogenic elements underlying stroke pathogenesis[63].

Informed by modern scientific insights into the gut-brain axis, contemporary TCM theory has further developed the concept of “brain-gut synchronous regulation”[64]. This framework posits that the spleen and stomach, as the source of qi and blood biochemistry, are intimately connected with the neurological system through their influence on the generation and distribution of qi, blood, and fluids. Dysregulation of the spleen and stomach impairs transportation and transformation, predisposing the body to the accumulation of pathological products such as phlegm turbidity, blood stasis, and damp-heat. Specifically, spleen dysfunction leading to qi and blood deficiency can generate phlegm turbidity and blood stasis; when phlegm and stasis bind, they may transform into heat, manifesting as a fire-heat pattern. This pathological cascade - progressing from spleen deficiency to phlegm-stasis and subsequently to heat transformation - constitutes a core pathogenic mechanism that can either precipitate or exacerbate stroke.

With advances in modern systems biology and microecology, the theory of the “spleen-stomach-gut-brain connection” is acquiring robust scientific validation. Contemporary discoveries regarding gut microbiota composition, metabolic functions, and intestinal barrier integrity provide critical modern biological annotations for classical TCM concepts. These include the spleen’s role in governing transportation and transformation - now interpretable through the lens of nutrient metabolism - as well as its function as a guardian of the body, a concept that resonates with the modern understanding of immune defense mediated by the gut ecosystem[65].

Empirical evidence: The paradigm of total flavonoids from hawthorn leaves

Total flavonoids from hawthorn leaves, a class of polyphenolic compounds extracted from the leaves of Crataegus pinnatifida, contain major bioactive constituents including quercetin, kaempferol, and hyperoside[66]. Within the framework of TCM, hawthorn is traditionally recognized for its properties of invigorating the spleen, promoting digestion, and activating blood circulation to resolve stasis. Modern pharmacological investigations have substantiated that total flavonoids from hawthorn leaves exhibits a spectrum of biological activities, including antioxidant, anti-inflammatory, endothelial function-improving, lipid metabolism-regulating, and platelet aggregation-inhibiting effects[67-69]. As a core component of commercially available cardiovascular TCM formulations such as Yixintong tablets, total flavonoids from hawthorn leaves have demonstrated a favorable clinical safety profile and exhibits multi-target and multi-pathway characteristics in the prevention and treatment of cardiovascular and cerebrovascular diseases.

Emerging evidence indicates that total flavonoids from hawthorn leaves exerts significant modulatory effects on the gut microbiota. Bi et al[70] observed that total flavonoids from hawthorn leaves alters the gut microbial composition in obese rats, influencing microbial functions associated with choline metabolism. Zheng et al[67] demonstrated that total flavonoids from hawthorn ameliorate hyperlipidemia through activation of the AMP-activated protein kinase/sterol regulatory element-binding protein 1-c and peroxisome proliferator-activated receptor alpha/peroxisome proliferator-activated receptor gamma coactivator 1-alpha/carnitine palmitoyltransferase 1A pathways, as well as modulation of the gut microbiota. Furthermore, Zhang et al[71] suggested that total flavonoids from hawthorn leaves may influence systemic metabolites through microbiota regulation, thereby improving cognitive function in a mouse model of Alzheimer’s disease.

Network pharmacology analyses have further revealed that the core constituents of total flavonoids from hawthorn leaves may precisely target key nodes in TMAO metabolism, notably flavin-containing monooxygenase 3 and AKT serine/threonine kinase 1, with relevant targets significantly enriched in inflammatory and metabolic pathways[72]. These findings collectively suggest that total flavonoids from hawthorn leaves possesses the potential to modulate the gut microbiota-TMAO metabolism-neuroinflammation axis. This may provide a preliminary scientific hypothesis for investigating how bioactive components from TCM, grounded in the treating from the spleen theoretical framework, may improve stroke outcomes through regulation of the gut-brain axis, though direct experimental evidence in stroke models is currently limited.

Empirical evidence: The paradigm of Huangqi Jianzhong decoction

Huangqi Jianzhong decoction, originating from the Synopsis of the Golden Chamber, is a classical TCM formula primarily indicated for tonifying and regulating the spleen and stomach, as well as harmonizing the nutritive and defensive qi[73]. Composed of Astragali Radix (Huangqi), Cinnamomi Ramulus (Guizhi), Paeoniae Radix Alba (Shaoyao), Glycyrrhizae Radix et Rhizoma (Gancao), Jujubae Fructus (Dazao), Zingiberis Rhizoma Recens (Shengjiang), and maltose (Yitang), Huangqi Jianzhong decoction possesses a long history of clinical application. Its compositional rationale centers on tonifying qi, invigorating the spleen, and harmonizing the nutritive and defensive qi, rendering it particularly suitable for elderly populations presenting with qi deficiency, constitutional weakness, and spleen-stomach disharmony - clinical characteristics that closely align with the manifestations of sarcopenia, including insufficient qi and blood and muscular weakness.

Modern pharmacological investigations have revealed that Astragali Radix, the sovereign herb in Huangqi Jianzhong decoction, exhibits immunomodulatory properties, suppresses inflammatory responses, and maintains intestinal microbial homeostasis. By increasing the abundance of beneficial bacterial taxa and modulating levels of metabolites such as SCFAs, Astragali Radix indicates potential for the prevention and treatment of sarcopenia[74,75]. Recent studies have shown that the constituent herbs of Huangqi Jianzhong decoction, such as Astragali Radix, can influence muscle health. For instance, Astragali Radix has been demonstrated to improve muscle function and mass in aged animal models, potentially by modulating the gut microbiota and its metabolites[74-76]. Furthermore, network pharmacology analyses and studies on related herbal components suggest that Huangqi Jianzhong decoction may modulate key immuno-metabolic signaling pathways, including TLR4/NF-κB and JAK-STAT, and influence macrophage polarization[77,78].

Building upon these findings, researchers have proposed a scientific hypothesis: Huangqi Jianzhong decoction exerts its preventive effects against sarcopenia through systemic regulation of the aging microbiota-immune-metabolic network. Specifically, Huangqi Jianzhong decoction is postulated to upregulate SCFA production, inhibit LPS, reshape macrophage immuno-metabolic profiles, and target key pathways such as TLR4/NF-κB, JAK-STAT, and NLRP3, as well as critical molecular targets including mammalian target of rapamycin and histone deacetylase[78]. This hypothesis is currently under investigation using multi-omics approaches, but no confirmatory results are yet available, and further validation in animal models and human cohorts is required.

From theory to translation: Challenges and opportunities

Although TCM suggests unique advantages in modulating the gut microbiota, future research faces several challenges. First, establishing molecular correspondences between traditional theoretical frameworks and specific microbial metabolic pathways remains a critical task. Second, the multi-component nature of TCM formulas increases the complexity of mechanistic elucidation, necessitating integrative approaches employing emerging methodologies such as network pharmacology and systems biology. Third, inter-individual variability in response to TCM interventions warrants greater attention; identifying response signatures through multi-omics technologies could provide a foundation for personalized interventions.

Nevertheless, these challenges also present opportunities. By integrating network pharmacology with gut microbiome research, a holistic perspective on drug-microbiota-host interactions can be employed to decipher the mechanisms of complex interventions such as TCM formulas[79]. This approach holds promise for transcending the limitations of traditional reductionist methods. This research paradigm, emphasizing systematic and holistic perspectives, resonates deeply with the TCM principle of systems thinking while providing novel tools for understanding the mechanisms of action underlying complex interventions.

The convergence of TCM and microbiome research represents a quintessential example of new blossoms on an old tree. Our research team posits that the core strength of TCM lies in its philosophy of systems regulation, which inherently aligns with the complexity of microbiota-host interactions. However, current research predominantly remains at the descriptive level of TCM modulates the microbiota, lacking in-depth elucidation of the causal chain linking TCM syndrome, microbiota, metabolites, and molecular targets. Future investigations should prioritize the following directions.

First, establishing syndrome-specific microbiota-metabolite signatures by correlating TCM syndrome patterns such as qi deficiency and phlegm-stasis with modern multi-omics phenotypes.

Second, validating microbiota-mediated effects of TCM formulas using network pharmacology integrated with functional assays such as fecal microbiota transplantation.

Third, conducting syndrome-stratified randomized controlled trials to enable precision TCM interventions tailored to individual phenotypes.

Furthermore, investigating the microbial biotransformation of TCM constituents, particularly the conversion of glycosides to their corresponding aglycones, represents a promising frontier that may uncover the true effector molecules responsible for TCM's therapeutic efficacy.

Despite the promising findings, several limitations should be acknowledged. TCM formulations exhibit substantial heterogeneity in composition and quality control, and the identification of active compounds remains incomplete. Moreover, most current evidence is derived from preclinical studies, with limited causal microbiome-focused investigations and a paucity of high-quality, syndrome-stratified clinical trials. These challenges highlight the need for more rigorous and standardized research frameworks.

ENVIRONMENTAL EXPOSURES: OVERLOOKED MODULATING FACTORS

Environmental factors shape the microbiota

Environmental exposures, encompassing dietary patterns, pollutant burden, and physical activity, are important factors in shaping the composition and function of the gut microbiota[18,80]. Diet represents one of the most significant environmental factors influencing the microbiota; distinct dietary patterns can rapidly and reproducibly alter the human gut microbiome[18]. High-fat diets, high-sugar diets, and plant-based diets each selectively enrich distinct microbial taxa, resulting in marked differences in microbial community structure and functional capacity.

Physical activity constitutes another important environmental modulator. Regular exercise influences the gut microbiota through multiple mechanisms, including altering intestinal transit time, modulating immune function, and affecting intestinal mucosal metabolism. Studies have demonstrated that athletes exhibit significantly higher gut microbial diversity and functional metabolic potential compared to sedentary individuals, suggesting a positive modulatory effect of exercise on the microbiota[81].

Environmental pollutants and microbiota-host interactions

Emerging evidence indicates that environmental pollutants can disrupt the microbial ecosystem and exacerbate systemic inflammation, potentially accelerating age-related pathophysiological processes[80]. Claus et al[80] comprehensively reviewed the role of the gut microbiota in environmental pollutant toxicity, highlighting that the microbiota can both metabolically transform pollutants - thereby altering their toxicity - and be disrupted by pollutants, leading to adverse host health outcomes.

Persistent organic pollutants, heavy metals, and microplastics represent environmental contaminants that influence the gut microbiota through multiple mechanisms, including direct antimicrobial effects, alterations of the intestinal microenvironment, and modulation of host immune responses. These perturbations can subsequently affect pollutant metabolism and toxicity, potentially establishing a deleterious feedback loop. Given the cumulative exposure over a lifetime and age-related decline in detoxification capacity, the health impact of environmental pollutants may be particularly pronounced in elderly populations.

An integrated research framework for environment-microbiota-host interactions

Future research should incorporate environmental exposures into the microbiome-aging research framework to better capture the tripartite interactions among environment, microbiota, and host. This integrated framework necessitates addressing several key questions: First, how do different environmental factors interact to collectively shape microbial changes during the aging process? Second, to what extent are the effects of environmental exposures on host aging mediated or modulated by the gut microbiota? Third, can modulation of the microbiota mitigate the adverse effects of environmental exposures on aging?

Addressing these questions requires large-scale, multicenter prospective cohort studies that integrate environmental exposure assessment, microbiome sequencing, multi-omics analyses, and rigorous application of causal inference methodologies. This represents an important future direction for microbiome-aging research.

Environmental exposure represents the most underestimated variable in current microbiome-aging research. We advocate that future studies should systematically collect and integrate environmental exposure data - including diet, physical activity, pollutants, medications, and lifestyle factors - and incorporate these as key covariates in analyses. Particularly in aging cohorts, long-term cumulative environmental exposures may exert greater influence on the microbiota than short-term interventions. Furthermore, environment-microbiota-host interactions likely exhibit nonlinear characteristics, threshold effects, and temporal accumulation, necessitating advanced modeling approaches such as machine learning.

From an interventional perspective, environmental optimization strategies - including dietary improvement, increased physical activity, and reduced pollutant exposure - may offer greater cost-effectiveness and broader applicability than pharmacological interventions. These approaches should therefore be prioritized as strategies for promoting healthy aging.

DISCUSSION AND FUTURE PERSPECTIVES: TOWARD PRECISION MICROBIOME-BASED ANTI-AGING INTERVENTIONS

Systematic dissection of the multi-organ axis network

In summary, accumulating evidence suggests that the gut microbiota may act as a regulatory hub in the aging process, though the strength of evidence varies across different axes and mechanisms. Through multiple pathways including the gut-liver, gut-brain, and gut-muscle axes, the microbiota influences systemic metabolism, immune function, and neurological activity. Future research should focus on systematically dissecting this multi-organ axis network, integrating studies across these axes to construct a systems biology map of how the gut microbiota influences systemic aging.

This systematic dissection necessitates the integrated application of multi-omics technologies. Metagenomics can reveal the genetic composition and functional potential of the microbial community. Metabolomics enables the detection of small-molecule metabolites originating from both microbial and host sources. Proteomics and transcriptomics reflect host responses to microbial signals. Through integrative analysis of multi-omics data, key microbial-host interaction modules may be identified, thereby providing a foundation for discovering intervention targets.

Identification of common intervention targets

Investigating whether common microbial functional modules or host metabolic pathways exist across different aging phenotypes - including muscle atrophy, cognitive decline, and metabolic disorders - may be important for developing broad-spectrum anti-aging intervention strategies. Enhanced microbial lipid metabolism pathways, particularly those involved in fatty acid oxidation, have been identified as a core feature of age-related dysbiosis and may represent a common microbial feature across multiple aging phenotypes[23]. This finding may provide a conceptual rationale for exploring broad-spectrum anti-aging interventions targeting microbial lipid metabolism.

However, whether different aging phenotypes share identical microbial characteristics requires further validation through comparative studies across multiple cohorts. Future research should systematically compare microbial signatures across diverse aging phenotypes to identify both commonalities and specificities, thereby informing the development of precision intervention strategies.

Development of precision modulation approaches

Identifying individual-specific age-related microbial signatures through multi-omics technologies and developing personalized microecological modulation regimens represent key directions for achieving precision anti-aging interventions. Individual factors including genetic background, lifestyle, and medication history influence microbiota composition and response to interventions, and should therefore be incorporated into the design of intervention protocols.

Significant inter-individual variability exists in the efficacy of interventions such as fecal microbiota transplantation, probiotics, prebiotics, and postbiotics. Future research should focus on identifying biomarkers that predict treatment response to guide personalized interventions. Additionally, the impact of medications, including TCM formulations, on the microbiota should be carefully considered in personalized intervention strategies to avoid unintended adverse effects on the microbial ecosystem.

Innovative research paradigms

Drawing upon approaches that integrate network pharmacology with gut microbiome research, a holistic perspective on drug-microbiota-host interactions can elucidate the mechanisms of complex interventions such as TCM formulas[79]. This approach holds promise for transcending the limitations of traditional reductionist methods. This research paradigm, emphasizing systematic and holistic perspectives, aligns deeply with the TCM principle of systems thinking while providing novel tools for understanding complex intervention mechanisms.

Furthermore, artificial intelligence and machine learning methods are increasingly applied in microbiome research. Through constructing predictive models, key microbial biomarkers can be identified, individual aging trajectories and intervention responses can be predicted, thereby supporting the development of precision intervention approaches.

Future research directions

Based on the foregoing analysis, this article proposes several important directions for future research, including integrated multi-organ axis research that transcends the single-organ paradigm by systematically dissecting interactions among gut-liver, gut-brain, and gut-muscle axes to construct a comprehensive microbiota-host multi-organ interaction network, with particular attention to the central role of neuroinflammation in multi-organ axis crosstalk. Integrated environment-microbiota-host analysis should incorporate environmental exposure factors into the research framework to elucidate how environmental factors influence aging processes through the microbiota. The establishment and validation of longitudinal cohorts through multicenter, large-sample longitudinal aging studies is essential to reveal causal relationships between microbial changes and aging phenotypes via long-term follow-up. In-depth mechanistic investigation combining germ-free animal models, fecal microbiota transplantation, and culturomics approaches is needed to validate the causal roles of key microorganisms and their metabolites while elucidating molecular mechanisms. The modernization of TCM interventions employing systems biology approaches can elucidate the mechanisms by which TCM formulas modulate the microbiota-multi-organ axis, providing modern scientific foundations for traditional theories such as treating from the spleen. Advancement of translational research should focus on developing novel probiotics, prebiotics, or pharmaceuticals based on intervention targets identified through basic research, followed by clinical trials to validate their safety and efficacy.

Looking forward, we firmly believe that microbiome-based anti-aging interventions will evolve from single-target approaches toward network regulation, and from isolated interventions toward multidimensional integration. Multi-organ axis integration represents an inevitable trend, as aging is not the failure of a single organ but rather a loss of coordinated regulation across multiple systems; therefore, constructing comprehensive models incorporating gut-liver, gut-brain, gut-muscle, and gut-bone axes may be important for fully understanding the complexity of aging. Common intervention targets are likely to be discovered, as despite differences among aging phenotypes, enhanced lipid metabolism, systemic low-grade inflammation, and immune-metabolic dysregulation may represent shared core hallmarks of aging, and interventions targeting these common pathways may confer broad-spectrum anti-aging effects. Precision microbiomics will drive personalized interventions, as advances in multi-omics technologies and artificial intelligence will enable customization of personalized probiotic, prebiotic, or dietary regimens based on individual microbial signatures, genetic backgrounds, and environmental exposures. TCM will offer unique solutions, as the multi-target, systems-regulatory characteristics of TCM formulas align remarkably well with the complexity of the microbiota-multi-organ axis network, and elucidating the microbiota-metabolite-target networks of TCM formulations through modern scientific approaches may catalyze the development of innovative anti-aging therapeutics. Environmental interventions represent the most cost-effective strategy, as environmental optimization measures including dietary improvement, increased physical activity, and reduced pollutant exposure should serve as foundational strategies for healthy aging, complementing pharmacological interventions. In conclusion, gut microbiome research is spearheading a paradigm shift in anti-aging interventions, and as researchers, we must embrace complexity, cultivate systems thinking, and facilitate the transition from reductionism to systems biology, ultimately achieving the ambitious goal of healthy aging. Key microbial metabolites and their systemic effects are summarized in Table 2.

Table 2 Major microbial metabolites and their organ-level effects.

Metabolite	Source	Target organ	Biological effect
SCFAs	Gut microbiota fermentation	Brain	Anti-inflammatory, BBB protection
TMAO	Choline metabolism	Cardiovascular	Pro-inflammatory, atherogenic
Bile acids	Liver-microbiota interaction	Liver/metabolism	Signaling regulation
LPS	Gram-negative bacteria	Systemic	Inflammation activation
Tryptophan metabolites	Microbial metabolism	Brain	Neurotransmitter modulation

SCFAs: Short-chain fatty acids; BBB: Blood-brain barrier; TMAO: Trimethylamine N-oxide; LPS: Lipopolysaccharide.

A note on evidence sources. It should be noted that a substantial proportion of the evidence discussed in this review is derived from disease-specific studies (e.g., stroke, Alzheimer's disease, sarcopenia) rather than primary normative aging research. Extrapolation of findings from disease contexts to healthy aging should be interpreted with caution, as mechanisms operative in disease may not fully recapitulate those underlying physiological aging. Key unresolved questions and future research directions are summarized in Table 3.

Table 3 Key unresolved questions and recommended experimental approaches in aging research.

Unresolved question	Current limitation	Recommended approach
Which microbial taxa regulate hepatic HADHB	Lack of causal evidence	Germ-free models + microbiota transplantation
Is TMAO causally involved in aging	Mostly associative data	Longitudinal human studies + intervention trials
How does microbiota affect neuroinflammation	Mechanisms unclear	Multi-omics + BBB models
Can TCM effects be linked to microbiota causally	Limited mechanistic studies	Standardized formulations + microbiome sequencing
Are findings aging-specific or disease-driven	Evidence mainly from disease models	Dedicated aging cohorts

HADHB: Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta; TMAO: Trimethylamine N-oxide; BBB: Blood-brain barrier; TCM: Traditional Chinese medicine.

CONCLUSION

The gut microbiome is increasingly recognized as a potential integrative hub that may influence multidimensional aspects of aging, operating through an integrated network of multi-organ axes that includes the gut-liver, gut-brain, and gut-muscle pathways. This review has synthesized current evidence linking microbiota dynamics to host aging, with particular emphasis on the neuroinflammatory network as a possible convergent point integrating peripheral immune activation, metabolic dysregulation, and central nervous system injury. The identification of microbial metabolites such as TMAO as candidate mediators of systemic aging, coupled with the recognition of enhanced microbial lipid metabolism as a common feature across aging phenotypes, may provide a conceptual basis for exploring broad-spectrum anti-aging interventions.

Importantly, the holistic regulatory philosophy inherent in TCM offers a unique and complementary perspective for microbiome-based aging interventions. Classical TCM theories, particularly the principle of treating from the spleen and the concept of the spleen-stomach-gut-brain connection, are gaining modern biological validation through their alignment with the microbiome-multi-organ axis framework. Bioactive compounds and formulas such as total flavonoids from hawthorn leaves and Huangqi Jianzhong decoction exemplify how multi-component, multi-target synergistic approaches have been shown in preliminary studies to modulate microbiome function and may contribute to host homeostasis, thereby addressing the systemic nature of aging.

Looking forward, the integration of environmental exposure factors into the microbiome-aging research paradigm represents a critical yet underappreciated direction, offering potential for cost-effective public health interventions. The convergence of multi-omics technologies, network pharmacology, and artificial intelligence will accelerate the transition from descriptive correlations to mechanistic understanding and from fundamental discovery to clinical translation. By integrating traditional wisdom with modern scientific approaches, the development of precise and personalized microecological interventions may offer potential opportunities for addressing the challenges of global population aging and advancing the goal of healthy longevity, though significant validation is still required.