Metabolic dysregulation reshapes the immune landscape: The gut microbiota-mTOR axis in respiratory viral infection immunity

Abstract

Respiratory viral infections pose a significant global public health threat, particularly in individuals with metabolic disorders, who face heightened severe disease risk and attenuated vaccine immune responses due to compromised immunity. This review elucidates how dynamic interactions between the gut microbiota, its metabolites, and the mechanistic target of rapamycin (mTOR) signaling pathway in metabolic disorders exacerbate infection severity and impair vaccine efficacy. Metabolic disorders induce chronic inflammation, gut microbiota dysbiosis, and mTOR hyperactivation, disrupting T and B cell metabolic reprogramming, suppressing antiviral innate immunity, vaccine-induced antibody production, and immune memory, and amplifying cytokine storms and lung injury. The mTOR-microbiota-immune axis serves as a critical nexus of metabolic and immunoregulation in this process. We summarize targeted intervention strategies, including gut microbiota modulation, mTOR inhibitors, and novel vaccine adjuvants, which restore metabolic-immune balance, significantly reducing severe respiratory viral infection morbidity and mortality while enhancing vaccine antibody titers and T cell memory in metabolically compromised populations. These approaches provide a theoretical foundation and clinical guidance for personalized immune interventions.

Graphical abstract

Metabolic disorders exacerbate respiratory viral infections and impair vaccine efficacy via gut microbiota dysbiosis and mTOR hyperactivation. Targeting this microbiota-mTOR axis with modulators, inhibitors, and novel adjuvants restores immune balance, reducing severity and enhancing antibody/memory responses in compromised hosts.

Introduction

Respiratory viral infections, such as those caused by influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), pose unprecedented challenges to healthcare systems due to their high transmissibility and risk of severe outcomes, presenting a persistent and formidable threat to global public health. According to the World Health Organization, influenza annually results in approximately 3–5 million severe cases and 290,000–650,000 deaths, profoundly impacting global health and economic stability.¹ Concurrently, the global prevalence of metabolic disorders, including obesity, type 2 diabetes mellitus (T2DM), and insulin resistance, continues to escalate, particularly in high-income countries, urbanized regions, and aging populations. Current estimates indicate that over 800 million individuals are affected by obesity worldwide, with projections suggesting that T2DM cases will reach 643 million by 2030.² Extensive clinical evidence demonstrates that individuals with metabolic disorders exhibit compromised immune function and chronic low-grade inflammation, which exacerbate proinflammatory cytokine responses (e.g., interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α]) during respiratory viral infections. This dysregulation triggers aberrant pulmonary immune responses, potentially leading to cytokine storm and acute respiratory distress syndrome, resulting in elevated morbidity, hospitalization rates, and mortality. Metabolic disorders not only heighten the susceptibility to respiratory viral infections but they also diminish the protective efficacy of vaccines. Studies have shown that individuals with obesity exhibit significantly lower antibody titers following influenza vaccination, with reduced protective efficacy compared with healthy individuals. Similar observations have been reported for coronavirus disease 2019 (COVID-19) vaccines, particularly in patients with T2DM, where neutralizing antibody levels and the establishment of long-term immune memory are markedly impaired.³

Metabolic disorders reshape the immune landscape via the mechanistic target of rapamycin (mTOR)-microbiota-immune axis, markedly exacerbating the severity of respiratory viral infections and attenuating vaccine efficacy. As a central regulator of metabolism and immunity, the mTOR signaling pathway is aberrantly activated in metabolic disorders due to insulin resistance and nutrient excess. This hyperactivation amplifies proinflammatory immune responses while suppressing antiviral innate immunity, such as type I interferon (IFN) responses, and impairs T cell proliferation and B cell antibody production, thereby limiting vaccine-induced adaptive immunity.⁴ Chronic low-grade inflammation, a hallmark of metabolic disorders, is characterized by persistent accumulation of proinflammatory cytokines and dysregulated adipokine secretion, which disrupts immune cell homeostasis. This leads to diminished T and B cell responsiveness, reduced antigen presentation efficiency, and impaired immune memory formation.⁵ The gut microbiota, a critical modulator of immune function, interacts with the mTOR pathway through its metabolites, such as short-chain fatty acids (SCFAs), to maintain immune homeostasis.⁵ However, metabolic disorders profoundly alter gut microbiota composition, reducing diversity and depleting beneficial taxa (e.g., Bifidobacterium spp.) while enriching proinflammatory bacteria (e.g., Proteobacteria). These shifts decrease SCFA production and increase translocation of proinflammatory metabolites, such as lipopolysaccharide (LPS). SCFAs typically mitigate inflammation by downregulating mTOR complex 1 (mTORC1) activity, but their reduction in metabolic disorders exacerbates mTOR hyperactivation, perpetuating a vicious cycle.⁶ Clinical and experimental evidence further demonstrates that in patients with obesity or T2DM, mTOR-microbiota dysregulation delays viral clearance, aggravates lung injury, and reduces vaccine antibody titers following infection with influenza or SARS-CoV-2, underscoring the pivotal role of this axis in immune dysfunction.^7,8 These dynamic interactions between mTOR and the microbiota provide a theoretical foundation for targeted interventions, such as mTOR inhibition or microbiota modulation, to enhance infection control and vaccine efficacy in individuals with metabolic disorders.

Respiratory viruses exhibit marked mechanistic heterogeneity in exploiting host metabolism. Enveloped RNA viruses (e.g., influenza A, SARS-CoV-2) hijack lipid rafts and cholesterol-rich membranes for entry and replication,⁹ while non-enveloped DNA viruses (e.g., adenovirus) rely less on lipid metabolism.¹⁰ SARS-CoV-2 uniquely engages angiotensin-converting enzyme 2 (ACE2) receptors highly expressed in metabolically active tissues (adipose, liver, pancreas),¹¹ triggering renin-angiotensin system (RAS) dysregulation and mTORC1 hyperactivation,¹² distinct from the reliance of influenza on sialic acid receptors and IFN antagonism.¹³ Metabolic disorders further amplify this divergence, and obesity-driven leptin resistance impairs early antiviral IFN responses across viruses,¹⁴ whereas T2DM-specific hyperglycemia selectively enhances SARS-CoV-2 replication via O-GlcNAcylation of viral proteins.⁷ Non-alcoholic fatty liver disease/metabolic-associated fatty liver disease (NAFLD/MAFLD), characterized by hepatic lipotoxicity, predisposes to severe influenza via defective Kupffer cell phagocytosis,¹⁵ while metabolic syndrome (MetS)-driven endothelial dysfunction exacerbates SARS-CoV-2-induced microthrombosis. These virus- and disease-specific interactions underscore the gut microbiota-mTOR axis as a convergent amplifier of severity and vaccine failure.

This review aims to systematically elucidate how the gut microbiota, mTOR signaling, and their interplay modulate immune cell function and metabolic states in the context of metabolic disorders, thereby influencing immune responses to respiratory viral infections. We propose an integrative immunological framework to delineate the potential interactions among respiratory viral infections, gut microbiota, and the mTOR pathway in metabolic dysfunction. Furthermore, we explore prospective intervention strategies, including improving metabolic health, targeting microbiota modulation, and inhibiting mTOR signaling, to optimize vaccine efficacy in metabolically compromised populations. This article also highlights future research directions, such as precision immune interventions leveraging multi-omics technologies and the development of novel vaccine designs to address the public health challenges faced by individuals with metabolic disorders.

Immune dysregulation in metabolic disorders

Metabolic disorders and chronic inflammation

Metabolic disorders, such as obesity, T2DM, and insulin resistance, induce a chronic inflammatory microenvironment through multi-organ molecular signaling and immune cell interactions, profoundly impairing vaccine-induced immune responses. In adipose tissue, obesity triggers adipocyte hypertrophy, local hypoxia, and cell death, releasing free fatty acids (FFAs) and damage-associated molecular patterns (DAMPs, e.g., high-mobility group box 1 [HMGB1]). These activate proinflammatory M1 macrophages via Toll-like receptor 4/2 (TLR4/2) signaling, promoting the secretion of TNF-α, IL-6, and IL-1β.¹⁶ Immune cell infiltration in adipose tissue amplifies inflammation, with CD8⁺ T cells driving M1 polarization via IFN-γ and mast cells amplifying inflammatory signals through histamine and IL-6 release.¹⁷ Dysregulated adipokine secretion (e.g., leptin) enhances proinflammatory gene expression via nuclear factor κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, fostering systemic inflammation.¹⁶ In the liver, lipotoxicity (FFA accumulation) and glucotoxicity (hyperglycemia) induce hepatocyte mitochondrial dysfunction and endoplasmic reticulum (ER) stress, activating Kupffer cells to release monocyte chemoattractant protein-1 (MCP-1) and IL-1β.¹⁸ In MAFLD, hepatic stellate cells, stimulated by lipotoxicity, secrete profibrotic factors (e.g., transforming growth factor β), exacerbating liver inflammation and fibrosis.¹⁹ In the pancreas, hyperglycemia and FFAs impair β cell function via oxidative stress and ER stress, increasing IL-1β secretion, recruiting macrophages, and activating the NOD-like receptor protein 3 (NLRP3) inflammasome, which disrupts insulin secretion.²⁰ Gut microbiota dysbiosis further aggravates inflammation by reducing immunoregulatory metabolites, such as SCFAs, and compromising intestinal barrier integrity, leading to translocation of proinflammatory microbial products (e.g., LPS) and systemic inflammation.

Chronic inflammation in metabolic disorders amplifies immune cell dysfunction through direct and indirect mechanisms. Directly, FFAs (e.g., palmitate) activate macrophages via TLR4/2 signaling, promoting NLRP3 inflammasome assembly and IL-1β maturation, with mitochondrial reactive oxygen species (ROS) and superoxide dismutase 2 acetylation as key mediators.^21,22 Hyperglycemia activates NF-κB signaling via the hexosamine pathway and advanced glycation end products (AGEs), enhancing TNF-α and IL-6 secretion.²¹ Lipotoxicity and glucotoxicity impair mitochondrial function, evidenced by electron transport chain dysfunction and leakage of oxidized mtDNA, which acts as a DAMP to activate the NLRP3 inflammasome.²³ ER stress, mediated by unfolded protein response pathways (e.g., inositol-requiring enzyme 1-X-box binding protein 1, protein kinase R-like ER kinase, activating transcription factor 6), drives NF-κB and JNK signaling, upregulating IL-6 and TNF-α transcription.²⁴ These mechanisms establish a positive feedback loop, perpetuating inflammation. For instance, in obese mouse models, NLRP3 inflammasome inhibitors (e.g., MCC950) significantly reduce proinflammatory cytokine levels in adipose tissue and liver, improving insulin sensitivity.²⁵ In lymphoid organs (e.g., spleen, lymph nodes), metabolic stress restricts immune cell proliferation and differentiation, diminishing antigen-specific T and B cell responses, disrupting immune homeostasis, and increasing susceptibility to respiratory viral infections while attenuating vaccine efficacy.

Poor prognosis in obese or metabolically compromised patients infected with influenza or SARS-CoV-2 stems from impaired immune defenses, a deteriorated metabolic microenvironment, and positive feedback mechanisms driving cytokine storms.¹⁴ Obesity and elevated leptin levels suppress type I IFN responses in bronchoalveolar cells, weakening early antiviral defenses, while SARS-CoV-2 infection triggers a distinct inflammatory cascade via ACE2-dependent entry in metabolically active tissues. Binding to ACE2 downregulates its expression, disrupting RAS homeostasis and increasing angiotensin II, which activates AT1R-NADPH oxidase signaling, generating ROS and NF-κB-driven IL-6/TNF-α transcription. In adipose tissue, ACE2⁺ adipocytes and macrophages amplify this loop, releasing leptin and resistin that sustain mTORC1 via phosphoinositide 3-kinase (PI3K)-Akt. Unlike influenza, SARS-CoV-2 ORF6 protein inhibits signal transducer and activator of transcription 1 (STAT1) nuclear translocation, blunting type I IFN while preserving mTOR-driven inflammation. This selective immunosuppression, combined with hyperglycemia-induced O-GlcNAcylation of spike protein, enhances viral stability and cytokine storm risk in T2DM. Clinical studies show 3- to 5-fold higher IL-6 in obese COVID-19 patients vs. influenza, correlating with mTORC1 hyperactivity.²⁶ Adaptive immune dysregulation manifests as CD8⁺ T cell exhaustion, defective memory formation, and rapid declines in vaccine-induced neutralizing antibody titers, increasing breakthrough infection risk.²⁷ The metabolic microenvironment further aggravates pathology, with hyperglycemia and oxidative stress disrupting the alveolar-vascular barrier, promoting microthrombosis and impairing lung repair. Ketone body deficiencies (e.g., β-hydroxybutyrate) and cholesterol metabolism abnormalities (e.g., elevated 25-hydroxycholesterol) drive pathological macrophage infiltration.^28,29 Adipose tissue, acting as a “cytokine factory,” sustains IL-6 and TNF-α release, amplifying cytokine storms via NF-κB signaling. In obese mice, lung proinflammatory cytokine levels are 3- to 5-fold higher than in controls, and viruses exploit lipid metabolism and insulin/insulin-like growth factor signaling to exacerbate metabolic dysfunction, forming an inflammation-tissue damage feedback loop.^15,30

Chronic inflammation alters immune cell activation thresholds and functional plasticity, severely impairing vaccine responses. Elevated proinflammatory cytokines and adipokines (e.g., leptin) upregulate inflammatory gene expression in immune cells via NF-κB and Janus kinase-STAT signaling, reducing responsiveness to vaccine antigens.³¹ Dendritic cell (DC) antigen presentation is compromised under metabolic stress, with reduced major histocompatibility complex class II (MHC class II) expression and downregulated co-stimulatory molecules (e.g., CD80/CD86) impairing T cell activation.³² T cell activation thresholds are elevated due to defective T cell receptor signaling and metabolic reprogramming, limiting effector T cell proliferation and differentiation, including CD8⁺ T cell cytotoxicity and CD4⁺ T cell T helper 1 (Th1)/Th2 polarization.³³ B cells exhibit impaired affinity maturation and reduced germinal center responses, driven by diminished interactions with T follicular helper (Tfh) cells, resulting in lower antibody quantity and quality.³⁴ Clinical data reveal that obese and diabetic patients generate significantly lower antibody titers following influenza or COVID-19 vaccination, with insufficient neutralizing antibodies, suppressed germinal center responses, and fragile immune memory. This is evidenced by reduced Tfh-B cell interactions, limiting high-affinity antibody production, and impaired CD8⁺ T cell cytotoxicity and CD4⁺ T cell polarization, weakening cellular immunity.^35,36 Clinical trials demonstrate that in obese individuals, influenza vaccine-induced antibody responses decline significantly within 4 weeks post-vaccination, with protective efficacy less than 50% of that in healthy individuals. COVID-19 vaccine studies further confirm that neutralizing antibody levels in T2DM patients decline more rapidly within 6 months post-vaccination, with impaired T cell immune memory maintenance.^7,37 Experimental models (e.g., high-fat diet mice) reveal that obesity-driven mTORC1 hyperactivation and adenosine monophosphate-activated protein kinase (AMPK) suppression disrupt immune cell metabolic reprogramming, reducing T cell glycolysis and oxidative phosphorylation (OXPHOS) adaptability and impairing B cell mTOR-AKT-B lymphocyte-induced maturation protein-1 (Blimp-1) signaling, which hinders plasma cell differentiation.^38,39 These findings underscore the pervasive impact of metabolic disorders on vaccine immunogenicity and durability, highlighting the urgent need for targeted interventions to enhance vaccine efficacy in affected populations (Figure 1).

Figure 1.

Immune dysregulation in metabolic disorders during respiratory viral infections

Metabolic disorders, including metabolic syndrome, steatotic liver disease, T2DM, and cardiovascular disease (CVD) risk, induce chronic low-grade inflammation, impair immune cell function, and disrupt key signaling pathways. This enhances immune susceptibility by reducing Tregs, mesenchymal stem cells, decoy cytokine receptors, and anti-inflammatory cytokines. Adipose tissue inflammation releases FFAs and DAMPs, activates M1 macrophages, and secretes proinflammatory cytokines. Lipotoxicity and glucotoxicity in the liver and pancreas trigger Kupffer cells and NLRP3 inflammasomes, exacerbating inflammation. Chronic inflammation impairs dendritic cells, T cells, and B cells, leading to immune hyperactivation with inappropriate or ineffective responses and failure to resolve inflammation. Host immune responses against viral infections are compromised, with reduced adaptive T cell (CD4⁺, CD8⁺) and innate antigen-presenting cell function, resulting in low vaccine antibody titers and rapidly decaying protective efficacy in metabolically disordered populations compared with healthy individuals.

Role of mTOR in metabolic disorders

The mechanistic target of the mTOR signaling pathway, comprising mTORC1 and mTORC2, integrates nutrient, energy, and growth factor signals to coordinate metabolism and immune function. mTORC1 senses amino acids, glucose, and insulin, activating ribosomal protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) to promote protein synthesis, lipid biogenesis, and nucleotide production while inhibiting autophagy to optimize resource utilization.⁴⁰ mTORC2 responds to insulin and the growth factors phosphorylating protein kinase B (Akt) and protein kinase C to regulate cell survival, glucose metabolism, and cytoskeletal remodeling.⁴¹ Both complexes dynamically sense metabolic states via upstream pathways, including PI3K-Akt, tuberous sclerosis complex 1/2-Ras homolog enriched in brain, and AMPK.^42,43,44 In metabolic disorders, mTOR signaling exacerbates severe respiratory viral infections (e.g., influenza, SARS-CoV-2) and impairs vaccine-induced immune responses by integrating dysregulated glucose and lipid metabolism, protein synthesis, and immune-metabolic interactions. The mTORC2-Akt axis enhances insulin signaling by phosphorylating Akt (Ser473), promoting glucose transporter 4 translocation and glucose uptake, while the mTORC1-hypoxia-inducible factor-1α (HIF-1α)/c-Myc axis sustains glycolysis enzyme activation (e.g., hexokinase) in metabolic disorders, aggravating metabolic stress and inflammation.^41,45,46 mTORC1 upregulates lipid synthesis enzymes (e.g., fatty acid synthase [FASN]) via sterol regulatory element-binding protein 1/2 (SREBP1/2), inhibiting AMPK-peroxisome proliferator-activated receptor α (PPARα)-mediated fatty acid β-oxidation, leading to ketone body deficiencies (e.g., β-hydroxybutyrate).⁴⁷ In protein synthesis, mTORC1 coordinates ribosome biogenesis and translation initiation via S6K1 and 4E-BP1, but its hyperactivation in metabolic disorders disrupts T and B cell metabolic reprogramming, suppressing antibody production and CD8⁺ T cell memory formation, thus reducing vaccine efficacy.^48,49 Tissue-specific regulation (e.g., hepatic glycogen synthesis, myocardial fatty acid oxidation) further amplifies metabolic dysregulation, accelerating inflammation. In obesity models, mTORC1 hyperactivation upregulates SREBP1, driving hepatic steatosis, while inhibiting autophagy genes (e.g., Atg5/7), exacerbating lipid accumulation and inflammation. mTORC2 dysregulation via defective Akt signaling worsens insulin resistance, perpetuating a vicious cycle.⁵⁰

Chronic mTOR hyperactivation profoundly impacts immune function. mTORC1-4E-BP1 dysregulation drives proinflammatory DC polarization, suppresses immune tolerance, and promotes proinflammatory cytokine secretion (e.g., IL-6, TNF-α), exacerbating SARS-CoV-2 infection severity and impairing vaccine responses.⁵¹ mTORC1 hyperactivation disrupts immune cell metabolic reprogramming, impairing T cell glycolysis and mitochondrial function and limiting proliferation and effector functions.⁴¹ In obese mice, CD8⁺ T cells exhibit OXPHOS defects due to sustained mTORC1 activation, reducing cytotoxicity and memory formation.⁵² B cell antibody production and germinal center responses are similarly suppressed, partly due to mTORC1-mediated inhibition of BCL6 expression, impairing Tfh-mediated B cell affinity maturation.⁵³ Mitochondrial electron transport chain disruption and ROS imbalance further impair B regulatory cell differentiation.⁵⁴ Additionally, mTORC1 hyperactivation reduces DC MHC class II and co-stimulatory molecule expression, lowering antigen presentation efficiency.⁵⁵ Clinical data indicate that obese and diabetic patients exhibit reduced antibody titers and T cell responses following influenza or COVID-19 vaccination, with shorter immune memory duration, partly attributable to mTOR-driven metabolic-immune deficits.⁵⁶

In metabolic homeostasis, mTOR signaling maintains metabolic and immune balance by integrating signals. However, in metabolic disorders, its chronic hyperactivation becomes a pathological driver. Its roles in glucose utilization, lipid synthesis, and protein synthesis, coupled with dysregulation in insulin resistance and nutrient excess, not only exacerbate metabolic disorders but also significantly impair vaccine efficacy by disrupting immune cell metabolism and function. Targeted mTOR interventions, such as rapamycin analogs or nutritional modulation, hold promise for mitigating immune deficits in metabolic disorders, offering novel strategies to enhance vaccine responses (Figure 2).

Figure 2.

mTOR signaling dysregulation in metabolic disorders

mTORC1 and mTORC2 regulate key metabolic processes, including lipid synthesis, glucose metabolism (glycolysis, gluconeogenesis), protein synthesis, mitochondrial one-carbon metabolism, and angiogenesis, via downstream effectors (e.g., S6K1, 4E-BP1, hypoxia-inducible factor-1α, sterol regulatory element-binding proteins [SREBPs]). Physiological mTOR activity balances nutrient sensing and metabolic homeostasis through insulin growth factor receptor signaling via PI3K-Akt and TSC1/2-Rheb pathways (TSC1/2 refers to the TSC protein complex [hamartin-tuberin heterodimer], which negatively regulates mTORC1 through its Rheb-GAP activity. It serves as a key inhibitory node in the PI3K-Akt-mTOR pathway, linking insulin/growth factor signaling to metabolic regulation). Chronic mTORC1 hyperactivation in obesity, driven by nutrient excess and insulin resistance, disrupts metabolic balance, promoting lipid synthesis, mitochondrial dysfunction, and inflammation. Chronic rapamycin treatment in obesity inhibits mTORC1, mitigating insulin resistance and ectopic lipogenesis but potentially impairing mTORC2-Akt signaling and highlighting the need for balanced therapeutic targeting of mTOR pathways in metabolic disorders.

Heterogeneity across metabolic disorders and viral pathogens: Immune cell exhaustion, senescence, and metabolic reprogramming

Metabolic disorders are not monolithic; obesity, T2DM, NAFLD/MAFLD, and MetS each impose distinct metabolic defects that interact differentially with respiratory viruses, leading to immune cell exhaustion, senescence, and defective metabolic reprogramming, thereby amplifying disease-specific immune vulnerabilities and vaccine outcomes. Beyond chronic inflammation, metabolic disorders drive immune exhaustion, cellular senescence, and defective metabolic reprogramming. In obesity and T2DM, CD8⁺ T cells exhibit exhaustion markers (PD-1, TIM-3, LAG-3) due to sustained mTORC1 activation and lipid overload, impairing effector function and memory formation during influenza and SARS-CoV-2 infection.⁵² B cell senescence, characterized by reduced activation-induced cytidine deaminase (AID) and Blimp-1 expression, restricts affinity maturation and long-lived plasma cell differentiation, resulting in rapid antibody waning post-vaccination. DCs show impaired antigen presentation (↓MHC class II, ↓CD80/CD86) under lipotoxic stress, reducing T cell priming efficiency.³² These non-inflammatory mechanisms synergize with inflammation to suppress antiviral immunity and vaccine durability.

Obesity is characterized by leptin resistance and adipocyte hypoxia as key metabolic defects, leading to diminished early IFN-α/β responses across all viral classes, while SARS-CoV-2 exploits adipose ACE2 overexpression for enhanced entry, resulting in significantly reduced antibody titers.¹⁴ T2DM features hyperglycemia and O-GlcNAcylation as core defects, promoting SARS-CoV-2 replication and disrupting DC glycolysis, causing rapid antibody decay within 6 months.⁷ NAFLD/MAFLD involves hepatic lipotoxicity and Kupffer cell dysfunction, predisposing patients to severe influenza due to impaired phagocytosis, yet relatively mild COVID-19, accompanied by marked decline in T cell memory.¹⁵ MetS is defined by endothelial dysfunction and hypercoagulability, exacerbating SARS-CoV-2-induced microthrombosis and blunting CD8⁺ T cell cytotoxicity.²⁹

Virus- and disease-specific mechanistic divergence is further evident at the signaling and cellular fate levels.⁵⁷ SARS-CoV-2 enters adipose and lung tissues via highly expressed ACE2, triggering RAS dysregulation and NLRP3 inflammasome activation, inducing mitochondrial ROS accumulation in endosomes and suppressing stimulator of IFN genes (STING) signaling—driving sustained mammalian target of mTORC1 hyperactivation and CD8⁺ T cell exhaustion (PD-1⁺TIM-3⁺) in obese hosts.^58,59,60 In contrast, influenza virus primarily engages sialic acid receptors on respiratory epithelium, activating the cytosolic retinoic acid-inducible gene I-mitochondrial antiviral-signaling protein axis,^61,62 resulting in transient mTORC1 activation (<48 h) in obese mice to support effector T cell expansion, followed by rapid resolution to avoid exhaustion.⁶³ In T2DM, SARS-CoV-2 leverages O-GlcNAc modification to stabilize spike protein and block DC glycolysis (reduced lactate dehydrogenase A activity), leading to a 70% reduction in memory B cells 6 months post-vaccination.⁶⁴ However, influenza primarily suppresses natural killer cell antibody-dependent cellular cytotoxicity via the AGE receptor for AGE axis and insulin signaling defects.⁶⁵ In NAFLD, hepatic lipotoxicity activates Kupffer cell TLR4-mTORC1 signaling, preferentially exacerbating influenza lung injury (58% reduced phagocytosis) while limiting SARS-CoV-2 replication due to low hepatic ACE2 expression.^66,67 These divergent mechanisms ultimately converge on mTORC1 hyperactivation via dysbiotic metabolites (increased trimethylamine N-oxide, decreased SCFAs), forming a unified hub of immune dysfunction.

How metabolic disorders alter the gut microbiota

Interactions between metabolic disorders and microbiota dysbiosis

Metabolic disorders such as obesity and T2DM engage in a complex bidirectional relationship with gut microbiota dysbiosis, collectively driving the progression of metabolic pathology. Metabolic disorders reshape gut microbiota composition through high-fat/high-sugar diets, chronic inflammation, and insulin resistance, significantly reducing microbial diversity. This is characterized by a decreased abundance of beneficial taxa (e.g., Bifidobacterium spp., Akkermansia muciniphila) and relative enrichment of proinflammatory bacteria (e.g., Enterobacteriaceae, Proteobacteria).⁶⁸ High-fat diets directly alter the intestinal carbohydrate and lipid metabolism environment, suppressing the growth of SCFA-producing bacteria, while insulin resistance-induced inflammatory cytokines (e.g., IL-6, TNF-α) disrupt the intestinal epithelial mucus layer via TLR/NF-κB signaling, promoting colonization by opportunistic pathogens.⁶⁹ Conversely, microbiota dysbiosis exacerbates metabolic disorders by compromising intestinal barrier function and translocating proinflammatory metabolites, inducing systemic low-grade inflammation.⁶⁹ LPS activates TLR4 signaling, upregulating proinflammatory gene expression in adipose tissue and liver and worsening insulin resistance and lipid accumulation.⁷⁰ In obese mouse models, germ-free mice receiving microbiota transplants from obese donors exhibit weight gain and reduced insulin sensitivity, demonstrating the direct pathogenic role of dysbiosis. This mutually reinforcing vicious cycle amplifies metabolic disorders through a metabolism-microbiota-inflammation axis.

Microbiota dysbiosis markedly alters the metabolite profile, particularly reducing the production of SCFAs, bile acids, and tryptophan metabolites, which exacerbate metabolic dysfunction by modulating adipocyte and hepatocyte function.⁷¹ SCFAs, produced by Bifidobacterium and other taxa through dietary fiber fermentation, are significantly diminished in metabolic disorders due to reduced beneficial bacteria and inadequate fiber intake.⁷² SCFAs activate G protein-coupled receptors (GPRs) and inhibit histone deacetylases (HDACs), promoting insulin signaling and lipolysis in adipocytes while suppressing lipogenesis. Propionate activates AMPK signaling via GPR43, enhancing fatty acid oxidation and reducing lipid accumulation.⁷³ However, SCFA depletion impairs these protective effects, leading to adipocyte hypertrophy and increased proinflammatory cytokine secretion.⁷⁴ In hepatocytes, butyrate inhibits SREBP1 and fatty acid synthase (FASN) expression via HDAC suppression, mitigating steatosis, but SCFA deficiency exacerbates hepatic lipid synthesis and inflammation.⁷⁵ Clinical studies show that reduced gut SCFA levels in obese patients correlate negatively with hepatic steatosis and insulin resistance severity, underscoring the critical role of SCFAs in metabolic regulation.⁷⁶

Microbiota dysbiosis also aggravates adipocyte and hepatocyte dysfunction through aberrant production of other metabolites. Secondary bile acids, generated by gut microbiota metabolism of primary bile acids, are markedly reduced in metabolic disorders due to a decreased abundance of bile acid-producing taxa (e.g., Clostridium spp.). Secondary bile acids regulate adipocyte and hepatocyte metabolic homeostasis via farnesoid X receptor (FXR) and Takeda GPR 5 (TGR5).⁷⁷ Deoxycholic acid activates TGR5 signaling in adipocytes, promoting PPARγ coactivator-1α (PGC-1α)-mediated mitochondrial biogenesis and energy expenditure,⁷⁸ while FXR activation in hepatocytes suppresses SREBP1-C-driven lipogenesis.⁷⁹ Bile acid depletion impairs these protective mechanisms, leading to adipocyte energy metabolism imbalance and exacerbated hepatic lipid accumulation.⁸⁰ Tryptophan metabolites are similarly affected by dysbiosis, with reduced production weakening aryl hydrocarbon receptor (AHR) signaling and diminishing adipocyte and hepatocyte anti-inflammatory and insulin-sensitizing effects.⁸¹ Conversely, proinflammatory metabolites such as LPS increase significantly in dysbiosis, inducing NF-κB activation in adipocytes and hepatocytes via TLR4 signaling, promoting IL-1β and TNF-α secretion, and aggravating insulin resistance and hepatic inflammation.⁸²

Dysbiosis-induced metabolite abnormalities also indirectly impair metabolic tissue function by disrupting the intestinal barrier. Downregulated expression of tight junction proteins (e.g., zonula occludens-1) facilitates the translocation of microbe-associated molecular patterns, such as LPS and peptidoglycan, activating the NLRP3 inflammasome in adipose tissue and liver and amplifying proinflammatory signaling.⁸³ In obese mouse models, LPS induces MCP-1 and IL-1β secretion via hepatocyte TLR4 signaling, promoting proinflammatory polarization of Kupffer cells and exacerbating hepatic steatosis and fibrosis.⁸⁴ In adipose tissue, LPS and FFAs synergistically activate the NLRP3 inflammasome in macrophages, increasing M1 macrophage proportions and inhibiting insulin signaling.⁸⁵ These direct and indirect effects of microbial metabolites establish a positive feedback loop, perpetuating adipocyte and hepatocyte metabolic dysfunction, driving systemic insulin resistance, and amplifying inflammation (Figure 3).

Figure 3.

Gut microbiota dysbiosis in obesity and its impact on metabolic cells

Obesity, characterized by metabolic syndrome, steatotic liver disease, T2DM, and CVD risk, induces gut microbial imbalance, increasing intestinal permeability, LPS levels, and Firmicutes/Bacteroidetes ratio while reducing beneficial taxa. Undigestible polysaccharides (dietary fiber) are fermented by gut microbiota (Bifidobacterium, Faecalibacterium, Roseburia) into SCFAs (acetate [60%], butyrate [20%], and propionate [20%]). SCFAs activate G protein-coupled receptors (GPR43, GPR41/43) and PPARγ, promoting lipid-buffering capacity, adipogenesis, and fatty acid oxidation in fat and hepatic cells while reducing lipogenesis, gluconeogenesis, and proinflammatory chemokines. Reduced SCFA production in obesity exacerbates metabolic dysfunction, highlighting the role of microbial metabolites in regulating metabolic homeostasis.

Shaping immune cell function by gut microbial metabolites

Gut microbial metabolites profoundly influence immune system function and homeostasis through complex interactions with host immune cells, with SCFAs (e.g., acetate, propionate, butyrate) serving as key regulators. These metabolites modulate immune cell metabolism, proliferation, and differentiation via multiple mechanisms, including activation of G protein-coupled receptors (GPRs: GPR41, GPR43, GPR109A), uptake/transport via monocarboxylate transporters (MCTs) and sodium-coupled MCTs (SMCTs), and inhibition of histone deacetylases (HDACs). GPR43 and GPR109A, highly expressed on T cells, DCs, and macrophages, mediate SCFA-induced cyclic AMP-protein kinase A signaling, suppressing proinflammatory cytokine secretion and fostering an anti-inflammatory microenvironment.⁷¹ MCTs and SMCTs facilitate SCFA uptake into cells, altering metabolic programs to support T cell activation and B cell antibody production.⁸⁶ Additionally, SCFAs modify epigenetic landscapes by inhibiting HDAC3 and HDAC6, upregulating immunoregulatory gene expression (e.g., Foxp3), enhancing T regulatory cell (Treg) differentiation, and suppressing proinflammatory Th17 cell activity.^87,88 These multilayered regulatory mechanisms maintain immune homeostasis but are significantly impaired in metabolic disorders due to reduced SCFA production, leading to diminished vaccine-induced antibody production and cellular immune responses.

SCFA-mediated regulation of the mechanistic target of the mTOR signaling pathway serves as a critical link between metabolism and immune function, finely balancing immune cell metabolic demands and functional states through direct and indirect mechanisms. SCFAs activate PI3K-Akt signaling via GPR43, upregulating mTORC1 activity to promote T and B cell metabolic reprogramming.⁸⁹ SCFAs exert cell-type-specific effects on immune cell differentiation, function, and metabolic states, directly influencing vaccine response strength and durability. In Treg cells, butyrate enhances Foxp3 gene histone acetylation via GPR109A and HDAC inhibition, promoting Treg differentiation and IL-10 secretion, which mitigates systemic inflammation.⁹⁰ This anti-inflammatory effect indirectly supports B cell germinal center reactions, enhancing vaccine-induced high-affinity antibody production.⁹¹ In Th17 cells, SCFAs downregulate retinoic acid-related orphan receptor γt expression by inhibiting mTORC1 and STAT3 signaling, reducing IL-17 secretion and improving Treg/Th17 balance, thus alleviating the proinflammatory microenvironment in metabolic disorders and fostering a favorable immune context for vaccine responses.⁹² In CD8⁺ T cells, propionate activates mTORC1 and mTORC2 signaling via GPR43, upregulating glycolysis and mitochondrial biogenesis-related genes (e.g., PGC-1α) and enhancing effector T cell cytotoxicity and memory T cell formation, which are critical for antiviral immunity and long-term vaccine protection.⁸⁹ In B cells, SCFAs promote acetyl-coenzyme A production via MCTs, enhancing histone acetylation and supporting BCL6 and AID gene expression, thereby facilitating germinal center reactions and antibody affinity maturation.⁹³ In DCs, butyrate upregulates immunoregulatory factors and MHC class II/CD80/CD86 expression via GPR41, enhancing antigen presentation and T cell activation efficiency.⁷¹ Clinical studies demonstrate that healthy individuals with higher SCFA levels exhibit stronger Treg and CD8⁺ T cell responses and higher neutralizing antibody titers following COVID-19 vaccination, underscoring the pivotal role of SCFAs in optimizing vaccine protection (Figure 4).

Figure 4.

SCFA-mediated immunoregulation in metabolic disorders

SCFAs, produced by microbial fermentation of undigestible polysaccharides, inhibit mTORC1 via AMPK and HDAC pathways, enhance tight junction protein expression (reducing intestinal permeability and proinflammatory cytokines), promote autophagy, and mitigate systemic inflammation and endotoxemia by inhibiting the LPS-TLR4 pathway. SCFAs enhance dendritic cell retinoic acid production via GPR109A and aldehyde dehydrogenase 1A2 (ALDH1A2), promoting Treg cell differentiation (Foxp3 expression) and IL-10 secretion. In goblet cells, SCFAs inhibit mTOR-S6K signaling via HDACs, increasing mucin production and reducing inflammation susceptibility. In naive T cells, SCFAs suppress Th17 cell differentiation (retinoic acid-related orphan receptor γt) while promoting Treg cells (Foxp3), balancing Th1/Th17 responses. SCFAs enhance B cell and plasma cell differentiation by increasing acetyl-coenzyme A and lipid synthesis (via monocarboxylate transporter 1 [MCT1]/sodium-coupled MCT1 [SMCT1]), boosting IgA production, and improving CD8⁺ T cell survival and effector function (tricarboxylic acid [TCA] cycle, oxidative phosphorylation [OXPHOS]) via HDAC inhibition. In CD4⁺ T cells, SCFAs activate GPR43 and AHR, promoting IL-10 and suppressing IL-22, mitigating inflammation.

Vaccine immunity and the gut microbiota

Mounting evidence underscores the pivotal role of the gut microbiota in shaping vaccine-induced immune responses, with alterations in its composition and function directly impacting vaccine efficacy. In germ-free or antibiotic-treated mice with depleted gut microbiota, vaccine-induced immune responses are significantly diminished. Clinical studies reveal that an elevated Firmicutes/Bacteroidetes ratio correlates with enhanced antibody levels following BBIBP-CorV vaccination,⁹⁴ while reduced microbial diversity may decrease antibody titers by up to 60%.⁹⁵ Probiotics (e.g., Lactobacillus spp.) enhance vaccine-induced secretory immunoglobulin (Ig) A levels by 2- to 3-fold by promoting B cell activation in Peyer’s patches, highlighting the indispensable role of the microbiota in initiating and sustaining adaptive immunity.⁹⁶ SCFAs, particularly butyrate, enhance B cell antibody secretion via HDAC inhibition, and exogenous SCFA supplementation can restore IgG titers by approximately 30%.⁹⁷ Additionally, tryptophan metabolites regulate IFN secretion by plasmacytoid DCs via the AHR pathway, influencing vaccine-induced cellular immunity.⁹⁸

Probiotic supplementation experiments provide compelling evidence for improving vaccine responses. In dysbiotic mice, supplementation with specific probiotics (e.g., Bifidobacterium, Lactobacillus spp.) partially restores vaccine-induced immune responses.⁹⁹ A study in aged mice demonstrated that oral administration of Lactobacillus casei prior to influenza vaccination increased IgG antibody titers by approximately 45%, enhanced T cell proliferation by about 35%, and reduced post-vaccination inflammatory markers by roughly 40%.¹⁰⁰ Probiotic treatment increased gut-associated lymphoid tissue DC co-stimulatory molecule (CD80) expression by 30%, optimized CD4⁺/CD8⁺ T cell ratios, and enhanced T cell proliferation by 25%.^33,101 Specific strains also modulated gut Th17 and splenic Th1/Th2 ratios via the STING pathway.¹⁰² These effects likely stem from probiotics enhancing DC maturation, MHC class I/II coactivation, and co-stimulatory pathways (e.g., OX40-OX40L), promoting sustained T cell activation.^103,104 Probiotics also correct age-related Th2 bias, increasing IFN-γ (Th1 marker) and reducing IL-4 (Th2 marker), restoring the IgG2a/IgG1 ratio.³³

Clinical relevance has been preliminarily validated in human studies. Multiple cohort studies indicate that gut microbiota composition in older adults is closely linked to COVID-19 vaccine responses. A prospective observational study from the University of Hong Kong found that older adults with higher neutralizing antibody levels post-CoronaVac vaccination exhibited significantly greater baseline abundance of specific microbiota.¹⁰⁵ Bifidobacterium may enhance vaccine immunogenicity by modulating DC activation or amplifying Th1 responses.¹⁰⁶ A South Korean cohort study showed that Faecalibacterium prausnitzii abundance positively correlated with antibody persistence following the mRNA vaccine BNT162b2.¹⁰⁷ The anti-inflammatory properties of F. prausnitzii (e.g., butyrate production) may prolong immune memory by maintaining intestinal barrier integrity or modulating Treg function, while its reduction in older adults may accelerate antibody decline.^108,109 Additionally, a study from BC Children’s Hospital (Vancouver, Canada) found that individuals with high-fiber diets associated with increased SCFA-producing bacteria, exhibited stronger COVID-19 vaccine antibody responses, highlighting the impact of diet-microbiota interactions on vaccine efficacy in older adults.⁹⁴ These studies collectively suggest that microbiota dysbiosis is a key driver of attenuated vaccine responses in aging populations.

Critical nexus: The gut microbiota-mTOR axis integrates metabolic and immune signals

Dysregulated mTOR signaling directly reshapes immune cell metabolic reprogramming and functional programs, markedly impairing the initial efficiency and long-term protection of vaccine responses. In CD8⁺ T cells, sustained mTORC1 activity drives the overexpression of glycolysis genes and impairs mitochondrial function, evidenced by downregulated PGC-1α and mitochondrial transcription factor A, inhibiting memory T cell formation and weakening long-term antiviral vaccine protection.¹¹⁰ CD4⁺ T cell differentiation is disrupted, with reduced Th1 and Tfh cell proportions due to mTORC1-mediated suppression of BCL6 and T-bet, limiting Tfh-driven B cell germinal center reactions.¹¹¹ In B cells, mTORC1 hyperactivation downregulates BCL6 and AID, hindering somatic hypermutation and antibody affinity maturation, resulting in low antibody titers and inadequate neutralizing capacity.¹¹² DCs exhibit reduced MHC class II, CD80, and CD86 expression due to mTORC1-driven proinflammatory metabolism, decreasing antigen presentation efficiency, and T cell activation.³⁸ LPS-exacerbated inflammation further upregulates proinflammatory cytokines via mTORC1, suppressing Treg cell Foxp3 expression and IL-10 secretion, disrupting immune tolerance. These findings provide a theoretical basis for developing mTORC1-targeted metabolic interventions as vaccine adjuvants, particularly for optimizing vaccine strategies in populations with metabolic abnormalities such as obesity and T2DM. Future approaches may involve temporally specific mTORC1 modulation to simultaneously enhance effector functions and memory formation.

Dysregulation of the gut microbiota-mTOR axis integrates metabolic and immune signals, synergistically contributing to inadequate initial immune responses and defective immune memory formation in infections and vaccinations, significantly increasing severe disease risk and compromising overall vaccine efficacy. SCFA depletion abrogates their protective inhibition of mTORC1 via AMPK/sirtuin 1 and HDAC pathways, while LPS induces systemic inflammation via the TLR4-mTORC1 axis, suppressing T and B cell metabolic adaptability.^113,114 Compromised intestinal barrier function exacerbates LPS and peptidoglycan translocation, activating TLR4-mTORC1 signaling in spleen and lymph nodes, inhibiting antigen-specific T cell proliferation and B cell germinal center reactions.¹¹⁵ In obese patients, post-vaccination memory B cell and CD8⁺ T cell populations are significantly lower than in healthy individuals, with faster antibody titer decay that is directly linked to SCFA reduction and mTORC1 hyperactivation driven by microbiota dysbiosis.⁹⁴ Animal model studies further confirm that SCFA or probiotic supplementation restores mTOR signaling balance and intestinal barrier function, significantly enhancing influenza vaccine T cell responses and antibody production efficiency. The dysregulation of this axis not only impacts local immunity but also exerts systemic immunosuppressive effects through circulatory and neuro-immune axes (e.g., vagus nerve), modulating mTOR activity in distal lymphoid organs, which highlights its critical role in metabolic disorders and vaccine failure (Figure 5).

Figure 5.

The gut microbiota-mTOR axis in vaccine efficacy and metabolic disorders

Metabolic disorders disrupt gut microbiota balance, exacerbating metabolic dysfunction via reduced SCFAs, which regulate mTOR signaling. Hyperactivation of mTOR signaling (mTORC1, mTORC2) via PI3K-Akt and nutrient-sensing pathways in metabolic disorders promotes insulin resistance, senescence, and apoptosis while inhibiting autophagy. mTORC1 inhibitors and curcumin mitigate these effects but may impair immune responses if not carefully dosed. Reduced vaccine immunogenicity in metabolic disorders results from impaired immune responses and rapid decay of protective efficacy, as shown by lower antibody concentrations in elderly individuals with mTOR dysregulation compared with those with balanced mTOR activity. The microbiota acts as a natural adjuvant for vaccine responses, with microbial metabolites enhancing immune development and reducing inflammation susceptibility, offering a therapeutic avenue to improve vaccine efficacy in metabolically compromised populations.

While the microbiota-mTOR axis is central, other pathways mediate microbial immunoregulation and intersect with mTOR signaling. The AHR pathway, activated by tryptophan metabolites (e.g., indole-3-aldehyde), promotes IL-22 and mucin production, enhancing barrier integrity; AHR crosstalk with mTORC1 modulates Treg/Th17 balance.¹¹⁶ The NLRP3 inflammasome, triggered by LPS or palmitate, amplifies IL-1β; mTORC1 enhances NLRP3 assembly via HIF-1α.¹¹⁷ The STING-cyclic guanosine monophosphate-adenosine monophosphate synthase pathway, stimulated by microbial DNA, drives type I IFN; mTORC2-Akt inhibits STING degradation.¹¹⁸ AMPK, activated by butyrate via GPR109A, directly antagonizes mTORC1, restoring autophagy and T cell metabolism. These pathways form a networked regulatory circuit with mTOR, amplifying or buffering microbial signals in metabolic contexts.¹¹⁹

Targeting the gut microbiota-mTOR axis to reduce severe respiratory viral infection risk and enhance vaccine efficacy

The gut microbiota-mTOR axis, a pivotal nexus of metabolic and immunoregulation, significantly exacerbates severe respiratory viral infection risk and impairs vaccine immune responses in metabolic disorders, with its dysregulation offering key targets for therapeutic interventions. Metabolic disorder-induced microbiota dysbiosis, characterized by reduced SCFA production and increased proinflammatory metabolites, synergistically drives mTORC1 hyperactivation, disrupting immune cell metabolic reprogramming. This suppresses antiviral innate immunity and weakens antigen-specific T and B cell responses, exacerbating viral replication, lung injury, and limiting vaccine-induced antibody production and immune memory. Targeted interventions focusing on the gut microbiota-mTOR axis—including microbiota modulation, mTOR signaling inhibition, combined approaches, and novel vaccine designs—aim to restore metabolic-immune balance, reduce severe outcomes and mortality from respiratory viral infections, and optimize vaccine efficacy in metabolically compromised populations. These strategies require precise optimization of dosage, timing, and target specificity to balance efficacy with potential side effects, offering innovative solutions to public health challenges (Table 1).

Table 1.

Therapeutic strategies targeting mTOR signaling and gut microbiota to enhance vaccine responses in metabolic disorders

Strategy	Target	Mechanism	Outcome	Evidence level
mTOR inhibitors (rapamycin, everolimus)	mTORC1	↓S6K1/4E-BP1, ↑autophagy	↑CD8+ memory, ↑antibody titers	preclinical
Probiotics (Bifidobacterium, Lactobacillus)	microbiota	↑SCFAs, ↓LPS	↑Treg, ↑IgA	clinical (pilot)
Prebiotics (inulin)	SCFA production	↑GPR43/HDAC inhibition	↑vaccine efficacy	clinical
FMT	microbiota restoration	normalize dysbiosis	↓inflammation, ↑T cell response	preclinical
Combined (probiotic + low-dose rapamycin)	dual	synergistic mTOR and microbiota modulation	maximal efficacy	emerging
Novel adjuvants (GPR43 agonist nanoparticles)	lymphoid delivery	localized immune activation	↑protection in obesity	preclinical

mTOR-targeted interventions

Inhibiting mTORC1 hyperactivation provides an effective strategy for reducing severe disease risk and enhancing vaccine responses. mTOR inhibitors, such as rapamycin and everolimus, block S6K1 and 4E-BP1 signaling, alleviating lipid metabolism hyperactivity and chronic inflammation in metabolic disorders while restoring immune cell function.¹²⁰ Animal models demonstrate that low-dose rapamycin optimizes CD8⁺ T cell metabolism (glycolysis/OXPHOS balance) in obese mice, promoting memory T cell formation and significantly enhancing COVID-19 vaccine antibody titers and long-term protection.⁴⁸ However, balancing mTORC1 and mTORC2 target specificity is critical, as short-term, low-dose mTORC1 inhibition enhances Treg differentiation and DC antigen presentation efficiency, whereas prolonged or high-dose inhibition may disrupt mTORC2-Akt signaling, which impairs B cell proliferation and antibody production.¹²¹ Preclinical studies should optimize dosing windows and develop specific mTORC1 inhibitors to minimize side effects such as hyperglycemia and gastrointestinal discomfort, ensuring safety and immune enhancement.^42,122

Microbiota-targeted interventions

Restoring gut microbiota balance and SCFA production shows promise for reducing severe disease risk and enhancing vaccine immune responses. Probiotics (e.g., Bifidobacterium, Lactobacillus spp.) increase SCFA-producing bacteria abundance, promoting anti-inflammatory effects via GPR41/43 activation and HDAC inhibition; enhancing Treg differentiation, intestinal barrier function, and T/B cell metabolic adaptability; and supporting antibody affinity maturation. Prebiotics (e.g., inulin, fructooligosaccharides) and high-fiber diets generate SCFAs through fermentation, improving the immune microenvironment and reducing LPS translocation-induced proinflammatory responses.¹²³ Animal models show that fecal microbiota transplantation (FMT) reshapes the gut microbiota in obese mice, reducing inflammation and partially restoring influenza vaccine CD8⁺ T cell responses. Clinical trials confirm that probiotic supplementation (e.g., Lactobacillus rhamnosus) or dietary fiber in obese individuals significantly improves influenza vaccine antibody titers and Treg/Th17 balance.^124,125 However, long-term efficacy, strain specificity, and applicability to different vaccine types require further validation, and FMT safety and individualized compatibility need confirmation through large-scale clinical trials.¹²⁶

Combined microbiota and mTOR-targeted strategies

Integrating microbiota modulation with mTOR-targeted interventions may maximize reductions in severe disease risk and enhance vaccine efficacy through synergistic effects. In COVID-19, microbiota dysbiosis is associated with cytokine storms, while mTOR hyperactivation exacerbates inflammation. Combining probiotics with mTOR modulators synergistically reduces proinflammatory cytokines (e.g., IL-6) and improves pulmonary immune homeostasis.¹⁰⁶ Personalized combined regimens, based on individual microbiota profiles and mTOR pathway activity, such as antibiotic pretreatment followed by FMT and mTOR inhibitors, have shown synergistic efficacy in cancer immunotherapy.¹²⁷ Future combined interventions should precisely design probiotic strains, mTOR inhibitor dosages, and intervention timing, leveraging multi-omics technologies to elucidate molecular mechanisms and ensuring efficacy and safety for personalized immune optimization in metabolically compromised populations.

Novel vaccine designs

Addressing immune deficits from mTOR-microbiota axis dysregulation, novel vaccine designs offer tailored solutions for metabolically compromised populations. Traditional adjuvants exhibit limited immunostimulatory efficacy in metabolic disorders, whereas GPR43 agonists (GLPG0974) combined with rapamycin in nanoparticle formulations increase vaccine efficacy in MetS models from 15% with alum to 72%.^128,129 Nanoparticle delivery systems enable precise delivery of SCFAs or mTOR inhibitors to lymphoid organs, locally modulating mTOR activity and minimizing systemic side effects. mRNA vaccines, optimized through LNP design, enhance antigen expression and T cell responses, showing promise in COVID-19 vaccines. Preclinical studies demonstrate that adjuvants combining TLR7/8 agonists and SCFA mimetics significantly enhance influenza vaccine antibody titers and memory B cell generation in obese mice.¹³⁰ Future efforts should explore multivalent vaccines and mucosal delivery systems to enhance local immunity, reduce severe infection risk in metabolically compromised populations, and validate long-term protection and applicability through clinical trials.

Conclusions

The gut microbiota-mTOR axis is a critical nexus in metabolic disorders, profoundly impacting immune function and vaccine efficacy in respiratory viral infections. This review systematically elucidates the following: (1) metabolic disorders disrupt immune responses through the gut microbiota-mTOR axis, increasing severe infection risk and impairing vaccine-induced immunity by altering immune cell metabolic reprogramming; (2) microbiota dysbiosis, marked by reduced SCFA production and increased proinflammatory metabolites such as LPS, drives mTORC1 hyperactivation, suppressing antiviral immunity and weakening T and B cell responses; (3) this dysregulation delays viral clearance, exacerbates lung injury, and reduces vaccine antibody production and immune memory, compromising efficacy in metabolically impaired populations; (4) targeted interventions, such as microbiota modulation (probiotics, prebiotics, FMT), mTOR inhibitors (e.g., rapamycin), and novel vaccine adjuvants (e.g., GPR43 agonists), restore metabolic-immune balance, mitigating severe disease and enhancing vaccine responses; and (5) future research leveraging multi-omics and clinical trials is essential to develop precision interventions and innovative vaccine designs, such as nanoparticle-based systems, to optimize immunity and reduce morbidity in metabolically compromised individuals.

Acknowledgments

This study was funded by the National Natural Science Foundation of China (U20A20410) (project no. 32571111), the Provincial Industry-University Cooperation Collaborative Education Project (no. 318 [2022] of the Zhejiang Development Reform Society, the University Level Scientific Research Project of Zhejiang Shuren University (grant no. 2024RO57) and Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province (grant no. SZD2025B020). The authors thank all the researchers, doctors, nurses, medical technicians, front-line workers, and public health officials for their hard work during COVID-19.

Author contributions

Writing – original draft, Jiaxuan Li; writing – review & editing, Jiaxuan Li and K.D.; project administration, Jianhua Li and K.D.

Declaration of interests

The authors declare no competing interests.