Link between physical activity,nutrition,and antimicrobial pharmacokinetics and therapeutic efficacy: Implications for resistance management

Class-specific pharmacokinetics and resistance mechanisms of antimicrobial agents

Antimicrobial agents encompass pharmacologically distinct classes, including antibiotics, antifungals, and antivirals, each characterized by fundamentally different pharmacokinetic profiles, mechanisms of action, and resistance pathways. Antibiotics primarily target bacterial structures or processes (e.g., cell wall synthesis, protein synthesis) and often exhibit rapid distribution and elimination, with many hydrophilic agents relying on renal clearance. In contrast, antifungal drugs, such as azoles and echinocandins, typically act on eukaryotic cell components (e.g., ergosterol synthesis or cell membrane integrity) and frequently undergo extensive hepatic metabolism, resulting in different susceptibility to host metabolic and nutritional states. Antiviral agents, on the other hand, often require intracellular activation and are highly dependent on host cellular machinery, with pharmacokinetics influenced by factors such as cellular uptake, enzymatic activation, and tissue-specific distribution. Moreover, resistance mechanisms vary considerably across these classes, ranging from enzymatic degradation and efflux pumps in bacteria to target mutations in fungi and rapid genomic variability in viruses. These differences are critical when considering the influence of lifestyle factors, as exercise, nutrition, and metabolic status may differentially affect drug absorption, distribution, metabolism, and efficacy depending on the antimicrobial class. Therefore, lifestyle–drug interactions should be interpreted within a class-specific pharmacological framework rather than under a generalized concept of “antimicrobials”.^1–4 It should be noted that, given the comparatively larger body of evidence available for antibacterial agents, the present review focuses predominantly on antibiotics, whereas the influence of lifestyle factors on antifungal and antiviral pharmacology is addressed more briefly and should be regarded as an area requiring dedicated future investigation.

Impact of lifestyle factors on antimicrobial resistance

AMR represents a growing global health threat, driven not only by antibiotic misuse but also by lifestyle-related factors that modulate host–microbe interactions and influence microbial evolution. Among these factors, physical inactivity, poor dietary patterns, chronic stress, and metabolic dysregulation play underappreciated roles in shaping microbial ecology, immune resilience, and the horizontal transfer of antibiotic resistance genes (ARGs). These behaviors modify both the human microbiome and systemic physiological states in ways that may compromise drug efficacy and increase microbial virulence.

Sedentary behavior has been associated with systemic inflammation, insulin resistance, and gut dysbiosis, all of which create a permissive environment for the selection of resistant bacterial strains. Physical inactivity has been reported to contribute to reduced microbial diversity, and some studies describe a relative decrease in beneficial genera such as Faecalibacterium prausnitzii and Akkermansia muciniphila, which have anti-inflammatory and colonization-resistant properties. ²² Low physical activity also impairs gut epithelial barrier function, increasing lipopolysaccharide (LPS) translocation and systemic endotoxemia. This persistent immune activation fosters immune exhaustion and disrupts mucosal immunity—conditions that favor chronic infections, increase antibiotic use, and potentially accelerate AMR propagation. ²³

Modern dietary habits, characterized by high intake of saturated fats, refined carbohydrates, and ultra-processed foods, profoundly shape the gut microbiome and its resistome. Evidence suggests that diets rich in animal protein and fat may promote the expansion of Bacteroides and Proteobacteria, taxa that have been associated with a higher prevalence of antimicrobial resistance genes (ARGs). ²⁴ Moreover, these dietary patterns reduce short-chain fatty acid (SCFA) production—particularly that of butyrate and acetate—by diminishing the number of fiber-fermenting bacteria. SCFAs are essential for mucosal immunity and limiting pathogen growth. It has been proposed that their deficiency may be associated with increased gut pH and impaired immune exclusion, conditions that could favour the persistence of opportunistic pathogens and resistance gene carriers, although this remains a largely hypothetical pathway requiring further confirmation. ²⁵ Some processed foods also contain trace amounts of antibiotics and antibiotic-like preservatives that exert subtherapeutic antimicrobial pressure, further selecting for resistant organisms. ²⁴ In this sense, it has been hypothesized that the Western diet might act as a selective pressure analogous to low-dose antibiotic exposure, although direct causal evidence in humans remains limited.

Obesity and metabolic syndrome, which are largely driven by poor diet and inactivity, have been proposed as indirect but potent enhancers of AMR. These conditions are linked to increased infection susceptibility, delayed immune responses, and impaired vaccine efficacy. Observational data suggest that individuals with metabolic dysfunction may carry a higher burden of multidrug-resistant enterobacteria, although such associations are correlational and do not establish a direct causal relationship. ²⁶ Mechanistically, and largely on the basis of preclinical and associative evidence, metabolic dysfunction affects bile acid metabolism, alters microbial signaling, and reduces antimicrobial peptide production. Furthermore, obesity promotes chronic low-grade inflammation (“metaflammation”), which not only compromises mucosal defenses but also facilitates biofilm formation—a critical factor in antibiotic evasion.

Chronic stress, poor sleep, and psychological dysregulation influence the hypothalamic‒pituitary‒adrenal (HPA) axis and the autonomic nervous system, which in turn modulate mucosal immunity and the gut microbial structure. These alterations may indirectly affect AMR by increasing colonization by Enterobacteriaceae and Clostridioides difficile, reducing the production of immunoglobulin A (IgA) and promoting antibiotic use due to recurrent subclinical infections.

A key mechanism potentially linking lifestyle factors and antimicrobial resistance is the modulation of horizontal gene transfer (HGT) within the gut microbiome.^27,28 Dysbiotic microbial communities have been shown—primarily in in vitro studies and animal models—to harbor increased densities of mobile genetic elements such as plasmids, integrons, and transposons, which facilitate the dissemination of antibiotic resistance genes (ARGs). ²⁷ Lifestyle-induced alterations in microbial composition may increase the relative abundance and proximity of commensal and opportunistic bacteria, creating conditions that could favor gene exchange. However, it is important to note that most of the mechanistic evidence supporting these processes derives from controlled experimental models,^29,30 and direct clinical evidence in humans remains limited.^29,30 Therefore, while these findings suggest a plausible link between lifestyle-modulated microbiota and HGT dynamics, further studies are required to establish their clinical relevance. ²⁹

Despite these limitations, emerging evidence indicates that lifestyle interventions may modulate the microbiome in ways that are associated with reduced ARG abundance and improved microbial resilience. Moderate physical activity, plant-rich diets, and stress management protocols have been linked to the reversal of dysbiosis and a lower prevalence of resistance-associated taxa. Similarly, the intake of fermented foods rich in bacteriocin-producing lactobacilli may competitively exclude ARG carriers and restore colonization resistance. ²⁸ These findings highlight the potential role of preventive lifestyle strategies within the antimicrobial stewardship continuum, although their direct impact on HGT dynamics in humans remains to be fully elucidated.

Lifestyle factors, including physical activity, dietary composition, stress levels, and metabolic health, shape both the structure and functional resistome of the human microbiota. Through effects on microbial ecology, immune function, and gene transfer mechanisms, these variables play decisive roles in AMR evolution. While antibiotic misuse remains a central driver, addressing behavioral and metabolic contributors offers a promising, underutilized strategy for curbing resistance. Future clinical frameworks may incorporate lifestyle screening into AMR risk stratification, aligning antibiotic therapy with individualized metabolic and microbiome profiles. In the following section, we explore how diet and physical activity comodulate the microbiome in more detail, laying the foundation for integrated resistance management.

An often overlooked contributor to lifestyle-associated AMR is environmental exposure in urban settings. Urban dwellers are frequently exposed to environmental reservoirs of ARGs, including wastewater, contaminated surfaces, and air particulates in public transport and healthcare settings. Physical inactivity and indoor-dominant lifestyles reduce natural immunological priming and the diversity of environmental microbiota exposure, contributing to immune dysregulation and a less competitive microbiota that cannot efficiently prevent colonization by resistant strains. ³¹ Furthermore, individuals with limited outdoor activity may be more frequently exposed to indoor antimicrobial cleaning agents, which exert selective pressure on the skin and gut microbiota. Over time, this may promote the enrichment of efflux pump-containing commensals or bacteria carrying multidrug resistance (MDR) plasmids.

Emerging research suggests that lifestyle factors may be associated with epigenetic modifications, including DNA methylation, histone acetylation, and miRNA expression, that could influence not only host immunity but also microbiome composition and ARG carriage. For example, sedentary lifestyles and ultraprocessed diets have been linked to hypermethylation of genes involved in mucosal defense and xenobiotic metabolism, which indirectly affects microbial colonization and resilience. ²⁹ Additionally, host–microbe coregulation of gene expression means that epigenetic environments influenced by diet and physical activity can select for microbial populations that are either more cooperative (commensal-dominant) or more virulent/resistant (pathobiont-dominant). This relationship suggests that resistance risk is not only microbial but also host programmed and therefore potentially reversible through lifestyle modulation.

Recognizing lifestyle behaviors as modifiable risk factors for AMR paves the way for precision prevention strategies. Just as pharmacogenomics is used to tailor medications, a lifestyle-based resistance risk profile could inform prophylactic measures or antimicrobial prescribing practices. For example, patients with sedentary, dysmetabolic, or highly urbanized profiles may benefit from microbiome-preserving antibiotic selection, increased probiotic support, or closer resistance monitoring during therapy. Moreover, public health policies could integrate AMR considerations into urban planning, dietary guidelines, and exercise promotion campaigns. Such approaches acknowledge AMR not just as a clinical outcome of drug misuse but also as a systems-level reflection of human–environment–microbiota interactions.

Modulation of the human microbiome through diet and exercise

The human gut microbiome plays a critical role in maintaining immune homeostasis, metabolic balance, and host defense. Both dietary composition and physical activity are recognized as primary modulators of microbial composition, diversity, and function. These lifestyle factors shape not only microbial abundance but also the production of bioactive metabolites such as short-chain fatty acids (SCFAs), which directly influence inflammation, barrier integrity, and antimicrobial resistance (AMR). In this section, we explore the molecular pathways through which diet and exercise comodulate the microbiome, highlighting the implications for host–microbe interactions and therapeutic resistance.

Diet is one of the most potent and rapid influences on the composition of the gut microbiome. Diets high in fiber, polyphenols, and complex carbohydrates increase the relative abundance of Bacteroidetes, Lactobacilli, and Prevotella, increasing the production of beneficial SCFAs, such as butyrate, propionate, and acetate. These metabolites improve colonic barrier function, suppress inflammatory signaling, and enhance mucosal immunity, collectively reducing pathogen colonization and ARG dissemination. ³² Conversely, Western diets rich in fat and refined sugars favor microbial shifts toward Firmicutes and Proteobacteria, increasing gut permeability and low-grade endotoxemia. This microbial configuration is associated with enhanced quorum sensing, biofilm formation, and the upregulation of resistance genes in commensals such as Escherichia coli and Enterococcus faecalis. ³³

Physical activity exerts a bidirectional influence on the microbiome, promoting diversity, enhancing SCFA synthesis, and enriching commensal species involved in immune regulation and anti-inflammatory pathways.^34–36 Both acute and chronic exercise have been shown to increase the abundance of Akkermansia muciniphila, a mucin-degrading bacterium that maintains barrier integrity and reduces intestinal inflammation. ³⁷ Moreover, endurance exercise has been shown to increase the abundance of butyrate-producing genera, such as Roseburia and Faecalibacterium, which act as critical suppressors of proinflammatory cytokine production. These microbes also indirectly reduce antibiotic resistance propagation by outcompeting ARG-harboring strains and maintaining ecological balance. ³⁸

SCFAs are fermentation products of dietary fibers and act as post-biotic messengers between the microbiota and the host. Butyrate inhibits histone deacetylase (HDAC) activity, inducing anti-inflammatory gene expression and promoting Treg cell differentiation. ³⁹ It also enhances the production of antimicrobial peptides (e.g., β-defensins) and tight junction proteins (occludin, claudin-1), which strengthen the intestinal barrier against pathogenic infiltration. Notably, SCFAs influence bacterial resistance by modulating the intracellular pH, interfering with efflux pump activity, and quenching virulence gene expression in enteropathogens. Thus, fiber-rich diets and exercise-derived SCFA profiles may indirectly reduce AMR risk beyond simply modulating immune responses.

Diet and exercise interact to shape the gut resistome—the collection of all resistance genes in the microbiota. For example, dietary restriction of antibiotics and processed additives reduces the selective pressure that is associated with ARG carriage. Concurrently, regular aerobic exercise enhances microbial gene richness and may contribute to horizontal gene transfer suppression by enriching taxa that secrete quorum-sensing inhibitors. ³⁵ In one clinical study, individuals adhering to a Mediterranean diet with moderate physical activity presented a 30% reduction in fecal ARGs over 12 weeks, alongside increased microbial diversity and SCFA levels. ³⁶ These findings suggest that microbiome-targeted lifestyle interventions can reverse dysbiotic and resistogenic states in metabolically compromised individuals.

Baseline metabolic status significantly influences the responsiveness of the microbiota to lifestyle changes. Obese and diabetic individuals often exhibit blunted SCFA production, increased bile acid deconjugation, and colonization by resistance-prone pathobionts. Exercise and prebiotic intervention can partially restore these deficits, although the magnitude of response varies with age, sex, and epigenetic background. ⁴⁰ Epigenetic interactions between SCFAs and host cells, such as butyrate-driven HDAC inhibition, highlight a host–microbe codependency that could be leveraged for therapeutic precision. These findings emphasize the potential for integrated lifestyle-microbiome therapeutics in future antimicrobial stewardship strategies.

The human microbiome is highly plastic and responds dynamically to dietary inputs and physical activity patterns. These lifestyle elements not only influence microbial ecology but also affect antimicrobial resistance potential via metabolite signaling, barrier regulation, and competition dynamics. Diet and exercise act synergistically to cultivate a microbial ecosystem that is more resilient, less susceptible to pathogenic colonization, and less prone to resistance propagation. Future antimicrobial strategies may include microbiome-responsiveness screening before antibiotic therapy, incorporation of SCFA-producing probiotic strains and targeted prebiotic–exercise protocols to support host–microbiome cooperation during infection or antibiotic treatment. Recognizing lifestyle as a modulatory axis in resistance evolution opens new frontiers for nonpharmacological resistance mitigation.

In addition to macronutrient composition, the inclusion of fermented foods such as yogurt, kefir, kimchi, and miso provides direct microbial supplementation and enhances gut ecosystem resilience. These foods deliver live lactic acid bacteria and bacteriocin-producing strains that suppress pathogens and outcompete ARG-harboring organisms. ²⁸ Furthermore, the postbiotic metabolites of fermentation, such as lactic acid, conjugated linoleic acid (CLA), and bacteriocins, modulate the gut pH, mucin production, and immune signaling. In clinical studies, the regular intake of fermented foods has been linked to a lower fecal ARG burden and greater microbial diversity, particularly when fermented foods are combined with physical activity. ⁴¹ These findings highlight the promising role of symbiotic strategies (diet + live organisms) in resistance control.

Prebiotics, which are nondigestible food components such as inulin, fructooligosaccharides (FOSs), and resistant starches, selectively stimulate the growth of beneficial microbes. When coupled with physical activity, prebiotics support the enrichment of SCFA-producing taxa and inhibit colonization by proteobacteria, which are known carriers of mobile ARGs. Resistant starches (e.g., from cooked-cooled potatoes or underripe bananas) act as delayed-fermenting substrates, promoting SCFA release along the distal colon. This not only enhances mucosal immunity but also lowers the luminal pH, creating an inhospitable environment for resistance-prone pathogens. These dietary fibers synergize with exercise-induced microbial changes, enhancing systemic metabolic and immune responses.

Emerging evidence suggests that early-life exposure to diet and exercise (or their absence) has long-term effects on microbiome plasticity and resistance outcomes. For example, childhood sedentary behavior and ultra-processed diets impair microbiome maturation, resulting in reduced microbial diversity and increased ARG susceptibility in adulthood. ³⁹ Conversely, physical activity and dietary fiber during developmental windows increase microbial adaptability, promote epithelial tolerance, and reduce long-term colonization by opportunistic pathogens. This developmental programming underscores the importance of lifestyle intervention across the lifespan, not merely during therapeutic windows.

The gut microbiome is a metabolically and immunologically active ecosystem that responds dynamically to lifestyle inputs. Diet and exercise not only remodel taxonomic diversity but also shift microbial function toward anti-inflammatory, barrier-stabilizing, and resistance-suppressing profiles. Strategies incorporating fiber-rich diets, fermented foods, prebiotics, and regular physical activity represent powerful, nonpharmacologic tools for shaping a microbiome that is less permissive to resistance proliferation. Translationally, future approaches may include lifestyle-based AMR risk screening, coadministration of SCFA-boosting dietary plans with antibiotic regimens, and personalized symbiotic protocols tailored to the baseline microbiota and metabolic status. These strategies will be particularly relevant in high-risk populations, such as elderly individuals, immunocompromised individuals, or individuals with recurrent infections, where microbiome-targeted therapy may enhance both drug efficacy and resistance prevention.

Nutritional status and its role in drug absorption, metabolism, and efficacy

Nutritional status is a critical determinant of the pharmacokinetics and pharmacodynamics of antimicrobial drugs. Nutrient deficiencies or excesses can alter the physiological environment in which drugs are absorbed, distributed, metabolized, and excreted.^42,43 For example, malnutrition may compromise the integrity of the gastrointestinal tract, reduce plasma protein levels, and impair hepatic and renal function, all of which are essential for proper drug metabolism and clearance. ⁴⁴ Specifically, according to Koziolek et al. (2019), nutritional imbalances modulate hepatic enzyme activity and plasma protein levels, directly affecting the pharmacokinetics of various antimicrobial agents. ⁴⁵ On the other hand, obesity is associated with increased adipose tissue and altered enzyme expression, which may lead to unpredictable drug distribution and efficacy. ⁴⁶ These variations necessitate a more personalized approach to antimicrobial dosing on the basis of nutritional profiling.

Immune adaptations to physical activity: From protection to vulnerability

Physical activity profoundly influences the human immune system and is capable of enhancing or suppressing immune surveillance, depending on the intensity, duration, and frequency of exercise. ⁷⁹ Regular moderate-intensity exercise has been consistently associated with beneficial adaptations in both the innate and adaptive immune responses. For example, moderate aerobic training stimulates the circulation of immunoglobulins, anti-inflammatory cytokines (e.g., IL-10), and natural killer (NK) cells, thereby improving host defense mechanisms and reducing systemic inflammation. Koelwyn et al. (2015) highlighted that exercise modulates multiple components of the inflammation–immune axis, suggesting that physical activity may serve as an adjunctive strategy to enhance immune function, not only in cancer prevention and control but also potentially in the context of infection management.^80,81

Additionally, this immunoenhancing effect is supported by clinical and epidemiological studies. Nieman et al. (1994), in a landmark study, reported that individuals engaging in regular moderate exercise experienced up to a 40–50% reduction in upper respiratory tract infections (URTIs) compared with sedentary controls. ⁸² Similarly, a study by Woods et al. (1999) revealed that physically active older adults had a more robust T-cell response and higher vaccine efficacy rates than their inactive peers did, highlighting the protective effects of exercise on immune aging (immunosenescence). ⁸³ More recently, a randomized trial by Şevgin and Özer et al. demonstrated that a 12-week program of light to moderate exercise significantly increased post–COVID-19 vaccine antibody levels in older adults (65+ years), confirming that physical activity is an effective behavioral adjuvant to improve the vaccine response in elderly individuals. ⁸⁴

However, excessive or prolonged high-intensity exercise, particularly when combined with inadequate recovery, can lead to transient immunosuppression—a phenomenon often referred to as the “open window” theory. During this period, which lasts from 3 to 72 hours post-exercise, several components of the immune system are temporarily downregulated, including reduced NK cell activity, suppressed salivary IgA levels, and decreased neutrophil function. ⁸⁵ Marathon runners and endurance athletes, for example, often report an increased incidence of URTI in the days following competition or intense training bouts. ⁸⁶ Nevertheless, Campbell and Turner (2025) challenge the long-standing “open window” hypothesis by demonstrating that acute bouts of vigorous exercise do not suppress but rather transiently redistribute immune cells to peripheral sites, enhancing immune surveillance and overall immunocompetence across the lifespan. ⁸⁷

The immunological outcomes of physical activity are therefore described by a J-shaped curve, where sedentary behavior and excessive exercise are associated with increased infection risk, whereas moderate activity is protective. ⁸⁸ This model underscores the need for dose‒response precision in exercise prescriptions, especially for individuals with underlying immune dysregulation, such as elderly individuals, immunocompromised individuals, or those recovering from illness. According to Gleeson (2013), overtraining syndrome significantly impairs immune function in athletes, increasing vulnerability to infections and reducing overall performance, thus necessitating proactive clinical strategies to preserve immune health during periods of intensive training. ⁸⁹ Moreover, factors such as nutrition, sleep, psychological stress, and the training environment modulate the immune effects of exercise. ⁹⁰ Athletes experiencing energy deficiency, poor diet, or chronic stress may exhibit heightened vulnerability to infections despite high fitness levels. Thus, physical activity should be considered within a broader biopsychosocial context when evaluating its effects on immunity and infection susceptibility. ⁹¹ Thus, physical activity should be considered within a broader biopsychosocial context when evaluating its effects on immunity and infection susceptibility. In this regard, the immunological benefits of exercise are primarily associated with regular moderate-intensity activity, whereas excessive or prolonged high-intensity training may induce transient immunosuppression and increase infection risk.

Implications for infection risk and antimicrobial therapy

The immunomodulatory effects of physical activity have direct implications for infection susceptibility and, consequently, for the use and efficacy of antimicrobial therapies. Individuals who engage in regular moderate exercise may not only experience fewer infections but also require shorter or less aggressive antimicrobial treatment owing to improved immune competence. Conversely, immunosuppression resulting from overtraining could necessitate earlier or more potent antimicrobial interventions.^92,93

Exercise-induced changes in immune function may also affect the pharmacodynamics of antimicrobial agents. Enhanced circulation, improved tissue perfusion, and altered expression of drug transporters in active individuals could theoretically influence drug distribution and efficacy. ⁹⁴ For example, physical activity has been shown to increase lymphatic flow and microvascular density, potentially facilitating better drug delivery to infected tissues. ⁹⁵ Although clinical studies on this topic are still emerging, animal models suggest that physical conditioning may improve the effectiveness of antibiotics in systemic infections. ⁹⁶

Moreover, physical activity can modulate inflammatory pathways that intersect with the immune response to infection. Chronic low-grade inflammation, often observed in sedentary individuals or those with metabolic syndrome, can blunt the immune system’s ability to respond to pathogens and interfere with antimicrobial efficacy. A 2025 meta-analysis of interventional studies confirmed that regular aerobic exercise significantly reduces systemic inflammatory markers—such as CRP, IL-6, and TNF-α—in individuals with metabolic syndrome, thereby potentially increasing the efficacy of antimicrobial treatments for infections such as pneumonia or cellulitis. ⁹⁷

In special populations—such as hospitalized patients, individuals with chronic respiratory diseases, or elderly individuals—integrating physical activity into the recovery plan may serve as a nonpharmacological adjunct to antimicrobial therapy. For example, pulmonary rehabilitation programs combining exercise and physiotherapy have been shown to reduce respiratory infections and antibiotic use in patients with chronic obstructive pulmonary disease (COPD). Similarly, mobilization strategies in hospital wards have been linked to shorter lengths of stay and a lower incidence of hospital-acquired infections. ⁹⁸

Given these findings, clinicians should consider a patient’s physical activity level when designing infection management strategies. Physical inactivity may be a modifiable risk factor for both infection occurrence and treatment failure. Moreover, excessive exercise should be approached cautiously in clinical contexts involving acute or unresolved infections. Personalized recommendations that balance immune stimulation with adequate recovery may contribute to better therapeutic outcomes and reduced antimicrobial burden.

These immunological adaptations have direct implications for antimicrobial therapy outcomes. Enhanced innate and adaptive immune responses associated with regular moderate physical activity may improve pathogen clearance, thereby reducing infection severity, shortening treatment duration, and potentially lowering the required antimicrobial dose. Conversely, impaired immune function resulting from physical inactivity or excessive training may contribute to prolonged infections, increased reliance on antimicrobial therapy, and greater variability in drug response. In this context, host immune competence should be considered a key modifier of antimicrobial effectiveness, highlighting the relevance of physical activity as a complementary factor in optimizing therapeutic outcomes and reducing the risk of treatment failure.

Interference of nutraceuticals and functional foods with antimicrobial agents

Nutraceuticals and functional foods can markedly influence the efficacy of antibiotic therapies through a variety of mechanisms. These dietary substances, ranging from vitamins, minerals, and herbal extracts to probiotic foods, may exert synergistic effects that enhance antimicrobial action or antagonistic interactions that impair drug effectiveness or alter pharmacokinetics. Understanding these interactions is crucial for optimizing treatment outcomes and avoiding unintended reductions in antibiotic efficacy.

It is important to note that the evidence supporting interactions between nutraceuticals, functional foods, and antimicrobial agents is derived from heterogeneous sources, including in vitro studies, animal models, and a more limited number of clinical investigations. While experimental studies provide mechanistic insights into potential synergistic or antagonistic effects, their direct translation to clinical outcomes remains uncertain. Clinical evidence, although growing, is still limited and often context-dependent, particularly with respect to dosage, bioavailability, and host-specific factors. Therefore, distinctions between experimentally observed effects, clinically validated interactions, and theoretical or mechanistic hypotheses should be carefully considered when interpreting the impact of nutraceuticals on antimicrobial therapy.

Synergistic effects and therapeutic benefits

Many nutraceuticals have been investigated as adjuvants to conventional antibiotics, with evidence of improved therapeutic outcomes. For example, vitamin E supplementation has demonstrated notable benefits when combined with antibiotics in infection management. In a clinical study of pediatric urinary tract infections, the addition of vitamin E to antibiotic therapy significantly reduced fever and urinary symptoms compared with the use of antibiotics alone. ⁹⁹ This effect is attributed to vitamin E’s antioxidant and immune-supportive properties, which help alleviate local inflammation and oxidative stress in the urinary tract, thereby facilitating recovery.^99,100 In addition to urinary infections, vitamin E has shown broad synergy with antibiotics against drug-resistant pathogens. In vitro studies indicate that vitamin E combined with various antibiotics can restore sensitivity in multidrug-resistant bacteria such as Pseudomonas aeruginosa and MRSA, increasing bacterial killing compared with antibiotics alone. ¹⁰¹ Mechanistically, vitamin E may inhibit bacterial proteins that neutralize antibiotics; for example, it interferes with a bacterial lipocalin that binds and sequesters antibiotics. Vitamin E also modulates host immunity; supplemental vitamin E has been found to increase the ability of neutrophils to kill Streptococcus pneumoniae, suggesting a nutritional strategy to bolster host defense during antibiotic treatment. ¹⁰² Collectively, these findings highlight that certain vitamins as nutraceuticals can serve as adjunct therapies that increase antimicrobial efficacy and help combat resistant infections.

Polyphenols and phytochemicals

Similarly, polyphenols and other phytochemicals in functional foods exhibit synergistic interactions with antibiotics. Dietary flavonoids are prominent examples: compounds such as quercetin and rutin, which are abundant in fruits and vegetables, have intrinsic antimicrobial properties and can work in tandem with antibiotic agents. Quercetin or rutin combined with conventional antibiotics significantly improved bacterial killing of clinical multidrug-resistant strains. In their study, the addition of these flavonoids restored the efficacy of gentamicin and ceftriaxone against resistant E. coli and Proteus mirabilis isolates, whereas antibiotics alone had limited effects.^103–105 Quercetin in particular has a strong synergistic effect with ceftriaxone, presumably due to its ability to disrupt bacterial membranes or inhibit efflux pumps, thereby allowing the antibiotic to accumulate at the infection site. Since quercetin and rutin are common dietary components, their use as nutraceutical adjuvants is a promising and accessible strategy to enhance antibiotic therapy and possibly reduce the required dosage of conventional drugs. Other plant-derived nutraceuticals under investigation include garlic allicin, tea catechins, curcumin, and propolis, many of which have been shown to potentiate various antibiotics in laboratory studies.^103–105 For example, green tea epigallocatechin (EGCG) can synergize with β-lactam antibiotics against Staphylococcus by damaging bacterial cell walls and inhibiting β-lactamase enzymes, according to some reports. ¹⁰⁶ These synergistic interactions suggest that diets rich in polyphenols or supplemented with specific nutraceutical extracts could improve clinical outcomes in infections, especially those caused by resistant microbes, by increasing antimicrobial potency.

Microbiome and immune modulation

In addition to direct antimicrobial synergy, nutraceuticals may benefit antibiotic therapy through immune modulation and microbiome support. Probiotic functional foods are a case in point: while not antibiotics themselves, probiotics (live beneficial microbes in yogurt, fermented foods, etc.) can enhance treatment by maintaining the gut microbiota balance and preventing opportunistic infections such as C. difficile. Clinical trials have shown that the coadministration of probiotics with antibiotics can reduce antibiotic-associated diarrhea and yeast overgrowth, thereby improving patient comfort and compliance. ¹⁰⁷ In one randomized trial, patients with recurrent tonsillitis who received Lactobacillus probiotics alongside antibiotics experienced faster symptom resolution and fewer secondary infections than did those who received antibiotics alone. These benefits likely stem from probiotics inhibiting pathogenic bacteria and modulating the host immune response. Similarly, prebiotic and nutraceutical fibers in functional foods (e.g., inulin) may feed protective gut bacteria during antibiotic treatment, helping to mitigate dysbiosis and speed recovery. ¹⁰⁸ While probiotics do not directly attack the infectious agent, their interference is beneficial in that they counteract the collateral damage caused by antibiotics, highlighting a positive relationship between diet and antimicrobial therapy.

Antagonistic interactions and impaired efficacy

Not all nutraceutical interactions are beneficial for certain foods, and supplements can negatively interfere with antibiotics, reducing their absorption or activity. One well-known example is the interaction between calcium-rich foods and tetracycline antibiotics. Divalent minerals such as calcium, magnesium, and iron can chelate tetracyclines and fluoroquinolones in the gut, forming insoluble complexes that the body cannot absorb. Even a small amount of dairy can drastically impair tetracycline bioavailability. The addition of milk (containing minimal calcium) to coffee or tea severely reduces tetracycline absorption in healthy volunteers, decreasing drug availability in the bloodstream. The presence of calcium ions needs to be carefully controlled to avoid >50% loss of active drug levels. Similarly, taking oral antibiotics with supplements such as calcium tablets, iron tonics, or antacids has been reported to significantly reduce absorption; one pharmacokinetic study revealed that milk coadministration reduced tetracycline absorption by ∼30% and iron supplementation by over 75%. ¹⁰⁹ Thus, patients are usually advised to avoid dairy or mineral supplements around the time of dosing for antibiotics susceptible to chelation. This food‒drug interaction exemplifies how a functional food (milk) can inadvertently cause treatment failure by preventing adequate antibiotic uptake. ¹¹⁰

Herbal nutraceuticals and botanical supplements can also alter antibiotic effectiveness via metabolic interactions. Certain herbs modulate the same liver enzymes that metabolize drugs, leading to changes in antibiotic clearance. For example, St. John’s Wort, a popular herbal antidepressant, is a potent inducer of cytochrome P450 (CYP3A4) enzymes and P-glycoprotein transporters. Coadministration of St. John’s Wort has been shown to lower the plasma levels of various drugs; in the context of antibiotics, it could reduce the concentrations of macrolides or antitubercular drugs that are CYP3A4 substrates, risking subtherapeutic exposure. ¹¹¹ Conversely, grapefruit and certain citrus fruits act as CYP3A4 inhibitors in the intestine. Drinking grapefruit juice can increase the systemic levels of some antibiotics by preventing their first-pass metabolism. A classic case is the interaction with erythromycin (a macrolide antibiotic): grapefruit juice can increase erythromycin blood levels, which may exacerbate side effects such as QT prolongation. ¹¹² Although not all antibiotics are affected, clinicians caution against grapefruit when patients take medications such as erythromycin or clarithromycin. Similarly, traditional Chinese and Ayurvedic herbal formulations containing compounds such as berberine have been shown to influence antibiotic pharmacokinetics. In a rat study, the herbal remedy Huang Lian (rich in berberine) significantly altered the oral absorption of ciprofloxacin, likely by inhibiting metabolic enzymes and efflux pumps in the gut. ¹¹³ These findings underscore the need for awareness of herb‒drug interactions during antibiotic therapy, while nutraceuticals are “natural,” they can behave pharmacologically like drugs and must be considered in the regimen to avoid unexpected under- or over-exposure to the antibiotic.

In some cases, nutraceutical interference may protect bacteria and promote antimicrobial resistance. Antioxidant supplements are a double-edged sword in this context. Bactericidal antibiotics often kill microbes by generating reactive oxygen species (ROS) inside bacteria, contributing to oxidative damage to bacterial proteins and DNA. High doses of exogenous antioxidants (e.g., vitamin C and N-acetylcysteine) might quench these ROS, unintentionally shielding bacteria from antibiotic-induced oxidative stress. Laboratory experiments have shown that the addition of antioxidants can significantly reduce the killing ability of several bactericidal antibiotics.^114,115 In one study, antioxidant compounds and even bacterial antioxidant enzymes were found to reduce antibiotic lethality, resulting in increased survival of bacteria in the presence of drugs such as quinolones. This effect could allow some bacteria to persist and possibly develop resistance mutations. In one study, antioxidant compounds—and even bacterial antioxidant enzymes—were shown to reduce antibiotic lethality, resulting in increased bacterial survival in the presence of drugs such as quinolones. This effect could allow some bacteria to persist and potentially develop resistance mutations. However, the role of reactive oxygen species (ROS) in antibiotic-mediated killing remains debated, and its relative contribution to bacterial lethality is not fully established. While some experimental studies suggest that exogenous antioxidants may attenuate bactericidal activity by reducing antibiotic-induced oxidative stress, others report context-dependent or minimal effects. These discrepancies highlight the complexity of ROS-mediated mechanisms and suggest that the impact of antioxidant supplementation on antibiotic efficacy may vary depending on the drug class, bacterial species, and experimental conditions.^114,116

Interestingly, a paradoxical effect has also been reported, as certain antioxidants may reduce antibiotic-induced oxidative DNA damage in bacteria, thereby lowering mutation rates and potentially slowing the development of resistance. Therefore, caution is warranted when interpreting the interaction between antioxidants and antimicrobial therapy.^114,116 These nuanced outcomes illustrate that the timing, type, and dose of nutraceutical antioxidants relative to antibiotic therapy are critical. In general, it is advisable to avoid indiscriminate high-dose antioxidant use during antibiotic treatment unless supported by evidence, as it may undermine the antibiotic’s mode of action. This example highlights how metabolic context matters: the same nutraceutical can have either antagonistic or beneficial interference with antimicrobials depending on the scenario.

In summary, the relationship between diet-derived substances and antimicrobial agents is complex. Nutraceuticals and functional foods can interfere with antibiotics in positive ways, such as increasing their efficacy, reducing side effects, or reversing bacterial resistance, or in negative ways, such as impeding drug absorption or altering metabolism. Tableing these interactions, we can group them as follows in Table 1:

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Table 1.

Interactions between nutraceuticals/functional foods and antimicrobial agents.

Category	Nutrient/Compound	Mechanism of interaction	Effect on antimicrobial therapy	Example(s)
Pharmacodynamic synergy	Vitamin E	Antioxidant & immune modulation, reduction of oxidative stress	Enhances antibiotic efficacy and symptom resolution	Vitamin E + antibiotics in pediatric UTI
	Flavonoids (quercetin, rutin)	Membrane disruption, efflux pump inhibition	Restores antibiotic activity against resistant strains	Quercetin + ceftriaxone vs. E. coli
	Garlic allicin	Inhibits bacterial enzymes, synergizes with β-lactams	Potentiates anti-Staphylococcal drugs	Allicin + oxacillin vs. MRSA
Microbiome/immune modulation	Probiotics (Lactobacillus, fermented foods)	Maintain gut flora, inhibit pathogens	Reduce antibiotic-associated diarrhea, fewer secondary infections	Probiotics + antibiotics in tonsillitis
	Prebiotics (inulin, resistant starches)	Feed SCFA-producing bacteria, lower luminal pH	Enhance colonization resistance	Prebiotic + exercise interventions
Pharmacokinetic interference	Calcium/iron supplements, dairy	Chelation with tetracyclines/fluoroquinolones	Reduced absorption and plasma levels	Milk + tetracyclines (>30% ↓ absorption)
	Grapefruit juice	Inhibits intestinal CYP3A4	Increased systemic levels, potential toxicity	Grapefruit + erythromycin
	St. John’s Wort	Induces CYP3A4, P-gp	Accelerates clearance, reduced efficacy	Risk with macrolides, anti-TB drugs
Redox/ROS interference	Antioxidants (Vitamin C, NAC)	Quench antibiotic-induced ROS	May reduce bactericidal activity but also limit resistance mutations	Antioxidants + quinolones

Moving forward, clinicians and researchers emphasize the importance of considering a patient’s diet and supplement use as part of antimicrobial stewardship. By recognizing both synergistic opportunities (e.g., combining antibiotics with specific nutraceuticals to overcome resistance) and antagonistic risks (e.g., nutrient‒drug binding or metabolism interference), healthcare providers can tailor treatments better. In practice, this means advising patients on the proper timing of meals/supplements relative to antibiotic dosing, exploring evidence-based nutraceutical adjuncts in difficult infections, and monitoring for any unexpected changes in drug efficacy that could arise from dietary habits. Ultimately, integrating nutrition science with pharmacology offers a more holistic approach to infection management, one that could improve outcomes and help curb antibiotic resistance through complementary strategies.

Protein binding and free drug levels

Physical activity can acutely alter plasma biochemistry, which in turn affects drug binding. During exercise, there is an increase in circulating free fatty acids (FFAs) as the body mobilizes fat for energy. FFAs can displace drugs from their binding sites on serum albumin and other proteins because FFAs themselves have a high affinity for albumin. This is especially relevant for antibiotics that are moderately to highly protein-bound (e.g., oxacillin, ceftriaxone, doxycycline). ¹²¹ An elegant animal experiment demonstrated that exercise-induced stress (repeated cold-water swimming in rats) led to elevated FFAs and was associated with significantly increased free levels of ampicillin in the bloodstream. Compared with sedentary controls, rats subjected to daily exercise presented increased serum and tissue ampicillin concentrations, despite receiving the same dosage. ¹²² This was attributed to FFAs competitively displacing ampicillin from protein binding sites, effectively increasing the active unbound fraction of the drug.

In human terms, an athletic person who engages in exercise around the time of dosing might experience transiently higher free antibiotic levels, which could increase bacterial killing but also risk toxicity if the spike is significant. Drug designers could consider these dynamics by, for example, formulating antibiotics with binding characteristics that are less susceptible to displacement or by advising dosing schedules (timing doses during rest periods) in physically active patients. ¹²³ Additionally, chronic exercise tends to lower baseline triglyceride and possibly free fatty acid levels at rest (due to improved metabolic efficiency), which might mean that chronically active individuals have lower interference with protein binding outside of acute exercise bouts. Tailoring antibiotic dosing or delivery (such as sustained-release formulations) could help maintain stable free drug levels in the face of these fluctuations. ¹²⁴

Cardiovascular function and tissue perfusion

Another distinction is that physically fit individuals usually have greater cardiac output reserve and muscle perfusion, especially during activity, whereas sedentary individuals may have poorer peripheral circulation. Enhanced blood flow in active persons can aid in the distribution of antibiotics to infection sites. During exercise, blood flow to skeletal muscles, skin, and lungs increases, whereas splanchnic (gut) and renal blood flow may decrease.^125,126 These changes can have immediate effects on drug kinetics. An early clinical pharmacology study by Ylitalo et al. (1977) demonstrated that intense physical exercise beginning shortly after oral antibiotic intake significantly altered the pharmacokinetic profile of the drug in humans. In that crossover trial, volunteers who performed vigorous exercise after taking tetracycline or doxycycline had higher serum concentrations and area under the curve (AUC) values for the antibiotic than did those at rest (Ylitalo et al., 1977). Exercise strongly suppresses renal blood flow and thus renal excretion of drugs, leading to their accumulation in the plasma. Although total urinary recovery of the dose was unchanged (implying that overall absorption was similar), the rate of absorption appeared faster and peak levels were higher during exercise, likely due to increased gastrointestinal motility and perhaps quicker transit to absorption sites. ¹²⁷

This study highlighted that a person’s physical activity at dosing time can impact antibiotic exposure; consequently, dosing strategies might be adjusted (e.g., avoiding immediate intense exercise after taking an antibiotic that is heavily reliant on renal clearance to prevent excessive levels). For drug development, one might consider designing antimicrobials with robust pharmacokinetics that are less sensitive to transient changes in perfusion. For example, antibiotics eliminated primarily by the liver (hepatic clearance) with low extraction ratios might be less affected by exercise-induced liver blood flow reduction than high-extraction drugs are. Recognizing these differences, modern physiologically based pharmacokinetic (PBPK) models sometimes include scenarios for exercise vs. rest to predict drug levels under various conditions. ¹²⁷

Chronic differences in perfusion and organ function also play a role. Sedentary individuals, especially if they have underlying conditions such as diabetes or vascular disease, may have impaired microcirculation in tissues (slower antibiotic penetration into, say, peripheral limb infections). In contrast, an athlete’s well-vascularized muscle might achieve higher antibiotic tissue concentrations, aiding infection control in those tissues. Drug designers might respond to this by targeting drug delivery for at-risk populations. For example, for a predominantly sedentary population with peripheral artery disease, developing an antibiotic with better tissue penetration or using drug carriers that home to poorly perfused tissue could improve outcomes.^128,129 Nanocarrier antibiotics could be engineered to exploit alternate transport pathways (e.g., lymphatic delivery) to reach infection sites in patients with compromised circulation. Moreover, in highly active patients, one might worry about antibiotics being distributed so well into muscle that serum levels drop faster—as was observed with digoxin in athletes—although for most antibiotics, this is less of an issue given regular dosing. ¹³⁰ Nonetheless, exercise-induced changes in Vd and clearance underscore the importance of confirming dosing in both active and sedentary subjects during drug development rather than only testing drugs in resting individuals. Historically, drug trials often assume a resting baseline; Basso (2017) argues that failing to account for exercise can miss important kinetic interactions. ¹³¹ The incorporation of exercise conditions in preapproval studies or at least postmarketing surveillance can ensure that dosing guidelines are adequate for the physically active segment of patients. ¹³²

Metabolic enzyme activity

Perhaps the most significant impact of lifestyle on pharmacology is through metabolic enzyme modulation. Long-term physical activity (exercise training) has been associated with changes in the expression of drug-metabolizing enzymes in the liver and other tissues. Regular endurance exercise can increase liver volume and increase hepatic blood flow at rest, potentially increasing the content of cytochrome P450 (CYP) enzymes, which are responsible for drug metabolism. Niederberger and Parnham (2021) noted that specific types of chronic exercise have been linked to increased clearance of drugs, likely due to increased CYP450 expression (and concomitant increases in mitochondrial density that can support metabolic processes). ¹³³ For antibiotics that are metabolized primarily by the liver, an active individual might clear the drug more rapidly, shortening its half-life and reducing exposure unless doses are adjusted.

For example, if an antibiotic is metabolized by CYP3A4, one could speculate that a marathon runner might have slightly higher 3A4 activity (akin to how other inducers work), necessitating a higher dose or more frequent dosing to maintain therapeutic levels, although concrete clinical data on specific antibiotics are still limited. On the other hand, acute strenuous exercise can transiently suppress certain metabolic functions. Intense exercise triggers the release of inflammatory cytokines and stress hormones, which, in some studies, lead to temporary downregulation of the mRNAs of some CYP enzymes.^134,135 There is also an exercise-induced drop in blood pH (lactic acidosis) during heavy exertion, which can alter enzyme kinetics and drug ionization states. For drugs with pH-sensitive absorption or distribution (e.g., weakly basic antibiotics such as aminoglycosides), acidosis can increase the unbound fraction in plasma and tissues. These complex effects indicate that the timing of exercise relative to dosing could momentarily change how fast a drug is metabolized or eliminated. ¹³⁶

From a drug design perspective, one might mitigate these variances by developing prodrugs or formulations activated by specific metabolic pathways that are more consistent between individuals. For example, an antimicrobial prodrug that relies on ubiquitous esterases (which are less likely to be affected by lifestyle) might achieve more predictable activation in both sedentary and active bodies than one that depends on a particular CYP enzyme level. Alternatively, developers might create dosing algorithms that incorporate patient activity level as a factor — akin to how renal dosing is adjusted for kidney function. As pharmacogenomics and digital health monitoring advance, it is conceivable that future antibiotic prescriptions could use wearable data (such as activity trackers) to inform dosing schedules (e.g., “take this dose in the evening when at rest” for drugs affected by exercise or use higher nightly doses if daytime exercise increases clearance). While this level of personalization is still emergent, it underscores that precision medicine for infections could extend beyond genetic factors to include lifestyle factors such as exercise. ¹³⁷

Immune response and inflammation

In addition to pharmacokinetics, physical activity versus sedentariness can influence the host’s baseline immune competence and inflammatory status, which in turn affects infection outcomes and possibly the required potency of an antimicrobial. Regular moderate exercise is known to enhance immune surveillance and reduce chronic inflammation, whereas a sedentary lifestyle (especially obesity) is often associated with a state of chronic low-grade inflammation and immune dysregulation. An active individual might mount a faster or stronger immune response to infection, effectively assisting the antibiotic in clearing the pathogen. In such cases, the therapeutic efficacy of a bacteriostatic antibiotic, for example, might be greater in an active person because their immune system can quickly eliminate growth-inhibiting bacteria.^138,139

On the other hand, sedentary patients, particularly those with metabolic syndrome or frailty, might have impaired leukocyte function and a sluggish immune response, placing greater onus on the antibiotic to perform. This suggests that when new antimicrobials are designed or antibiotic classes are chosen, one could consider the typical patient profile. For example, for an antibiotic intended primarily for hospital-associated infections in immobile, critically ill patients (very sedentary by circumstance), it might be advantageous to design the drug to have some immunomodulatory or anti-inflammatory properties to counteract the host’s weak immune contribution. ¹⁴⁰ Some newer antimicrobial and host-directed therapies aim to modulate the immune system (e.g., boosting macrophage activity) in tandem with direct antibacterial effects, which could be particularly useful for sedentary or immunocompromised populations. Conversely, if an antibiotic is developed for generally healthy outpatients (who may include young athletic individuals), the priority might be maximizing pharmacokinetic stability during varied daily activities and minimizing any deleterious effects on exercise capacity (for example, avoiding mitochondrial toxicity that could hamper muscle function or avoiding agents that carry the risk of tendon injury, which is exacerbated in active people). ¹⁴¹

A salient example of tailoring drug design to active vs. sedentary users is the case of fluoroquinolone antibiotics and tendon toxicity. Fluoroquinolones (such as ciprofloxacin and levofloxacin) are effective broad-spectrum agents, but they are infamous for causing tendinopathy and even tendon rupture in some patients, especially those who are physically active. Athletes and military trainees on fluoroquinolones have reported that Achilles tendon injuries are likely due to the effects of drugs on collagen turnover and the blood supply to tendons. ¹⁴² This side effect profile has prompted caution in prescribing these drugs to younger, athletic individuals unless absolutely necessary. This finding also suggests the need to develop safer antimicrobial alternatives for active populations, such as the design of new quinolone derivatives without the chemical substructures implicated in tendon damage or the use of nanocarrier delivery to infected tissues to reduce systemic exposure to joints and tendons. Thus, the “physically active” metabolic profile concerns not only kinetic differences but also unique adverse effect susceptibilities. Drug development pipelines sometimes assess musculoskeletal toxicity in animal models under exercise conditions to address issues that might only manifest with mechanical strain.

Thus, while an antibiotic’s primary design goals are usually centered on broad-spectrum efficacy and minimizing resistance and toxicity, considering the patient’s metabolic profile is an emerging aspect of personalized antimicrobial therapy. Physically active and sedentary individuals represent two ends of a spectrum, and optimal drug design strives for efficacy across this range. By accounting for differences in distribution (body composition), metabolism (enzyme levels, organ perfusion), excretion (renal function variations), and host factors (immune response, tissue environment), we can develop antimicrobials that are robust to these variables or even tailored to specific subpopulations. Such foresight in design and testing can improve clinical outcomes—ensuring that, whether a patient is an athlete or couch-bound, they receive the full benefit of the antimicrobial with minimal side effects, ultimately aiding in better infection control and reducing the chance of resistance stemming from underdosing or erratic drug levels. The relationship of lifestyle and drug action is a reminder that infectious disease treatment is not one-size-fits-all, and future antibiotics may come with the nuance and flexibility required to treat patients as whole persons with unique physiological contexts. ¹⁴³

Influence of physical exercise on the gut‒brain axis

Regular physical exercise is recognized as a positive modulator of the intestinal microbiota and, therefore, of the gut‒brain axis. In general, moderate-intensity exercise has been shown to increase microbial diversity and the abundance of beneficial bacteria, particularly within the phylum Firmicutes. ²⁰⁵ This enrichment of the “friendly” microflora contributes to greater production of anti-inflammatory metabolites such as short-chain fatty acids, which strengthen the intestinal barrier and exert systemic neuromodulatory and anti-inflammatory effects. Additionally, exercise stimulates the secretion of immunoglobulin A in the gastrointestinal mucosa, reinforcing protection against pathogens in the intestinal lumen. These changes indicate that physical activity can train the intestinal immune system to keep infections at bay, acting through the microbiota and components of the gut‒brain axis. ²⁰⁶

Recent studies have explored the effects of exercise on microbiota-mediated infection resistance. Notably, moderate exercise can increase host resistance to colonization by multidrug-resistant pathogens. Xu et al. demonstrated in a murine model that moderate exercise significantly reduced intestinal colonization by methicillin-resistantStaphylococcus aureus (MRSA) compared with sedentary animals. This protective effect was attributed to specific changes in the microbiota: physical activity increased an intestinal probiotic strain (Dubosiella newyorkensis, strain L8) that hinders MRSA growth by depleting key nutrients such as fucose, which is necessary for the virulence of this pathogen. ³⁴ This study exemplifies how exercise, which acts through the gut–microbiota axis, improves resistance to serious bacterial infections by strengthening host defenses. Likewise, regular exercise has been shown to decrease chronic systemic inflammation associated with dysbiosis, which could translate into better infection outcomes by preventing unbalanced immune responses. Therefore, exercise acts as a modulatory factor of the gut‒brain axis, promoting a favorable microbial and immune environment that can improve the host’s ability to prevent and control infections.^40,207

Influence of nutrition on the dynamics of the gut–brain axis

Diet is one of the most powerful determinants of intestinal microbial composition and, therefore, of the signals flowing along the gut‒brain axis. Adequate and balanced nutrition (rich in dietary fiber, fermentables, and essential nutrients) tends to foster a diverse microbiota with a predominance of beneficial bacteria (for example, butyrate-producing genera such as Faecalibacterium), which strengthens intestinal barrier integrity and reduces systemic inflammation. In contrast, Western diets high in saturated fats and simple sugars have been linked to proinflammatory dysbiosis. Agus et al. (2016) reported that a fat/sugar-rich Western diet in mice induced an inflammatory intestinal environment with overgrowth of Proteobacteria (including pathogenic E. coli strains) and decreased the number of protective bacteria. This microbial change was associated with reduced concentrations of short-chain fatty acids (SCFAs) and lower expression of the intestinal SCFA receptor (GPR43). Consequently, the transfer of the microbiota from Western diet-fed mice to germ-free mice increased their susceptibility to infection by adherent-invasiveE. coli, demonstrating that an unhealthy diet alone can select for a microbiota that exacerbates vulnerability to enteric infections.^208,209 Furthermore, SCFA deficiency and insufficient GPR43 activation under these conditions have been linked to dysregulated immune responses and a greater predisposition to colitis, illustrating how nutrition influences microbe‒host interactions at the intestinal mucosal level.

Host nutritional states, such as obesity, malnutrition, and fasting, also modify the gut‒brain axis and the response to pathogens. Obesity, for example, is often associated with dysbiosis with lower diversity and predominance of proinflammatory bacteria, along with a state of chronic low-grade inflammation in the host. This inflammatory environment can compromise intestinal barrier function and alter vagal signaling, affecting both neuroendocrine homeostasis and innate immunity. As a result, individuals with obesity may exhibit less efficient responses to certain infections and greater severity in outcomes (for example, increased risk of complications in respiratory viral infections), partly owing to this altered gut–brain–immune axis.^210,211 On the other hand, malnutrition and micronutrient deficiencies compromise the development and maintenance of beneficial microbiota and weaken the intestinal barrier. Children with severe malnutrition exhibit immature and less diverse microbiota, which contributes to local immunosuppression, villous atrophy, and increased intestinal permeability. This creates a vicious cycle in which bacterial translocation and systemic inflammation worsen the clinical state. From the perspective of the gut‒brain axis, malnutrition can limit the production of neurotransmitters derived from microbes and alter enteric neural signaling, which even affects appetite and eating behaviors in a negative feedback loop.^210,212

A special case of nutritional influence is fasting or acute caloric restriction, which triggers systemic metabolic changes (ketogenesis, increased ketone bodies) and modulates both the microbiota and the immune response. It was traditionally thought that a lack of intake during an infection could be harmful; however, recent evidence suggests that controlled fasting could have beneficial effects in certain contexts of gastrointestinal infection. A study in mice revealed that 48 hours of fasting before and during oral infection with Salmonella enterica serotype Typhimurium almost completely suppressed bacterial invasion of the intestinal mucosa and attenuated the intestinal inflammatory response.^213,214 This effect was due to fasting inhibiting the expression of virulence genes (SPI-1) in Salmonella through microbiota-mediated changes in the luminal environment, preventing the pathogen from crossing the epithelium. In gnotobiotic mice without a microbiota, a protective effect of fasting was not observed, underscoring the importance of the microbial community in mediating how a lack of food affects the host‒pathogen‒microbiota triad. Furthermore, even when Salmonella virulence was restored in the absence of microbiota, fasting induced a reduction in the host’s proinflammatory signals, reducing tissue damage. These findings indicate that the anorexigenic response during infection (loss of appetite mediated by the brain) could be an evolutionary mechanism beneficial to the host, modulating the gut‒brain axis in a way that favors the commensal microbiota and hinders the establishment of invasive pathogens. ²¹⁵