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Gut-Skin Axis: Fix Your Microbiome to Clear Your Skin

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dr. Karunia Valeriani Japar

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Introduction

The gut-skin axis represents a bidirectional communication network connecting the intestinal microbiota, immune system, and skin barrier integrity. This intricate cross-talk operated through microbial metabolites, immune mediators, and neuroendocrine pathways that collectively maintain systemic homeostasis. The gut and skin, both major interface organs, share structural and immunological similarities, each acting as a dynamic barrier that mediates host-environment interactions. Increasing evidence demonstrates that alterations in gut microbial composition, termed dysbiosis, can influence cutaneous inflammation, sebum production, keratinocyte differentiation, and overall skin health through systemic immune modulation and metabolite signaling.

Within the context of metabolic wellness, the gut-skin relationship extends beyond cosmetic health into systemic inflammatory regulation. Low-grade chronic inflammation, insulin resistance, and lipid dysregulation, hallmarks of metabolic imbalance are increasingly recognized as interconnected with gut dysbiosis and cutaneous pathophysiology. Dermatologic conditions such as acne, psoriasis, and atopic dermatitis share overlapping immunometabolic mechanisms with metabolic syndrome and obesity, suggesting that the gut–skin axis may serve as a shared biological target for integrative prevention and therapy.

Emerging advances in AI-enabled precision medicine offer the potential to unravel the complexity of this gut-skin-metabolic nexus. Machine learning tool can synthesize multi‑omic, clinical, and microbiome data to identify individual microbiota–metabolite–inflammation signatures associated with specific skin disorders. Such approaches may facilitate the development of personalized interventions, ranging from microbiome-modulation nutrition plans to targeted probiotic therapies, aimed at restoring systemic and cutaneous equilibrium. As AI increasingly integrates microbiome science with digital biomarkers and real‑world data, the gut–skin axis may become a pivotal framework in precision metabolic wellness and skin health optimization.

Anatomy and Physiology of the Gut-Skin Interface

The gut–skin interface is organized around two large barrier organs that share fundamental structural and functional properties despite their distinct embryologic origins. Both the intestinal tract and the skin are lined by stratified or single‑layered epithelial cells interconnected by tight junction complexes that regulate selective permeability to water, ions, nutrients, and xenobiotics while preventing entry of pathogens and toxins. In the intestine, a monolayer of columnar epithelial cells covered by mucus overlies the lamina propria, which contains an extensive vascular and lymphatic network, enteric neurons, and gut‑associated lymphoid tissue (GALT), collectively forming a dynamic interface with luminal microbiota. Similarly, the skin epidermis, with its stratum corneum, tight junctions in the granular and spinous layers, and appendageal structures is supported by a richly vascularized and innervated dermis that hosts immune cells and provides rapid communication with systemic circulation. Both organs are densely colonized by site‑specific communities of bacteria, fungi, and viruses, and this resident microbiota is now recognized as an integral component of barrier function and tissue homeostasis [1,2,3,4,5,6].

Immunologically, the gut and skin constitute highly specialized mucosal and peripheral immune environments that are tightly coupled through shared cellular and molecular pathways. In the gut, GALT including Peyer’s patches, isolated lymphoid follicles, and mesenteric lymph nodes—coordinates antigen sampling and tolerance or effector responses via dendritic cells, macrophages, innate lymphoid cells, and T and B lymphocytes that continuously traffic into the systemic circulation. The cutaneous immune system, comprising Langerhans cells, dermal dendritic cells, tissue‑resident memory T cells, mast cells, and innate lymphoid cells, mirrors this organization and responds to microbial and environmental cues at the skin surface. Neuroendocrine circuits further integrate gut and skin signalling: the hypothalamic–pituitary–adrenal (HPA) axis and autonomic nervous system modulate barrier integrity, immune activation, and microbial composition through systemic cortisol, catecholamines, and neuropeptides, while both organs also possess local HPA‑like machinery capable of producing corticotropin‑releasing hormone, adrenocorticotropic hormone, and glucocorticoids in situ. These convergent epithelial, immune, vascular, neural, and microbial features provide the anatomical and physiological basis for a bidirectional gut–skin axis in health and disease [1,2,4,7,8,9,10].

Gut Microbiome, Immune crosstalk, and Skin Homeostasis

Gut microbial composition and diversity are central determinants of systemic immune homeostasis and, by extension, cutaneous inflammatory tone and barrier integrity. In a eubiotic state, commensal bacteria constantly engage pattern‑recognition receptors (PRRs) such as Toll‑like receptors (TLRs) and NOD‑like receptors on intestinal epithelial and immune cells, promoting the maturation of gut‑associated lymphoid tissue and fostering a balanced network of effector and regulatory responses. This controlled PRR signaling leads to the production of cytokines and growth factors that favor regulatory T‑cell differentiation, maintenance of barrier function, and suppression of excessive Th1/Th17‑driven inflammation. When dysbiosis and increased intestinal permeability occur, microbial products including lipopolysaccharide and other PAMPs gain systemic access, driving NF‑κB activation and the release of pro‑inflammatory mediators such as TNF‑α, IL‑1β, IL‑6, IL‑17 and IL‑23. These circulating cytokines and chemokines act on keratinocytes, dermal dendritic cells, and tissue‑resident T cells to promote epidermal hyperproliferation, barrier disruption, and pruritic inflammation characteristic of disorders such as psoriasis and atopic dermatitis, thereby providing a mechanistic link between gut microbial imbalance, systemic inflammatory tone, and impaired skin homeostasis [8,11,12,13,14,15,16].

A major route through which the gut microbiome communicates with the skin involves microbial metabolites, particularly short‑chain fatty acids (SCFAs) generated by fermentation of dietary fiber. Acetate, propionate, and especially butyrate bind to G‑protein‑coupled receptors on epithelial and immune cells and act as histone deacetylase inhibitors, thereby reshaping transcriptional programs that control cytokine production, T‑cell polarization, and barrier gene expression. Experimental models show that high‑fiber diets or oral SCFA supplementation reduce systemic allergen sensitization and ameliorate atopic dermatitis‑like skin inflammation, an effect mediated by butyrate‑driven enhancement of keratinocyte mitochondrial metabolism, accelerated differentiation, and increased synthesis of structural proteins and lipids in the stratum corneum. These changes translate into tighter epidermal barrier function, reduced transepidermal water loss, and diminished penetration of irritants and allergens. At the immunologic level, SCFAs decrease production of pro‑inflammatory cytokines by dendritic cells and macrophages while promoting regulatory T‑cell responses, thereby lowering systemic inflammatory load that would otherwise sustain cutaneous inflammation. Collectively, these data position SCFAs as key mediators by which a fiber‑supported gut microbiome stabilizes both systemic immunity and skin barrier integrity [8,12,13,16,17].

Beyond SCFAs, microbiota‑dependent bile acid transformations and tryptophan metabolism further refine gut–skin immune crosstalk. Gut bacteria convert primary bile acids into secondary species that signal through receptors such as FXR and TGR5 on intestinal, hepatic, and immune cells, modulating lipid metabolism, glucose homeostasis, and inflammatory responses. Disturbances in these bile acid pools have been linked to chronic inflammatory and metabolic diseases, conditions that often coexist with inflammatory dermatoses, suggesting that altered bile acid signalling may influence sebum composition, keratinocyte lipid handling, and cutaneous inflammation indirectly through systemic metabolic and immune pathways. In parallel, commensal metabolism of dietary tryptophan yields a spectrum of indole derivatives such as indole-3 -lactic acid and indole‑3‑aldehyde that function as ligands for the aryl hydrocarbon receptor (AhR) and pregnane X receptor in epithelial and immune cells. Recent work demonstrates that microbial tryptophan metabolites can directly fortify the epidermal barrier, promoting repair and enhancing tight junction function in reconstructed human epidermis and murine models of atopic‑like damage, largely via AhR‑dependent signalling. These indole derivatives also drive the differentiation of tolerogenic dendritic cells and regulatory T cells, reducing pro‑inflammatory responses that would otherwise fuel chronic skin inflammation [8,11,13,15,16,18,20].

Polyamines such as spermidine and putrescine, produced both by host tissues and by gut bacteria through decarboxylation of amino acids, constitute another metabolite class implicated in barrier regulation. In the intestine, bacterially derived spermidine promotes epithelial proliferation, migration, and wound repair, contributing to timely restoration of barrier integrity after injury. Polyamines reach the systemic circulation and may influence distant epithelia, where their well‑described roles in cell growth, differentiation, and autophagy suggest potential effects on keratinocyte turnover, follicular epithelium, and sebaceous gland activity. Although direct mechanistic data on polyamines in human skin remain limited, their integration into the broader metabolite network underscores the concept that a structurally and functionally diverse gut microbiome generates a metabolomic environment capable of shaping keratinocyte biology, sebum production, and cutaneous barrier function in concert with systemic immune cues [8,11,13,16,21].

Dysbiosis, Leaky Barriers, and Cutaneous Inflammation

Intestinal dysbiosis and the consequent disruption of epithelial barrier integrity constitute a primary pathophysiological axis linking gut microbial imbalance to cutaneous inflammation. Dysbiosis, characterized by reduced microbial diversity, depletion of short‑chain fatty acid (SCFA)‑producing taxa, and expansion of pro‑inflammatory Gram‑negative bacteria directly compromises tight junction protein expression and mucosal defense, leading to increased intestinal permeability. This barrier failure facilitates the translocation of microbial products, particularly lipopolysaccharide (LPS), into the portal and systemic circulation, a condition termed metabolic endotoxemia. Elevated circulating LPS activates Toll‑like receptor 4 (TLR4) signalling in liver, adipose tissue, and immune cells, triggering a cascade of pro‑inflammatory cytokines including TNF‑α, IL‑1β, IL‑6, and IL‑17—that propagate low‑grade systemic inflammation, a hallmark of both metabolic syndrome and chronic inflammatory skin diseases [22,23,24,25,26,27].

The systemic inflammatory milieu generated by endotoxemia and dysbiosis directly impacts cutaneous homeostasis through multiple convergent pathways. In psoriasis, intestinal barrier dysfunction evidenced by elevated plasma claudin‑3, zonulin, and intestinal fatty acid‑binding protein correlates with disease severity, suggesting that gut‑derived inflammatory signals amplify cutaneous Th17 responses and keratinocyte hyperproliferation. Similarly, in atopic dermatitis, reduced SCFA production and compromised epithelial barrier function permit increased allergen and toxin penetration, triggering local and systemic immune activation that exacerbates skin inflammation and barrier breakdown.. The translocated microbial components and inflammatory mediators also induce oxidative stress in target tissues, generating reactive oxygen species (ROS) that further damage epidermal lipids, proteins, and DNA. Oxidative stress‑related signalling pathways, particularly NF‑κB activation, amplify production of IL‑6, IL‑8, and IL‑33, creating a self‑perpetuating cycle of cutaneous inflammation and tissue injury [23,26,27,28,29,30].

Beyond direct immune activation, dysbiosis‑driven alterations in lipid metabolism provide a metabolic‑syndrome framework linking gut dysfunction to skin pathology. Metabolic endotoxemia and systemic inflammation disrupt hepatic lipid handling, promoting dyslipidemia, insulin resistance, and adipose tissue dysfunction, the core features of metabolic syndrome that frequently co‑occur with inflammatory dermatoses. In psoriasis patients, increased circulating levels of oxidized low‑density lipoprotein (ox‑LDL) and lipid peroxidation products reflect ROS‑mediated damage that not only accelerates atherosclerosis but also aggravates cutaneous inflammation through activation of phospholipase A2 and pro‑inflammatory lipid mediator production. Recent experimental evidence demonstrates that intestinal microbiota‑derived changes in fatty acid metabolism directly regulate psoriatic phenotype: transfer of dysbiotic microbiota from aged psoriasis‑prone mice elevates intestinal and systemic oleic and stearic acid levels, which in turn exacerbate skin inflammation by enhancing Th17 cell activation and dendritic cell priming.. This metabolic shift, characterized by increased saturated fatty acids and reduced anti‑inflammatory SCFAs, mirrors the lipid abnormalities observed in obesity and type 2 diabetes, where advanced glycation end products (AGEs) and receptor for AGE (RAGE) signalling promote oxidative stress and inflammation while favouring pathogenic skin colonization by Staphylococcus aureus and Cutibacterium acnes [22,28,31,32,33].

Thus, the gut–skin axis disruption within a metabolic‑syndrome context operates through a triad of endotoxemia‑driven systemic inflammation, oxidative stress, and altered lipid metabolism. Dysbiosis compromises barrier function, allowing microbial products to trigger TLR4‑mediated cytokine release that reaches the skin and amplifies local inflammatory circuits. Concurrently, ROS generation and lipid peroxidation damage cutaneous structures and sustain inflammatory signalling, while microbiota‑dependent shifts in fatty acid composition directly modulate immune cell function and disease severity. This integrated pathophysiology positions the gut–skin axis as a critical target for therapeutic strategies aimed at restoring microbial balance, enhancing barrier integrity, and mitigating the metabolic‑inflammatory drivers of chronic skin disease [16,22,28].

Gut-Skin Axis in Common Dermatologic Disorders

The gut–skin axis manifests distinct yet overlapping patterns of dysbiosis across major inflammatory dermatoses, each characterized by specific microbial signatures, barrier defects, and immune polarization that intersect with metabolic comorbidities. In acne vulgaris, both skin and gut microbiomes exhibits compositional shifts: the pilosebaceous unit shows overgrowth of Cutibacterium acnes phylotype IA1, reduced microbial diversity, and biofilm formation that enhances virulence and antibiotic tolerance, while the gut microbiome displays increased Bacteroides  and decreased short‑chain fatty acid (SCFA)‑producing taxa, compromising systemic immune regulation. This gut dysbiosis, coupled with increased intestinal permeability, permits translocation of microbial products that amplify systemic inflammation and may influence sebum composition and keratinocyte hyperproliferation through insulin‑like growth factor‑1 signalling, linking acne pathogenesis to underlying metabolic dysregulation [34,35,36,37].

Atopic dermatitis (AD) is characterized by profound gut microbiome immaturity and dysbiosis, with reduced diversity, depletion of Bifidobacterium and SCFA‑producing Firmicutes (notably Faebalibacterium prausnitzii) and expansion of pro‑inflammatory Proteobacteria such as Escherichia coli. This imbalance reduces butyrate and propionate availability, impairing regulatory T‑cell differentiation and intestinal barrier integrity, which facilitates allergen penetration and systemic Th2/Th17 polarization. The resulting low‑grade endotoxemia and cytokine milieu (IL‑4, IL‑13, IL‑17, TNF‑α) exacerbate epidermal barrier dysfunction, increase transepidermal water loss, and promote Staphylococcus aureus colonization on lesional skin. Obesity further aggravates AD severity by amplifying gut dysbiosis and SCFA deficiency, creating a metabolic‑inflammatory feedback loop that worsens cutaneous inflammation and impairs barrier repair [23,38,39,40].

In psoriasis, gut microbiome analyses consistently reveal decreased Bacteroidetes and Akkermansia muciniphila, increased Firimicutes and Actinobacteria, and a higher Firmicutes/Bacteriodetes ratio compared with healthy controls. his dysbiosis reduces SCFA production, particularly butyrate, and alters bile acid metabolism, leading to compromised intestinal barrier function and increased systemic exposure to LPS and other microbial metabolites. The consequent activation of TLR4‑dependent signalling drives Th17 differentiation and IL‑23/IL‑17 axis hyperactivity, which are central to psoriatic plaque formation. Notably, psoriasis exhibits strong metabolic comorbidity clustering: patients have markedly elevated rates of obesity, insulin resistance, dyslipidemia, and non‑alcoholic fatty liver disease, conditions that themselves are associated with gut dysbiosis and endotoxemia. Experimental models demonstrate that transferring dysbiotic microbiota from aged, metabolically impaired mice to germ‑free recipients exacerbates psoriatic inflammation via increased systemic oleic and stearic acid levels, directly linking lipid metabolic derangements to cutaneous Th17 activation [23,26,31,32,33,41,42,43].

Rosacea presents  a unique gut–skin axis profile strongly associated with small intestinal bacterial overgrowth (SIBO) and Helicobacter pylori colonization, which are markedly more prevalent in rosacea patients than in controls. SIBO‑mediated disruption of the intestinal mucosal barrier enhances permeability, allowing bacterial antigens and endotoxins to enter the bloodstream and trigger aberrant Toll‑like receptor 2 signalling, excessive cathelicidin expression, and reactive oxygen species production—key pathogenic mechanisms in rosacea.. Eradication of SIBO with rifaximin leads to dramatic and sustained improvement in rosacea lesions, supporting a causal role for gut dysbiosis. The immune signature in rosacea is distinct from Th17‑dominated psoriasis, featuring innate immune hyperreactivity, vasodilation, and neurovascular dysregulation, yet both conditions share the common upstream driver of gut barrier dysfunction and endotoxemia [44,45,46,47].

Comparative analysis reveals shared mechanisms across these dermatoses: all exhibit gut dysbiosis with reduced SCFA‑producing taxa, increased intestinal permeability, and systemic low‑grade inflammation driven by endotoxemia and cytokine release. However, disease‑specific patterns emerge: acne is linked to C. acnes virulence and androgen‑mediated sebaceous hyperplasia; AD is dominated by Th2/Th17 polarization and IgE‑mediated hypersensitivity; psoriasis is characterized by robust Th17/IL‑23 axis activation and strong metabolic comorbidity; and rosacea is uniquely associated with SIBO and innate immune dysregulation.. These distinctions underscore that while gut–skin axis disruption is a common denominator, the downstream immunometabolic consequences are shaped by organ‑specific microenvironments and genetic predispositions, offering tailored therapeutic opportunities targeting both microbial restoration and disease‑specific immune pathways [23,34,37,40,41,42,48].

Lifestyle, Diet, and Metabolic Modulators of the Gut-Skin Axis

Dietary and lifestyle patterns exert profound effects on the gut–skin axis by reshaping the intestinal microbiome, modifying epithelial barrier integrity, and altering systemic metabolic signalling. High intake of fermentable fibers supports the growth of SCFA‑producing bacteria and increases colonic production of butyrate, propionate, and acetate, metabolites that enhance intestinal tight junction integrity and exert anti‑inflammatory effects on mucosal and systemic immune cells. Experimental models demonstrate that a fiber‑rich diet or oral SCFA supplementation, particularly butyrate, strengthens the epidermal barrier by augmenting keratinocyte mitochondrial metabolism, accelerating differentiation, and increasing synthesis of structural proteins and lipids within the stratum corneum, thereby reducing allergen penetration and severity of atopic‑like dermatitis. In contrast, Western dietary patterns characterized by low fiber and high saturated fat, refined carbohydrates, and ultra‑processed foods drive a shift toward dysbiosis with reduced SCFA‑producing taxa, increased intestinal permeability, and systemic low‑grade inflammation that can manifest as or exacerbate inflammatory skin disease [17,34,49,50,51].

High glycemic load diets and frequent consumption of ultra‑processed, rapidly absorbable carbohydrates further influence the gut–skin axis by promoting hyperinsulinemia, insulin resistance, and IGF‑1 upregulation. Clinical and mechanistic studies in acne consistently show that high glycemic index/load dietary patterns increase circulating insulin and IGF‑1, which in turn stimulate sebocyte proliferation, sebum production, and keratinocyte hyperproliferation, all key events in comedogenesis. Low‑glycemic interventions reduce acne lesion counts, improve insulin sensitivity, and normalize endocrine signalling, supporting a causal metabolic–nutritional axis. Dairy intake, especially milk and skim milk, can further aggravate this axis through exogenous hormones and IGF‑1–stimulating bioactive components, while dairy‑induced gut perturbations and lactose intolerance may amplify dysbiosis and systemic inflammation that feedback on skin health. Alcohol consumption adds a separate insult: ethanol and its metabolites disrupt gut microbiota composition, suppress tight junction protein expression, and acutely increase intestinal permeability, leading to endotoxemia and immune activation. These changes have been linked with higher rates or flares of psoriasis and rosacea, where alcohol both aggravates systemic inflammation and directly promotes keratinocyte proliferation and vascular permeability [34,52,53,54,55,56].

Lifestyle factors such as psychological stress, sleep disruption, and physical inactivity act as additional modulators of the gut–skin axis and systemic metabolism. Chronic stress activates the hypothalamic–pituitary–adrenal axis and sympathetic nervous system, raising cortisol and catecholamine levels that impair gut barrier function, alter microbiome composition, and increase circulating inflammatory mediators implicated in both metabolic dysfunction and inflammatory dermatoses. Insufficient or poor‑quality sleep is associated with reduced microbial diversity, dysregulated circadian control of barrier and immune genes, and greater systemic inflammatory tone, which can translate into impaired cutaneous repair and heightened susceptibility to flare in conditions such as atopic dermatitis and psoriasis. By contrast, regular moderate exercise improves insulin sensitivity, reduces visceral adiposity, and has been shown to enhance gut microbial diversity, including enrichment of SCFA‑producing taxa; these changes are expected to indirectly benefit skin health by lowering systemic inflammation and improving barrier homeostasis [57].

These behavioural inputs converge on a set of metabolic mediators which are insulin resistance, adipokine imbalance, and lipotoxicity that ntersect with gut‑derived signals to influence cutaneous disease expression. Obesity and metabolic syndrome are accompanied by gut dysbiosis, reduced SCFA levels, and enhanced endotoxemia, driving chronic activation of innate and adaptive immunity. Visceral adipose tissue functions as an endocrine organ, secreting pro‑inflammatory adipokines such as TNF‑α, IL‑6, leptin, resistin, and chemerin, while anti‑inflammatory adiponectin is relatively suppressed. In psoriasis, most studies report significantly lower plasma adiponectin, which correlates with increased disease severity and coexisting insulin resistance, non‑alcoholic fatty liver disease, and atherogenic dyslipidemia. Experimental models indicate that adiponectin deficiency enhances NF‑κB activation, ROS generation, and lipid droplet accumulation, aggravating both hepatic steatosis and inflammatory signaling pathways (MAPK, NF‑κB, JAK–STAT) that drive keratinocyte proliferation and Th17‑mediated skin inflammation. Lipotoxicity arising from elevated saturated fatty acids in obesity and dysmetabolism synergizes with gut‑derived LPS and reduced SCFA to promote endothelial dysfunction, oxidative stress, and pro‑inflammatory cytokine production that impact the skin directly and via immune cell programming. Collectively, these data support a model in which diet and lifestyle sculpt the gut microbiome and barrier, which then interface with insulin resistance, adipokine signalling, and lipid toxicity to determine systemic inflammatory tone and, ultimately, the onset and severity of cutaneous disease along the gut–skin–metabolic axis [28,33,58].

Therapeutic Modulation: From Probiotics to Fecal Microbiota Transplantation

Therapeutic modulation of the gut–skin axis encompasses a spectrum of interventions aimed at restoring microbial and barrier homeostasis, ranging from well‑established probiotics to emerging fecal microbiota transplantation (FMT) and targeted antimicrobial strategies. Probiotics, live microorganisms conferring health benefits when administered in adequate amounts have been most extensively studied in atopic dermatitis (AD), where meta-analyses demonstrate modest but consistent reductions in SCORAD scores, particularly for moderate‑to‑severe disease in children and adults. Strain‑specific effects are evident: combinations of Lactobacillus and Bifidobacterium species appear more effective than single strains, and both oral and topical formulations show promise, with topical applications improving skin barrier function, reducing Staphylococcus aureus colonization, and decreasing inflammatory markers within two to four weeks. In acne vulgaris, a 12‑week randomized trial of an oral probiotic mixture improved clinical outcomes and quality of life, supporting a gut‑directed approach, though the overall evidence base remains limited by small sample sizes and heterogeneous formulations. For psoriasis and rosacea, preliminary data are encouraging but insufficient to draw definitive conclusions, highlighting the need for larger, standardized trials [59,60,61,62,63,64,65].

Prebiotics, symbiotic, and postbiotics represent complementary or alternative strategies that circumvent some limitations of live‑cell therapies. Prebiotics, non-digestible substrates that selectively nourish beneficial microbes enhances endogenous short‑chain fatty acid (SCFA) production and have been combined with probiotics in synbiotic formulations to amplify anti‑inflammatory effects in AD and acne. Postbiotics, which include microbial metabolites such as butyrate and other SCFAs, offer the advantage of defined chemical composition and reduced infection risk; experimental models show that butyrate directly enhances keratinocyte differentiation and barrier integrity, while human studies indicate improved hydration, reduced wrinkles, and decreased erythema when postbiotic‑containing products are applied topically. Despite mechanistic plausibility, clinical translation requires rigorous dosing studies and long‑term safety monitoring, as the optimal concentration and delivery vehicle for postbiotic actives remain undefined [66,67,68].

Fecal microbiota transplantation (FMT), a procedure that transfer stool from a healthy donor to a recipient, has emerged as a novel investigational therapy for refractory inflammatory skin diseases. Case series and pilot trials in moderate‑to‑severe AD report significant improvements in EASI scores, reduced Th2 and Th17 cell proportions, and lowered serum TNF‑α and total IgE following FMT, with benefits sustained for several months. In psoriasis, anecdotal reports describe marked reductions in PASI, BSA, and DLQI after repeated FMT infusions, suggesting that wholesale restoration of a eubiotic gut community can reset systemic immune tone. However, FMT remains experimental: donor selection criteria, stool processing protocols, and treatment schedules vary widely, and large randomized controlled trials are lacking. Safety concerns include transmission of infectious agents, engraftment failure, and unpredictable metabolic consequences, necessitating stringent donor screening and regulatory oversight before FMT can be integrated into routine dermatologic care [69,70].

Targeted antibiotics continue to play a role in gut–skin axis modulation, particularly for rosacea associated with small intestinal bacterial overgrowth (SIBO). Rifaximin, a non‑absorbed antibiotic, clears SIBO and improves rosacea lesions, supporting a causal link between gut dysbiosis and cutaneous inflammation. Tetracyclines (doxycycline, minocycline, sarecycline) are standard for papulopustular rosacea, exerting anti‑inflammatory effects independent of antimicrobial activity; sub‑antimicrobial‑dose doxycycline (20 mg twice daily) achieves 80–100% reduction in inflammatory lesions with fewer adverse events and lower resistance risk. Nevertheless, long‑term broad‑spectrum antibiotic use can perturb both gut and skin microbiomes, fostering resistance and potentially exacerbating dysbiosis, which limits their suitability as chronic therapy. Nutraceuticals including polyphenols, omega-3 fatty acids, and vitamin D may indirectly support  the gut–skin axis by modulating microbial composition and reducing systemic inflammation, but evidence specific to dermatologic outcomes remains preliminary and requires standardized trial designs [71,72,73].

Integration of these modalities into dermatologic and metabolic care pathways faces several challenges. The strength of evidence is highly variable: probiotics have the most robust data in AD but suffer from heterogeneity in strains, doses, and treatment durations, precluding definitive guidelines. FMT shows dramatic efficacy in select refractory cases but lacks phase III trials and long‑term safety data. Antibiotic strategies are effective for SIBO‑driven rosacea but carry resistance risks, while prebiotic/postbiotic approaches remain largely preclinical. Knowledge gaps include the precise mechanisms of cross‑talk, optimal timing of interventions (e.g., prevention vs. active disease), patient‑specific factors predicting response, and the impact of concurrent metabolic comorbidities on treatment efficacy. Future research must prioritize large, multicenter randomized trials with standardized endpoints, multi‑omic profiling to identify responders, and rigorous safety surveillance to establish the place of gut‑directed therapies within precision dermatology and metabolic wellness framework [60,65,71].

Digital Health and AI Opportunities in Gut-Skin-Metabolic Medicine

Digital health technologies provide an emerging framework to continuously characterize gut–skin–metabolic interactions at the individual level, enabling dynamic, data‑rich phenotyping rather than static, episodic assessment. Wearables and smartphones can capture multi‑dimensional behavioural and physiological signals such as heart rate variability, sleep architecture, physical activity, temperature, and stress‑related proxies that serve as digital phenotypes of autonomic tone, circadian alignment, and lifestyle patterns known to modulate the gut microbiome, systemic inflammation, and skin disease activity. Continuous glucose monitoring (CGM), increasingly used beyond diabetes, adds a dense metabolic time series that reflects postprandial dynamics, glycemic variability, and early dysglycemia, all of which intersect with insulin signalling, lipotoxicity, and inflammatory pathways implicated in acne, psoriasis, and atopic dermatitis. When combined with patient‑reported outcomes (itch, pain, flare frequency), high‑resolution skin imaging, and standardized clinical scores, these digital streams can be aligned with longitudinal stool microbiome profiles, skin microbiome sequencing, and targeted metabolomics to construct individualized gut–skin–metabolic trajectories [2,16,74,75,76,77].

Multi‑omic technologies further deepen this characterization by providing mechanistic layers that link microbiota structure to host response. Metagenomics and metatranscriptomics define taxonomic and functional features of gut and skin communities, while host transcriptomics, proteomics, lipidomics, and metabolomics capture immune, barrier, and metabolic states within blood and cutaneous tissues. Integrative approaches such as canonical correlation, based frameworks and other intermediate integration methods can identify “multi‑omic modules” in which specific microbial taxa, metabolites (e.g., short‑chain fatty acids, bile acids, tryptophan catabolites), and host inflammatory or metabolic signatures shift together and associate with disease activity. In the context of the gut–skin axis, such modules may delineate reproducible patterns. For example, a cluster linking reduced butyrate‑producing bacteria, elevated IL‑17/IL‑23 signalling, and increased oxidized lipid species in patients with psoriatic disease and metabolic syndrome. Coupling these omic datasets to continuous digital measures (sleep, exercise, CGM traces) allows construction of high‑granularity, real‑time maps of how lifestyle exposures propagate through the microbiome and immune–metabolic networks to influence skin homeostasis or flare [76,77].

Artificial intelligence is well positioned to extract clinically actionable patterns from this high‑dimensional ecosystem. In other domains, interpretable AI models trained on hundreds of wearable‑derived features have already classified complex phenotypes and uncovered genetic associations more efficiently than traditional approaches, demonstrating the feasibility of using digital phenotypes as inputs for disease modelling. Similar architectures can be adapted to gut–skin–metabolic medicine: supervised learning algorithms can integrate multi‑omic profiles, CGM metrics, and dermatologic outcomes to identify microbiome and metabolite signatures that predict onset, severity, or treatment response in acne, psoriasis, atopic dermatitis, and rosacea. Unsupervised and clustering methods can define data‑driven endotypes that cut across classical diagnostic labels. For example, a high‑endotoxemia, high‑glycemic‑variability, Th17‑dominant” cluster versus a “stress‑reactive, Th2‑skewed, barrier‑fragile” cluster, each with distinct microbiome configurations and therapeutic implications. These models can support risk stratification in routine care, flagging patients whose combined digital and omic profiles indicate elevated risk of both cardiometabolic events and severe dermatologic disease, thereby justifying earlier or more aggressive preventive strategies [2,16,76,77,78,79].

Beyond risk prediction, AI can enable personalized intervention design and the development of digital twins for complex inflammatory skin diseases. In dermatology, prototype digital twin systems already simulate treatment trajectories by integrating genetic, molecular, and lifestyle data to forecast biologic therapy responses in psoriasis. Extending this paradigm, gut–skin–metabolic digital twins could incorporate microbiome composition, metabolite levels, CGM‑derived metrics, and behavioral phenotypes to virtually test the impact of proposed interventions such as high fiber diet, probiotic formulation, GLP-1 receptor agonist, or biologic on both metabolic and dermatologic endpoints before implementation. Reinforcement learning and adaptive trial algorithms embedded in digital health platforms may then iteratively optimize diet, exercise prescriptions, microbiome‑directed therapies, and topical regimens based on real‑time feedback from wearables, CGM, and symptom tracking, moving toward closed‑loop, N‑of‑1 optimization of the gut–skin–metabolic axis [16,74,76,78,79,80].

However, several challenges and knowledge gaps must be addressed before these AI‑enabled systems can be fully integrated into clinical pathways. Data heterogeneity across devices, limited standardization of microbiome sampling and sequencing, and confounding by environmental and socioeconomic factors complicate model generalizability and external validity. Most current datasets are relatively small, cross‑sectional, and geographically constrained, raising concerns about algorithmic bias, especially for skin phototypes and cultural dietary patterns that are under‑represented in existing cohorts. Privacy, consent, and governance for continuous, multi‑modal data streams including genomic and microbiome data require robust ethical frameworks and regulatory oversight. Methodologically, transparent and interpretable AI is essential so that clinicians can understand the drivers of a given risk score or treatment recommendation; black‑box outputs are unlikely to be trusted in high‑stakes decisions involving immunomodulatory or microbiome‑targeted therapies. Addressing these limitations through prospective, multi‑center studies, standardization of digital and omic pipelines, and co‑design with patients and clinicians will be critical to realizing the promise of digital health and AI in gut–skin–metabolic medicine [2,74,75,78].

Future Directions and Research Gaps

Future research on the gut–skin–metabolic axis must address major gaps in causal inference, mechanistic understanding, and standardized outcome frameworks by moving beyond predominantly cross‑sectional association studies toward large, well‑phenotyped longitudinal cohorts with repeated stool, blood, and skin sampling, combined with detailed digital lifestyle and metabolic data, to clarify temporal relationships between microbiome shifts, metabolic perturbations, and skin flares and to leverage Mendelian randomization and other genetic instrumental variable approaches for testing causal links between specific microbial taxa or metabolites (such as short‑chain fatty acids, bile acids, and indole derivatives) and the risk of acne, psoriasis, atopic dermatitis, or rosacea. Mechanism‑focused interventional trials should incorporate deep multi‑omic profiling (metagenomics, metabolomics, host transcriptomics, lipidomics) and integrative analytical methods capable of identifying reproducible “gut–skin–metabolic modules” that connect defined microbiome configurations and metabolite signatures with precise immunologic and clinical phenotypes, thereby enabling a shift from generic “dysbiosis” labels to mechanistically anchored endotypes that can be targeted with precision therapies. Priority interventional studies include rigorously designed randomized trials of high‑fiber, low‑glycemic, anti‑inflammatory dietary patterns; strain‑defined probiotics, synbiotics, and postbiotics; microbiome‑sparing metabolic drugs (such as GLP‑1 receptor agonists) evaluated for dual metabolic and dermatologic benefit; and carefully controlled fecal microbiota transplantation in refractory disease, all using harmonized core endpoints that span microbiome metrics (diversity indices, SCFA‑producing taxa, functional pathway scores, permeability markers like zonulin, claudin‑3, and lipopolysaccharide‑binding protein), dermatologic outcomes (EASI, PASI, IGA, lesion counts, patient‑reported outcomes, barrier biophysics, skin microbiome profiles), and metabolic markers (fasting glucose and insulin, HOMA‑IR, detailed lipid panels including oxidized species, inflammatory markers, continuous glucose monitoring metrics, and adipokine profiles) [2,16,75,79].

Conclusion

The gut–skin axis has emerged as a clinically and translationally important bridge linking metabolic health, immune regulation, and dermatologic disease, reframing common skin conditions as systemic disorders rooted in barrier biology, microbiome composition, and immunometabolic crosstalk rather than isolated cutaneous events. Convergent evidence across acne, atopic dermatitis, psoriasis, and rosacea shows that intestinal dysbiosis, leaky epithelial barriers, endotoxemia, oxidative stress, and disturbed lipid and glucose metabolism interact to shape both systemic inflammatory tone and skin-specific immune signatures, positioning the gut–skin–metabolic network as a shared therapeutic target for prevention and disease modification. Within this framework, microbiome‑directed strategies including diet, probiotics, prebiotics, postbiotics, and fecal microbiota transplantation offer rational avenues to restore microbial and barrier homeostasis, while digital health tools and AI enable integration of multi‑omics, continuous metabolic data, and real‑world behaviours into dynamic, individualized gut–skin–metabolic profiles that can support risk stratification, endotyping, and adaptive, N‑of‑1 intervention algorithms. Together, these advances suggest that combining microbiome‑centred therapeutics with AI‑assisted decision support could usher in a more precise, preventive, and integrative model of care in metabolic wellness and skin health, in which interventions are tailored not only to a given diagnosis but to the evolving gut–skin–metabolic phenotype of each patient across the life course.

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