Celiac disease (CeD) is an immune-mediated disorder that leads to chronic inflammation of the small intestine in response to gluten intake. Gluten is a protein complex specific to wheat, while structurally related prolamins, such as secalin in rye, hordein in barley, and avenins in oats, may also provoke immune activation in genetically predisposed individuals [1, 2]. This susceptibility is primarily linked to the presence of HLA-DQ2 and/or HLA-DQ8 alleles. CeD is also characterized by the production of autoantibodies against tissue transglutaminase (tTG) type 2, as well as immunoglobulin A (IgA) anti-endomysium and intestinal IgM antibodies targeting gluten [3]. Gastrointestinal symptoms typically manifest upon the ingestion of gluten-containing foods [4].

The global prevalence of CeD, based on serological testing, is estimated at 1.4%, making it the most common immune-mediated disorder affecting the gastrointestinal tract [5]. Currently, the only effective treatment for CeD is strict adherence to a gluten-free diet (GFD). Nevertheless, the restrictive nature of the GFD presents multiple challenges, including financial burden, social isolation, and potential adverse health effects such as macro- and micronutrient deficiencies and long-term metabolic complications [6–8]. Previously, CeD was recognized as a condition associated with significant weight loss, micronutrient deficiencies, and low body mass index (BMI) [9]. However, recent findings have revealed that CeD can present with extraintestinal manifestations and may occur without obvious signs of malnutrition [9]. According to Verma [10], malnutrition is common among individuals with CeD, both at diagnosis and during long-term follow-up. In this context, malnutrition may result from impaired nutrient absorption due to intestinal inflammation and/or the inadequate nutritional quality of the GFD [8, 11].

Furthermore, although the link between CeD and malnutrition has been well-established, recent research indicates that a wider range of patients, including those with normal weight or overweight, are now being diagnosed with the condition [12, 13]. A systematic review reported that 14% of CeD patients present overweight and 6% are obese at diagnosis [14]. Another concern is the rising incidence of metabolic syndrome (MetS) and liver disorders among CeD patients adhering to a GFD [15–17]. Several factors have been proposed to explain the association between CeD in patients following a GFD and metabolic disorders. First, the reduction in intestinal inflammation and restoration of absorptive capacity following a GFD often lead to improved nutrient absorption, sometimes described as a compensatory hyperphagic state [18]. Second, gluten-free processed foods frequently contain high amounts of saturated fats added to enhance palatability, which contributes to increased caloric intake [19]. Third, the GFD is generally associated with higher consumption of simple carbohydrates and saturated fats and lower intake of complex carbohydrates and dietary fiber [20]. Fourth, stress-related emotional eating may partly contribute to weight gain, especially among children and adolescents [14, 21]. Moreover, studies suggest that adherence to a GFD may increase the risk of metabolic complications such as weight gain, obesity, and MetS due to these dietary imbalances [16, 22, 23], as well as nutritional deficiencies, toxicity, morbidity, mortality, and mental health problems [24].

A paucity of studies has been conducted on the evaluation of risk factors for MetS in patients diagnosed with CeD. An investigation involving Italian patients found that a high BMI at diagnosis and exposure to proton pump inhibitors (PPIs) were the only factors significantly associated with MetS development in a multivariable logistic regression model. Variables such as age at diagnosis, baseline waist circumference, sex, insulin resistance, hyperglycemia, hypertension, hypercholesterolemia, hypertriglyceridemia, and elevated liver enzymes were not linked to MetS onset [25]. The mechanisms through which PPIs influence MetS risk remain to be fully elucidated. Emerging evidence indicates a possible connection between PPIs and gut microbiome (GM) alterations, which may promote intestinal dysbiosis and impair nutrient absorption. These changes could contribute to abdominal obesity, dyslipidemia, insulin resistance, and hepatic fat accumulation [26]. The role of medications in modulating MetS risk among CeD patients requires further investigation and represents a promising area for future research.

One of the non-gluten environmental factors implicated in the development of CeD is the GM, defined as the complex community of microorganisms residing in the gastrointestinal tract that contributes to the host’s immune, metabolic, and physiological functions [27–29]. Multiple studies have shown that the GM in CeD patients undergoes significant alterations, characterized by an increase in opportunistic bacterial taxa alongside a reduction in beneficial bacteria, leading to a dysbiotic state [30].

Therefore, CeD is a systemic disorder with significant metabolic implications, and growing evidence suggests a pivotal role of GM dysbiosis in its onset and associated metabolic disturbances. The present narrative review examines (i) the connections between CeD and metabolism-related comorbidities, including MetS and metabolic dysfunction-associated steatotic liver disease (MASLD); (ii) the role of the GM in CeD, including the outcomes of GM dysbiosis in celiac children and adults; and (iii) the potential of microbial therapeutic strategies within the context of personalized medicine for patients with CeD and comorbid metabolic conditions.

A GFD has been shown to alter the GM through a decrease in beneficial bacterial species and an increase in potentially harmful ones [30]. The link between CeD, MetS, and MASLD may be related to increased intestinal permeability (i.e., the “leaky gut” phenomenon) and the subsequent development of small intestinal bacterial overgrowth (SIBO) induced by dysbiosis [52]. The translocation of luminal microbiota or microbial products across a compromised intestinal barrier has been shown to initiate immune responses that contribute to the onset of MetS and MASLD. Proposed mechanisms involve alterations in the bile acid pool, decreased production of short-chain fatty acids (SCFAs), and reduced activation of the farnesoid X receptor in the distal small intestine by bile acids, all of which are associated with impaired intestinal barrier integrity [53].

In the context of CeD, the abundance of protective bacteria, including bifidobacteria and members of the phylum Bacillota such as the families Lactobacillaceae and Streptococcaceae, is reduced in comparison to healthy controls. Conversely, the prevalence of harmful bacteria (i.e., pathobionts) belonging to the phylum Bacteroidota, including Bacteroides and Prevotella, as well as members of the phylum Pseudomonadota such as Escherichia, Haemophilus, Serratia, and Klebsiella, is elevated [54, 55]. Consequently, the disruption of metabolic processes due to dysbiosis can elevate the risk of metabolic diseases, including MetS and MASLD [56].

The sustained inflammation or the overgrowth of bacterial pathobionts may disrupt the regulation of adhesion molecules at tight junctions. This disruption facilitates the translocation of foreign microorganisms and toxic substances, promoting the release of partially digested gliadin peptides into the lamina propria [28, 30, 57]. CeD causes structural changes in the small intestine, characterized by focal defects in the epithelial barrier, increased apoptosis, and altered expression of tight junction proteins [58]. These alterations affect barrier permeability, leading to the loss of ions and water into the gut lumen. Specifically, barrier-forming claudins (claudin-3, claudin-5, and claudin-7) are downregulated, while channel-forming claudins (claudin-2 and claudin-15) are upregulated, resulting in increased selective paracellular solute transport [59]. In addition, zonulin, which is a protein that reversibly regulates intestinal permeability by modulating tight junction molecules, has been linked to CeD [60]. Gluten peptides and certain enteric bacteria, such as Escherichia coli (E. coli), have been found to induce zonulin, suggesting its involvement in CeD pathogenesis [61]. Moreover, pro-inflammatory mediators, including TNF-α and interferon-gamma (IFN-γ), have been identified as contributors to the downregulation of barrier and tight junction proteins [59].

Furthermore, microbial dysbiosis has been demonstrated to augment the magnitude and complexity of gliadin peptides, a process attributed to the differential proteolytic activity of the GM [62, 63]. Recent studies indicate that peptidases from various microbial sources can degrade gluten and its derived peptides [62, 63]. In this context, certain gut bacteria, such as Bifidobacterium spp., Lactobacillus spp., and Rothia spp., possess the ability to degrade gluten, alter intestinal permeability, and activate the host immune response, all of which contribute to the pathogenesis of CeD. Therefore, maintaining an eubiotic GM composition may help modulate symptoms associated with gluten-related disorders (GRDs) [62].

Although evidence supports a role for the GM in the pathogenesis of CeD, there remains no clear consensus regarding the specific microbial alterations associated with the condition. Previous research has primarily focused on characterizing the GM composition in infants to identify potential predictors of CeD development [64–66]. Moreover, factors such as the timing of initial gluten exposure and other environmental influences, including premature birth, mode of delivery, type of infant feeding, antibiotic use, and early infectious exposures, have been shown to affect epigenetic regulation through modifications of the GM ecosystem. These alterations can disrupt the maturation of the intestinal barrier, gut-associated lymphoid tissue (GALT), and the balance of innate and adaptive immune responses [66–68].

Premature birth has been proposed to result in delayed gut bacterial colonization, reduced microbial diversity, decreased abundance of obligate anaerobic commensals such as Bifidobacterium and Bacteroides, and an increased prevalence of facultative and pathogenic anaerobes, including Enterobacter, Enterococcus, Escherichia, Klebsiella, Clostridioides difficile, and Staphylococcus. This microbial profile favors an inflammatory gut environment that may promote the development of CeD [69]. Similarly, the mode of delivery is a critical determinant of neonatal GM colonization [70]. Cesarean section results in neonatal microbial colonization predominantly from environmental and maternal skin sources, characterized by increased Enterococcus faecalis, and decreased Bacteroides spp. and Parabacteroides spp., changes associated with a heightened risk of CeD [71]. Within this context, Tanpowpong et al. [72] reported an adjusted hazard ratio of 1.39 for CeD in cesarean-born infants compared to those delivered vaginally.

Infant feeding type significantly influences early GM composition, playing a key role in its initial structuring. Breastfeeding has been shown to increase the prevalence of genera such as Lactobacillus, Bifidobacterium, Enterococcus, Corynebacterium, Propionibacterium, Streptococcus, and Sneathia, while reducing Bacteroides and Staphylococcus [70]. Cenit et al. [73] observed that continued breastfeeding at the time of gluten introduction correlates with increased transfer via milk of immunomodulatory factors, including IL-12p70, transforming growth factor-β1 (TGF-β1), secretory IgA (sIgA), and Bifidobacterium spp., which may delay or reduce the risk of CeD development. However, large epidemiological studies have not consistently demonstrated a protective effect of breastfeeding against CeD onset in genetically predisposed children [74].

In addition, multiple studies have linked early antibiotic exposure to an increased risk of chronic autoimmune and inflammatory bowel diseases, including CeD [64, 75]. Lindfors et al. [76] demonstrated a cumulative effect in which enterovirus infection combined with gluten exposure increased the risk of CeD development in children. Viral pathogens such as rotavirus, enterovirus, adenovirus type 12, and orthoreovirus have been identified as potential triggers of CeD by activating innate immunity via Toll-like receptor 3 (TLR3), leading to intestinal inflammation and loss of tolerance to gliadin peptides [77, 78].

Furthermore, researchers have identified that certain microbial species, metabolites, and pathways undergo alterations regarding abundance in infants at high risk of developing CeD prior to the manifestation of the disorder, thereby indicating that HLA-DQ alleles can exert an influence on early GM composition [79]. Specifically, these alterations in taxa abundance have been observed to result in an increase of members belonging to the phylum Pseudomonadota in patients diagnosed with CeD, accompanied by a concurrent decrease in members of the Bacillota and Actinomycetota phyla [80–83].

Figure 1 shows a proposed model for the pathogenesis of CeD. This model incorporates a series of factors that contribute to the development of CeD. Specifically, it considers the influence of host genetics, environmental factors, and gluten consumption. The consumption of gluten has been proven to result in an increase of pathobiont colonization, a reduction in autochthonous gut microbiota, and a disruption in GM dysbiosis. This, in turn, results in a disruption of immune homeostasis and gut integrity. Consequently, this disruption favors the onset of CeD and its clinical manifestations.

A substantial body of research has examined the microbial composition in patients with active CeD compared to healthy controls. To this end, samples are typically obtained from duodenal biopsies, intestinal aspirates, and stool specimens to analyze GM composition. In addition, salivary and pharyngeal microbiota have been examined, although these studies were conducted under specific research questions [84]. The methodologies employed for microbial identification in these studies are highly heterogeneous, each presenting distinct advantages and limitations. Common techniques include culture-based approaches (culturomics), quantitative polymerase chain reaction (qPCR), next-generation sequencing (NGS) methods (e.g., targeted amplicon sequencing, shotgun metagenomics, shallow metagenomics), denaturing gradient gel electrophoresis (DGGE), temperature gradient gel electrophoresis (TGGE), fluorescence in situ hybridization (FISH), flow cytometry, gas chromatography, and 16S–23S rRNA intergenic spacer region analysis [85, 86]. Beyond methodological differences, other factors influencing GM composition in CeD include disease activity status, adherence to a GFD, and patient age [87]. While stool samples are commonly employed as proxies for GM composition, notable discrepancies often exist between fecal microbiota and the actual microbial communities adhering to the intestinal mucosa. Despite its invasiveness, biopsy sampling is generally regarded as providing a more precise representation of the GM content [88].

Currently, the most effective treatment for CeD involves strict and lifelong adherence to a GFD. However, evidence indicates that GFDs may be nutritionally inadequate, often lacking essential nutrients such as protein, folate, iron, niacin, riboflavin, thiamine, vitamin B12, zinc, selenium, and dietary fiber [8, 112]. Moreover, an improperly balanced GFD has been associated with adverse metabolic outcomes, including impaired glucose and lipid metabolism, as well as heightened risk of MetS and obesity [113]. As a result, ongoing research is exploring novel therapeutic targets with the aim of developing alternative or adjunctive therapies for CeD [114].

A deeper understanding of the role of the GM in the pathogenesis of CeD is expected to facilitate the development of novel preventive strategies, particularly via the early correction of dysbiosis prior to the onset of increased intestinal permeability. A multitude of review studies have highlighted the pivotal role of the GM in gluten metabolism, modulation of immune responses, and regulation of intestinal barrier integrity [78, 115–117]. These investigations have focused on targeting active CeD via modulation of the GM, including the use of probiotics, postbiotics, and synbiotics to restore beneficial microbial communities and promote SCFA-producing commensals, as well as the utilization of naturally occurring gluten-degrading microbial enzymes. Table 1 summarizes human studies that have employed microbial-based interventions in the therapeutic management of CeD.

Certain bacterial taxa have been identified for their dual roles in gluten metabolism: some degrade gluten peptides that trigger strong immune responses, while others possess the ability to detoxify these peptides. A combination of Lactobacillus and Bifidobacterium strains has been shown to hydrolyze the immunogenic gliadin 33-mer peptide generated during gluten digestion by pepsin and trypsin. In vitro studies using Caco-2 cell lines demonstrated that these bacterial strains produce low-molecular-weight peptides and inhibit the release of the pro-inflammatory cytokine IL-6, as well as the differentiation of cytotoxic T cells [133]. Another study utilizing the same cell model revealed that B. longum and B. bifidum strains reduced gliadin-induced activation of the NF-κB p65 signaling pathway, alongside decreased production of TNF-α and IL-1β. This protective effect was mediated by the degradation of gliadin peptides, resulting in diminished cytotoxicity [134]. Similarly, in a mouse model replicating CD4⁺ T cell-mediated enteropathy in response to gliadin, administration of B. longum strain CECT 7347 increased IL-10 levels and decreased CD4⁺ T cell populations, thereby mitigating gliadin’s deleterious effects [135]. In addition, co-culturing this strain with Caco-2 cells exposed to gliadin enhanced cell viability and prevented gliadin-induced alterations in key proteins, including regulator of G-protein signaling 5, actin filament-associated proteins, sorting nexin-20, and T cell receptor R chain V region CTL-L17, which are typically upregulated during pro-inflammatory responses [136].

Another potential mechanism by which bacteria may influence CeD development involves the production of aryl hydrocarbon receptor (AhR) ligands. The AhR is activated in various cell types by indole-containing ligands derived from tryptophan metabolism, many of which are produced by the GM. AhR plays a critical role in modulating host immune responses. Notably, a study demonstrated that AhR activation by bacterial tryptophan metabolites inhibits the activation of actin-regulatory proteins MyoIIA and ezrin [137]. This inhibition helps maintain the integrity of tight and adherens junctions, which are essential for preserving the structural stability of enterocytes and, consequently, the intestinal barrier. Preservation of these junctions contributes to decreased intestinal permeability, a key factor in CeD pathogenesis.

In the intestinal mucosa of patients with active CeD, AhR expression is decreased. A study reported that these patients exhibited reduced levels of AhR ligands in stool samples, and their GM displayed a diminished capacity to activate this receptor compared to non-celiac controls [138]. Using a murine model expressing the HLA-DQ8 susceptibility gene, the researchers modulated the intestinal microbiota via a tryptophan-enriched diet. This intervention enhanced the production of AhR ligands and subsequent receptor activation, which mitigated gluten-induced immunopathology. Furthermore, a study utilizing intestinal organoids co-cultured with lamina propria lymphocytes demonstrated that a metabolite produced by a strain of Limosilactobacillus reuteri stimulated lamina propria lymphocytes to secrete IL-22 through AhR activation. This process promoted the proliferation of intestinal stem cells and facilitated epithelial recovery following TNF-α-induced damage [139]. Another beneficial bacterial mechanism has been identified in a preclinical study using a DQ8 mouse model of gluten sensitivity, where the protective effect of bifidobacteria was attributed to the production of a serine protease inhibitor, known as serpin, which prevented gliadin-induced immunopathology [140]. In addition, other microbial metabolites have shown the ability to modulate both the epithelial barrier and the immune system. Freire et al. [132] demonstrated that organoids derived from CeD patients exhibited a distinct response to gliadin and an improvement in barrier function when treated with bacterial metabolites such as lactate and butyrate, as well as B. fragilis polysaccharide A. These microbial bioproducts, termed postbiotics, enhanced the expression of genes involved in mucin production, trefoil factor 1 (TFF1), and claudin-18, genes known to be downregulated in CeD organoids. Furthermore, Serena et al. [141] identified a direct correlation between the alternative splicing of FOXP3 isoforms and the beneficial bacterial metabolite butyrate. FOXP3, which is a key transcription factor regulating T cell development and function, exists in multiple splicing variants in humans, and its deficiency is a critical factor in systemic autoimmunity. This study showed that butyrate, together with IFN-γ, upregulated FOXP3 isoforms in the intestinal tissue of CeD patients.

Microbial TG (mTG) is a commonly used food additive and has been identified as a potential inducer of autoimmune and neurodegenerative diseases [142, 143]. This enzyme increases intestinal permeability, suppresses mechanical (mucus) and immunological (anti-phagocytic) enteric protective barriers, stimulates luminal bacterial growth, and enhances the uptake of gliadin peptide. mTG and gliadin molecules are co-transcytosed through the enterocytes and subsequently deposited subepithelially. Additionally, mucosal dendritic cell surface TG induces gliadin endocytosis, and enzyme-treated wheat products elicit immune reactivity in CeD patients [144, 145]. Recently, Lerner et al. [146] found that sequence similarity and cross-reactivity between mTG and various tissue antigens could underlie the link between mTG and autoimmune disorders. Furthermore, cross-reactivity and sequence homology between gluten/gliadin peptides and human epitopes may contribute to molecular mimicry, potentially triggering autoimmunity. A GFD has been shown to prevent these phenomena via various mechanisms [147].

CeD is linked to both internal genetic factors and potential external influences, such as dietary habits and antibiotic use [148]. These factors can alter the microbial composition, leading to dysbiosis, which may increase the risk of developing CeD later in life [149]. The diagnosis of CeD involves a combination of clinical, serological, and histopathological data. In children, diagnosis can be performed without biopsy, and it is based on strict criteria, including small bowel symptoms, positive HLA-DQ2/DQ8, as well as IgA and tTG levels [150]. In elderly subjects, the diagnosis still requires the presence of duodenal villous atrophy, and it is carried out through the analysis of IgA/IgG anti-tTG and anti-endomysium antibodies in a small intestinal biopsy [151].

The findings of this review underscore several important implications for managing patients diagnosed with CeD. First, the results challenge the traditional belief that CeD patients universally suffer from poor nutritional status due to malabsorption. Instead, it is common for patients with CeD to present with MASLD and MetS at diagnosis. Second, the rising prevalence of MASLD and MetS after starting a GFD requires serious attention, as the severity of these conditions may worsen with prolonged adherence to GFD. Third, both MASLD and MetS have been shown to increase the risk of CVD, stroke, T2DM, and cirrhosis [16, 152, 153]. Therefore, it is crucial to take preventive steps to avoid the onset of MASLD and MetS in CeD patients. Specifically, patients should be screened for MASLD and MetS at diagnosis using standardized tests, enabling closer monitoring for those already affected at the start of GFD. Furthermore, ongoing monitoring after beginning GFD is essential to identify and manage any delayed complications. Lastly, patients must be informed about the risks of developing metabolic complications and consistently counseled to maintain a balanced diet and engage in regular physical activity.

The only current treatment for CeD is a strict GFD, which is often difficult to maintain and costly, leading to high rates of non-adherence. Moreover, despite following a GFD, 25–50% of patients fail to show significant clinical improvement [68]. The requirement for continuous monitoring of food intake has been shown to negatively impact patients’ quality of life, highlighting an unmet need for adjunctive therapies [154]. Therefore, ongoing research aimed at discovering novel and supplementary treatments for CeD is imperative [155]. It is crucial to recognize the need for additional prospective studies with larger sample sizes and standardized definitions of MetS. Such studies are essential for thoroughly assessing the impact of a GFD on MetS development in CeD patients. Furthermore, the pathophysiological mechanisms underlying MetS in individuals with CeD remain unclear. Thus, it has to be determined whether the same processes that drive MetS in non-CeD populations also contribute to its development in CeD populations or if distinct immunologic or inflammatory pathways are involved [8].

Notably, adherence to a GFD has been shown to negatively affect microbial homeostasis in healthy individuals [156]. However, a major limitation in current research is the lack of longitudinal studies analyzing GM composition in CeD patients before and after the initiation of a GFD. The typical GFD often relies heavily on ultra-processed and refined foods that are high in fat and sugar while being low in dietary fiber, folic acid, iron, calcium, selenium, magnesium, zinc, niacin, biotin, riboflavin, pyridoxine, and vitamin D [157]. This highlights the broader shortcomings of the Western diet, which are particularly detrimental for individuals with CeD. As an alternative, CeD patients should be encouraged to adopt a Mediterranean or vegetarian dietary pattern that emphasizes the consumption of seasonal, organic vegetables and foods rich in fiber, micronutrients, and bioactive vitamins [158, 159]. In this context, incorporating pseudocereals such as quinoa, amaranth, and sorghum, as well as naturally gluten-free cereals, is recommended due to their richness in fiber, minerals, thiamine, carotenoids, flavones, tannins, proteins, and healthy fats [157]. In addition, ketogenic diets have been recognized for their efficacy in managing various metabolic conditions, as well as for their potential to modulate autoimmune diseases by reducing inflammation [160]. Building on these dietary patterns, a plant-based ketogenic diet has been proposed as a potential health-promoting approach [161]. For patients with CeD, this diet may offer promising benefits when appropriately adapted to exclude gluten and meet individual patient requirements. However, the potential benefits of ketogenic diets for CeD are primarily based on theoretical considerations, and research in this area is needed to determine their efficacy. Furthermore, nutraceutical supplementation, including the targeted use of probiotics, has emerged as a promising strategy to support both nutritional balance and gut health in CeD patients [162].

A range of probiotics has been investigated in the context of CeD. However, current evidence from clinical studies remains inconclusive regarding their efficacy. A recent meta-analysis concluded that probiotics may alleviate gastrointestinal symptoms in individuals with CeD, yet emphasized that higher-quality studies are necessary before firm recommendations can be made, given the heterogeneity among existing trials [163]. Notably, most probiotics studied thus far have been selected based on their general anti-inflammatory properties rather than their specificity to CeD pathophysiology. It is important to emphasize the specificity of probiotic strains, such as B. longum CECT 7347, which have shown efficacy in clinical applications [127, 135]. In this respect, the therapeutic potential of probiotics is strain-dependent, and selecting the appropriate strain is crucial for achieving the desired clinical outcomes. Future probiotic and microbial-based interventions should focus on strains that target pathways directly implicated in CeD. For example, the enzymatic degradation of immunogenic wheat proteins represents a promising research direction, as it could mitigate the inflammatory responses triggered by gluten and other wheat-derived peptides. In addition, the development of combination therapies using multiple strains that act synergistically, or a single probiotic engineered to affect multiple targets, holds potential. Nevertheless, these strategies must be guided by a clear mechanistic rationale to optimize both efficacy and safety. In this context, the use of genetically engineered microbes customized to modulate key immune or metabolic pathways in CeD also requires further investigation. Precision probiotics and postbiotics represent a promising avenue, but their role in CeD and related metabolic conditions remains to be fully defined, as their use is still at an early stage and more evidence is needed to clarify their clinical relevance.

The next generation of microbial therapeutics represents an emerging class of pharmaceuticals, encompassing live biotherapeutic products (LBPs) and genetically modified microorganisms engineered to express or secrete bioactive molecules relevant to the pathogenesis of CeD [164]. The therapeutic efficacy of engineered bacteria has been demonstrated in animal models of CeD. However, their translation to human use remains limited, primarily due to safety concerns associated with plasmid-based gene delivery systems [165]. Recent advances have proposed novel approaches in which genes of interest are stably integrated into the chromosomal DNA of probiotic strains, thereby minimizing the risk of horizontal gene transfer and enhancing their potential suitability for clinical application [166]. In addition to the detoxification of immunogenic gluten peptides, emerging microbial therapeutic strategies for CeD include the restoration of AhR signaling through microbial modulation of tryptophan metabolism, as well as the reestablishment of intestinal proteolytic homeostasis via the production of serine protease inhibitors [138]. These mechanisms offer promising avenues for the development of adjuvant therapies aimed at modifying disease progression and improving outcomes in patients with CeD.

A recent review by Herrera-Quintana et al. [167] outlined several emerging therapeutic strategies for the prevention and treatment of CeD. Among these, oral enzyme therapy has garnered attention for its ability to degrade immunogenic gluten peptides within the gastrointestinal tract. Agents such as latiglutenase, zamaglutenase, and AGY-010 are currently under investigation for their capacity to neutralize gluten toxicity by hydrolyzing immunodominant epitopes in the stomach prior to their interaction with the intestinal immune system [168]. Another promising therapeutic avenue involves targeting tissue TG2, an enzyme central to CeD pathogenesis. TG2-mediated deamidation enhances the binding affinity of gluten peptides to HLA-DQ2/DQ8 molecules, thereby promoting CD4⁺ T helper cell activation and the subsequent release of pro-inflammatory cytokines [169, 170]. Inhibition of TG2 enzymatic activity has thus emerged as a viable strategy for mitigating gluten-driven immune activation [171]. Additionally, monoclonal antibody (mAb)-based therapies targeting inflammatory mediators have shown clinical promise. IL-15, which is a key cytokine implicated in CeD, plays a crucial role in the activation of intraepithelial cytotoxic CD8⁺ T cells, leading to epithelial damage and villous atrophy [172]. In a clinical trial evaluating AMG 714, a mAb directed against IL-15, patients with CeD demonstrated significant improvement in clinical symptoms, particularly diarrhea, underscoring the potential of cytokine-targeted therapies [173].

Inflammation is a shared pathophysiological hallmark of CeD, MetS, and MASLD, despite their differing primary etiologies and target tissues. Emerging biomarkers, such as the systemic immune-inflammation index and uric-acid-to-creatinine ratio, reflect this inflammatory burden in MASLD and MetS, respectively [174, 175]. This shared inflammatory process may partly explain their clinical convergence and supports further investigation into common immunometabolic pathways. In addition, the interaction between the GM and sIgA has been shown to modulate intestinal inflammation, with shifts in GM composition potentially playing a role in reducing inflammatory responses [176]. Thus, the convergence of immunometabolic dysfunction in these conditions suggests that targeting inflammatory pathways may offer therapeutic benefits across disease contexts, requiring integrated treatment strategies.

Within the context of this discussion, it is also important to highlight that CeD is associated with a range of psychiatric manifestations, including depression, anxiety, eating disorders, autism spectrum disorder, attention deficit/hyperactivity disorder, bipolar disorder, schizophrenia, and mood disorders [177]. Nutritional psychiatry is an emerging field that employs rigorous scientific methods to evaluate the efficacy and define appropriate therapeutic applications of dietary supplements and nutraceuticals in individuals with and without mental health conditions [178]. This approach addresses safety concerns and side effects commonly associated with pharmacological treatments, such as dyslipidemia, altered glucose metabolism, extrapyramidal symptoms, sexual dysfunction, weight gain, MetS, and T2DM [178]. Consequently, nutritional psychiatry may play a pivotal role in CeD management, as personalized dietary interventions could not only alleviate disease-specific symptoms but also improve comorbid psychiatric conditions. Moreover, nutritional psychiatry encompasses the use of psychobiotics, which are a novel class of psychotropic agents that include live microorganisms and bioactive compounds demonstrated to be effective in treating stress, anxiety, and depression [179]. Thus, these therapeutic strategies hold significant potential as adjunctive treatments in CeD.

As with all narrative reviews, the present study is subject to several inherent limitations. First, considerable heterogeneity was observed across the reviewed studies, stemming from differences in sequencing technologies, experimental protocols, analytical pipelines, and sample types. These methodological discrepancies complicate cross-study comparisons and hinder the identification of consistent microbial biomarkers for tracking disease progression. Furthermore, differences in sample collection procedures and storage conditions may introduce additional variability, impacting the reproducibility and reliability of findings. This underscores the need for standardized methodologies and reporting guidelines to improve study comparisons and facilitate meta-analyses. Second, short-term studies typically highlight the immediate alleviation of gastrointestinal symptoms and inflammatory markers, but they often fail to capture the long-term impact on metabolic dysfunctions commonly associated with CeD. These metabolic complications may persist even in patients adhering to a GFD, and their long-term consequences are still not fully understood. Longitudinal studies are crucial to determine whether microbial interventions can provide sustained benefits in modifying the GM in a way that addresses not only the acute inflammatory responses but also the chronic metabolic imbalances of CeD. Moreover, the dynamic nature of the GM and its complex interactions with diet, lifestyle, and disease progression require longer intervention periods to assess the potential of microbial therapies in preventing or mitigating metabolic dysfunctions over time. Third, the diagnosis of CeD remains challenging due to the broad spectrum and non-specific nature of clinical manifestations. A substantial proportion of individuals with CeD remain undiagnosed, with an average diagnostic delay of approximately 12 years [180]. In this context, predictive models aimed at estimating CeD risk based on symptomatology and clinical risk factors offer potential utility. However, these models often demonstrate limited efficacy when relying solely on clinical data [181]. To address these challenges, future studies should consider the following recommendations: (i) the incorporation of microbial biomarkers derived from stool samples, which offer a non-invasive and accessible diagnostic modality, may significantly enhance the predictive performance of current risk models; (ii) the integration of microbial signatures with clinical markers of mucosal integrity could provide a more robust framework for disease monitoring and prognosis. Notably, evidence suggests that the GM composition differs among CeD patient subgroups with varying clinical phenotypes, indicating a potential role of GM in the persistence of symptoms despite adherence to a GFD [182].

CeD constitutes a heterogeneous condition with diverse clinical presentations and underlying mechanisms, which complicates the development of a universal treatment strategy. The emergence of personalized medicine is likely to become increasingly important, as it offers the potential for customizing therapeutic interventions to the individual’s genetic, immunological, microbial, and metabolic profiles. Consequently, this personalized approach may enhance treatment efficacy and minimize adverse outcomes. Moreover, it is pivotal to educate patients about the potential risks associated with CeD and its management, particularly those related to metabolic complications and dietary imbalances. Encouraging the adoption of a healthy lifestyle mainly consisting in a nutritionally plant-based balanced diet and regular physical activity should be an integral component of comprehensive care for individuals with CeD.

A synthesis of existing studies underscores the potential of several protective factors and targeted interventions for future research aimed at preventing CeD. Among these, the adoption of a health-promoting dietary pattern within the first two years of life, such as the Mediterranean or vegetarian diet, has demonstrated a protective role in reducing CeD risk. These diets are rich in dietary fiber and phytochemicals, which foster the growth of beneficial commensal gut microbiota and support the production of SCFAs. SCFAs, in turn, play a critical role in maintaining intestinal barrier integrity by enhancing mucus production and upregulating the expression of tight junction proteins. Furthermore, SCFAs exert immunomodulatory effects, promoting immune tolerance through the induction of Tregs, which secrete IL-10 and mitigate pro-inflammatory Th1 responses and autoantibody production. These findings highlight the relevance of early-life nutritional strategies as a foundation for future preventive approaches in CeD.

Precision probiotics have demonstrated multifaceted therapeutic potential in the context of CeD. These probiotics exert their effects through several key mechanisms. They attenuate inflammatory responses associated with CeD by disrupting the activity of pathogenic and pro-inflammatory microbial species and restoring eubiotic populations that produce SCFAs. In addition, certain microbial strains synthesize peptidases capable of degrading immunogenic gliadin peptides, thereby mitigating antigenic stimulation. Precision probiotics also contribute to immune homeostasis by enhancing Treg activity and modulating intestinal barrier integrity through the regulation of tight junction proteins. Moreover, they are capable of producing AhR ligands, which are associated with increased IL-22 production, enhanced intestinal stem cell proliferation, and the repair of mucosal injury. Complementing these effects, postbiotics have been shown to further support gut barrier function by reinforcing tight junctions and preventing gliadin-induced inflammatory effects. All these promising outcomes highlight the potential of precision probiotics and postbiotics. However, further well-designed clinical studies are needed to confirm their proven efficacy.

Therefore, the integration of clinical models with microbial biomarkers holds considerable promise for enhancing both the diagnosis and longitudinal monitoring of CeD. This combined approach would substantially improve current clinical practice by enabling more accurate risk stratification, earlier detection, and personalized management strategies that reflect the heterogeneous nature of the disease.