MS and Celiac: Are They Linked by Autoimmune Processes?

Multiple sclerosis (MS) and celiac disease are both autoimmune conditions in which the immune system mistakenly attacks the body’s own tissues. MS affects the central nervous system, causing neurological symptoms, while celiac disease targets the small intestine in response to gluten consumption. Despite their distinct manifestations, research suggests potential links between these disorders.

Understanding shared immune mechanisms could provide insights into their development and management.

Immune Factors Potentially Involved

Dysregulation of the immune system plays a central role in both MS and celiac disease, with overlapping mechanisms contributing to tissue damage. In MS, autoreactive CD4+ T cells cross the blood-brain barrier, triggering inflammation that leads to neuronal demyelination. These cells, skewed toward a pro-inflammatory Th1 and Th17 phenotype, release cytokines such as interferon-gamma (IFN-γ) and interleukin-17 (IL-17), exacerbating neuroinflammation. Similarly, in celiac disease, an immune response to gluten peptides expands Th1 and Th17 cells in the intestinal mucosa, causing villous atrophy and malabsorption.

Regulatory T cells (Tregs), which normally suppress excessive immune activation, are dysfunctional in both diseases. In MS, reduced Treg activity allows sustained neuroinflammation, while in celiac disease, impaired Tregs fail to control the heightened immune response to gluten. Antigen-presenting cells, such as dendritic cells and macrophages, further amplify the autoimmune response by presenting self-antigens in MS and gluten peptides in celiac disease. B cells also contribute, producing myelin-targeting antibodies in MS and anti-tissue transglutaminase (tTG) antibodies in celiac disease, which serve as diagnostic markers.

Cytokine profiles in both diseases further highlight their immunological overlap. Elevated levels of tumor necrosis factor-alpha (TNF-α) and IL-6 are observed in MS lesions and the intestinal mucosa of celiac patients, promoting chronic inflammation. Interferon-beta (IFN-β), a common MS treatment, has been shown to modulate immune responses in celiac disease, suggesting potential therapeutic cross-applicability.

Genetic Associations in Both Conditions

Genetic predisposition plays a significant role in both MS and celiac disease, with overlapping risk loci suggesting a hereditary link. The human leukocyte antigen (HLA) region, particularly HLA class II genes, is a major genetic determinant in both conditions. In MS, the HLA-DRB115:01 allele significantly increases susceptibility. Likewise, celiac disease is strongly associated with HLA-DQ2 and HLA-DQ8 haplotypes, which are present in nearly all affected individuals. These HLA variants influence antigen presentation and immune regulation, pointing to shared genetic pathways.

Beyond HLA associations, genome-wide association studies (GWAS) have identified non-HLA loci contributing to susceptibility in both disorders. Variants in IL2RA and SH2B3, which regulate immune signaling and lymphocyte activation, have been implicated in both MS and celiac disease. IL2RA encodes the alpha chain of the interleukin-2 receptor, a key regulator of T-cell activity, while SH2B3 (LNK) modulates immune cell proliferation. These shared genetic markers suggest common immune regulatory mechanisms.

Family studies further support a genetic connection. Research indicates that first-degree relatives of individuals with MS have an increased risk of celiac disease and vice versa. A study published in JAMA Neurology found MS patients were more likely to have close relatives diagnosed with celiac disease. Twin studies reinforce the role of genetic predisposition, with higher concordance rates in monozygotic twins than in dizygotic pairs.

Gut-Brain Axis in Autoimmune Disorders

The gut-brain axis, a bidirectional communication network between the gastrointestinal system and the central nervous system, has been implicated in both MS and celiac disease. Disruptions in this axis suggest that gut physiology may influence neurological function and vice versa.

One key factor is gut barrier integrity. The intestinal epithelium prevents harmful substances from entering the bloodstream while allowing nutrient absorption. In celiac disease, gluten exposure increases intestinal permeability by stimulating zonulin, a protein that modulates tight junctions between epithelial cells. Elevated zonulin levels have also been observed in MS patients, suggesting that a compromised gut barrier may facilitate the entry of pro-inflammatory molecules and microbial metabolites into circulation, potentially affecting brain inflammation and neurodegeneration.

Microbial metabolites such as short-chain fatty acids (SCFAs) further underscore the gut-brain connection. Produced by gut bacteria during fiber fermentation, SCFAs regulate immune responses and support blood-brain barrier integrity. Butyrate, in particular, has neuroprotective effects. Reduced levels of butyrate-producing bacteria have been reported in both MS and celiac disease, linking dysbiosis to disease progression. Altered neurotransmitter production by gut bacteria, affecting serotonin, dopamine, and gamma-aminobutyric acid (GABA), may further contribute to MS-related symptoms.

Dietary Triggers for Immune Activation

Diet plays a crucial role in shaping immune responses, particularly in conditions where specific food components act as triggers. In celiac disease, gluten-containing grains such as wheat, barley, and rye provoke an inflammatory reaction, causing intestinal damage and systemic effects. While gluten is not traditionally linked to MS, some studies suggest a higher prevalence of gluten sensitivity among MS patients, raising questions about dietary interactions.

Other dietary factors have also been explored. High-sodium diets have been implicated in immune dysregulation, with research indicating that excessive salt intake can enhance pro-inflammatory T cell activity. A study published in Nature found that elevated sodium levels promote Th17 cell differentiation, which contributes to MS pathology. Processed foods with emulsifiers like carboxymethylcellulose and polysorbate-80 have also been shown to alter gut permeability, potentially influencing systemic inflammation.

Microbiome Interactions

The gut microbiome, composed of trillions of microorganisms, plays a key role in immune function and homeostasis. Disruptions in microbial composition, known as dysbiosis, have been linked to both MS and celiac disease. Studies show individuals with these conditions exhibit microbial imbalances, with reductions in beneficial bacteria such as Faecalibacterium prausnitzii and Bifidobacterium, which have anti-inflammatory properties. Meanwhile, an overrepresentation of pro-inflammatory species, including Akkermansia muciniphila and Prevotella, has been observed.

Microbial metabolites influence disease mechanisms. Short-chain fatty acids (SCFAs), particularly butyrate and propionate, regulate immune responses and maintain intestinal barrier integrity. Reduced SCFA production in MS and celiac patients may contribute to increased inflammation and gut permeability, allowing microbial byproducts to enter circulation. Additionally, bacterial-derived lipopolysaccharides (LPS) have been implicated in triggering systemic inflammation that may exacerbate neuroinflammation in MS. These findings highlight the potential for microbiome-targeted therapies, such as probiotics and dietary interventions, to mitigate disease severity.

Clinical Diagnostic Approaches

Accurate diagnosis of MS and celiac disease requires symptom assessment, laboratory testing, and imaging techniques. MS is typically identified through neurological evaluations and magnetic resonance imaging (MRI) to detect demyelinating lesions. Celiac disease is diagnosed using serological tests for anti-tissue transglutaminase (tTG) and anti-endomysial antibodies, followed by confirmatory intestinal biopsy. However, overlapping symptoms such as fatigue, cognitive impairment, and gastrointestinal discomfort necessitate thorough evaluation.

Emerging biomarkers and advanced imaging techniques may improve diagnostic accuracy. Neurofilament light chain (NfL) is gaining attention as a biomarker for neurodegeneration in MS, while intestinal permeability markers such as zonulin provide insights into gut dysfunction in celiac patients. Gut microbiome profiling is also being explored as a potential diagnostic tool, with microbial composition differences potentially serving as early indicators of disease susceptibility. Integrating these novel approaches may enhance early detection and enable more personalized treatment strategies.