Gluten,Inflammation,and Neurodegeneration

Abstract

Growing evidence supports a potential link between dietary gluten intake and neurodegenerative disease in susceptible populations. Observational data supporting this link are described along with interventional study data evaluating the effects of restricting gluten from the diet in patients with neurologic disorders. Suggested underlying mechanisms between gluten intake and neurodegeneration are discussed.

“...dietary gluten-induced chronic inflammation is linked to dysbiosis and a permeable gut...”

Gluten plays an established role in the pathogenesis of celiac disease (CD) and nonceliac gluten sensitivity (NCGS). ¹ Interestingly, a number of neurodegenerative conditions have been associated with grain intake or respond favorably when gluten is restricted from the diet.^2-4 Additionally, rates of comorbid CD/NCGS and neurodegenerative disorders, including bipolar, major depressive disorder, anxiety, and autism spectrum disorders (ASD), have been observed in unusually high rates.^5-8 These findings raise the question as to whether gluten may be implicated in the pathogenesis of neurodegenerative conditions.

Gluten, primarily comprising gliadin and glutenin proteins (8085%), is a member of the prolamin superfamily and is commonly found in wheat, barley, rye, and oats. The prolamin superfamily of proteins is characterized by a repetitive sequence of the amino acids glutamine and proline and is suspected to be responsible for gluten’s water insolubility. Gluten within grains is confined to the cells of the starchy endosperm where it supports germination. In food production, gluten proteins are valued for their cohesiveness and viscoelasticity, which allows for ideal dough and bread consistency.^9,10 As a result, gluten is highly prevalent in a variety of common foods (bread, pasta, bakery items, and cereal) as well as used for sauce thickeners, fillers, and stabilizers.

Gluten consumed through the diet has been linked to a pathological immune response in susceptible populations.^10-13 Upon consumption, gluten is partially hydrolyzed by proteases in the gastrointestinal tract to peptides of ∼1030 amino acids in length that cross the intestinal barrier via trans or paracellular transport. These peptides undergo deamidation by intestinal tissue transglutaminase-2 (tTG2) which increases their affinity for major histocompatibility complex II (MHC II) molecules and triggers an inflammatory response. In individuals with celiac disease (CD) who carry human leukocyte antigen class II with DQ2 and/or DQ8 molecules on antigen-presenting cells (HLA-DQ2 or DQ8 haplotype), these partially digested peptides are recognized by the DQ cell receptor and presented to T lymphocytes, resulting in an immune response. In patients with nonceliac gluten sensitivity (NCGS), who are DQ2 and DQ8 negative, it is suspected that gluten proteins in concert with other components of wheat activate an innate immune response in the body. Wheat germ agglutinin and amylase-trypsin inhibitors of wheat have also been shown to illicit an innate immune response.^10-13 As a result, due to loss of tolerance to gluten proteins, individuals with CD and NCGS experience gastrointestinal distress, fatigue, and pain including inflammation and increased permeability of the intestinal mucosa. ¹

These inflammatory effects of gluten may not be limited to the gastrointestinal system. Increased intestinal permeability leads to entry of toxic digestive metabolites, bacteria, and bacterial toxins into the bloodstream which may eventually reach the central nervous system. ¹ Neurological issues like cerebellar ataxia, peripheral neuropathy, cognitive impairment, and neuropsychiatric diseases have been associated with CD, suggesting the possibility of gluten-mediated inflammation playing a role in loss of bloodbrain barrier (BBB) integrity.^1,14-16 Furthermore, increased BBB permeability attributed to inflammation or bacteria is linked to other neurological disorders including ASD, dementia, Alzheimer’s disease, Parkinson’s disease (PD), depression, anxiety, and schizophrenia.^15,17 The following describes observed relationships between gluten and neurodegenerative conditions as well as potential mechanisms by which dietary gluten may lead to neurodegeneration.

Gluten and Neurodegenerative Conditions

Despite the paucity of evidence establishing a causal relationship between dietary gluten intake and neurological disorders, a number of studies demonstrate an association between the 2 and/or a beneficial effect on neurological symptoms when gluten is restricted from the diet. One example is the reduction in observed incidence of schizophrenia in populations who consume little to no grains compared to those consuming grain-rich diets. ² Patients with schizophrenia have markedly high levels of inflammation, and a gluten-free diet (GFD) has been shown to improve both psychiatric and gastrointestinal symptoms in these patients.^3,18,19 Likewise, GFD has been associated with improvements in ASD.^4,5,20,21 Unusually high rates of chronic diarrhea, constipation, and bloating have been observed in children with ASD. ⁵ Interventional studies have demonstrated improvements in both the prevalence of gastrointestinal symptoms and ASD behaviors in children with ASD who followed GFD. ⁴ Mood disorders (bipolar disorder, major depressive disorder, and anxiety) are commonly observed in individuals with CD and NCGS, with bipolar disorder 17 times more likely to affect individuals with CD relative to the general population.^6,7 Increased levels of gluten-related antibodies are found in individuals with bipolar disorder, depression, anxiety, hyperactivity, as well as schizophrenia suggesting the correlation between gluten consumption and mood disorders.^6-8

Putative Mechanisms

As stated earlier, intestinal tissue transglutaminase-2 (tTG2) is a calcium-dependent enzyme that mediates deamidation of glutamine residues present in gluten proteins, triggering gluten’s inflammatory response.^16,22 tTG2 not only mediates the post-translational modification/deamidation of the gluten protein gliadin, but was shown to act as an autoantigen and due to its ability to induce the production of tTG2 autoantibodies.^22,23 The presence of tTG2 autoantibodies were detected in almost 100% of patients diagnosed with CD and in a minor fraction of NCGS patients. ²³ Tissue transglutaminase is also involved in multiple neurodegenerative diseases. The neural isoform of tissue transglutaminase, tTG6, is implicated in the pathogenesis of Alzheimer’s disease (AD), Huntington’s disease (HD), and movement disorders like gluten ataxia and multiple sclerosis.^24-28 Increased levels of circulating anti-tTG6 antibodies are also present in adult patients with schizophrenia.^16,29

Overall, increased levels of tTG6 antibodies in CD patients with gluten ataxia and peripheral neuropathy suggest a plausible role for tTG6 in contributing toward these central and peripheral symptoms of CD.^26,29 With regards to NCGS patients, it is suggested that loss of integrity of the intestinal barrier facilitates access of partially hydrolyzed immunogenic gluten peptides to both the systemic circulation and the brain. Access of these toxic gluten peptides and HLA-DQ2/DQ8 restricted CD4 T cells to the brain may contribute to the neurological issues observed in NCGS patients.^30-33 It is also proposed that loss of intestinal barrier’s integrity aka leaky gut promotes increased access for circulating or gut-derived extracellular structures like biomolecular condensates (BMC) and extracellular vesicles (EV) to the brain of CD and NCGS patients. ¹⁶ Given the critical role of tTG in mediating gluten metabolism, its autoantigen properties, its ability to cause central β-amyloid accumulation, and foster inflammation and cancer, tTG is being pursued as a molecular target for a variety of disease states.^16,34

Additional mechanisms have been postulated to contribute to gluten sensitivity and neuronal dysfunction. One of them is the identification of a strong correlation between specific HLA haplotypes and dysregulation of the gut-brain axis in CD and NCGS patients diagnosed with ASD and/or Down’s syndrome (DS).^16,35,36 Also, in NCGS patients with neurological issues, antibodies for glutamic acid decarboxylase (GAD), a key enzyme involved in the biosynthesis of the primary inhibitory neurotransmitter gamma-aminobutyric acid, were detected.^16,37

The potential role of epigenetic mechanisms in regulating inflammatory responses has prompted focused attention toward micro-RNAs (MiRNAs) and CD. ¹⁶ The MiRNAs are ∼20–23 nucleotides in length, small RNA molecules that mediate a number of cellular processes like cell proliferation, differentiation, apoptosis, cell signaling, and immune, including inflammatory, responses. ¹⁶ Specifically, downregulation of miR-192-5p due to inflammation is suggestive of its role in maintaining intestinal homeostasis.^16,38,39 Moreover, chronic inflammation of the intestine combined with a leaky gut results in gut dysbiosis, which may in turn promote microbial entry into systemic circulation. Especially, loss of intestinal barrier’s integrity has the potential to allow increased access of lipopolysaccharides (LPS) across the BBB, activate microglial cells, and ultimately cause neuronal inflammation and damage in CD patients.^16,40

In CD and NCGS individuals, it is established that dietary gluten-induced chronic inflammation is linked to dysbiosis and a permeable gut. ¹⁶ This in turn affects factors that regulate neuronal inflammation, cognition, and neurodegeneration. For example, at the molecular level, the genetic expression of peroxisome proliferator activated receptor gamma (PPARγ) is reduced in patients diagnosed with ulcerative colitis and CD. Because PPARγ is an anti-inflammatory and anti-dysbiotic molecule, it may serve as a potential molecular target for the management of gluten-induced intestinal inflammation and dysbiosis.^16,41

Conclusion

While data supporting the direct link between gluten consumption and neurodegeneration is limited, available evidence highlights the relationship between gluten consumption, tTG antibody production, and disruption of the microbiota-gut-brain axis.^1,16 The beneficial effects of GFD in patients with CD, schizophrenia, and ASD, especially in mitigating gastrointestinal and neurological symptoms, highlight the need for more exploration and identification of definitive evidence. ⁴²