Pathogenesis

Neurological complications and cognitive impairment in coeliac disease

CD is primarily an intestinal disorder characterised histologically by intraepithelial lymphocytosis, crypt hyperplasia and villous atrophy. This broader view of the disease seen as an inflammatory disease is supported by clinical observations of extra-intestinal manifestations such as dermatological, hepatic, osteological, endocrine and neurological signs⁽ Reference Uygur-Bayramicli and Melih Özel ^{57 )}. The most severe neurological symptoms are dementia, amnesia, ataxia, acalculia, epilepsy, chronic neuropathies, confusion, personality changes⁽ Reference Hu, Murray and Greenaway ^{58 )}, cognitive deficits⁽ Reference Arnone and Conti ^{59 )}, multifocal encephalopathy, neuromyelitis optica, muscular hypotonia, delayed motor development⁽ Reference Vieira, Jatobá and Matos ^{60 )} and headaches⁽ Reference Parisi, Pietropaoli and Ferretti ^{61 ,} Reference Lerner, Makhoul and Eliakim ^{62 )}, some of which could improve with GFD treatment⁽ Reference Parisi, Pietropaoli and Ferretti ^{61 ,} Reference Neto, Costa and Magalhaes ^{63 )}.

Due to high levels of antigliadin antibodies, CD is seen as the common cause of neurological syndromes, particularly cerebellar ataxia, whose origin remains unknown. There is an increasingly wider spectrum of neurological syndromes identified both as complications of prediagnosed CD and as an initial manifestation of CD⁽ Reference Zelnik, Pacht and Obeid ^{64 )}. Studies show that the nervous system is compromised and acts as a complication in the pre-diagnosis of CD. Many studies have reported the involvement of the nervous system mainly as a complication of prediagnosed CD⁽ Reference Parisi, Pietropaoli and Ferretti ^{61 ,} Reference Bushara ^{65 )}. Several studies have investigated the prevalence of neuronal hyper-excitability and electroencephalogram (EEG) abnormalities in asymptomatic children and adolescents with newly diagnosed CD before the introduction of a GFD, and in particular any changes following the introduction of a diet. A recent study evaluated the role of a GFD on neurological symptoms, EEG characteristics and sleep breathing disorders (SBD) in children with CD⁽ Reference Parisi, Pietropaoli and Ferretti ^{61 )}. The authors enrolled nineteen children with a new biopsy CD diagnosis. At the diagnosis of CD, 37% of the patients complained of headaches and other neurological disorders that affected their daily activities and 32% of the patients were positive for SBD. The EEG tests revealed abnormal findings in 48% of children. After 6 months of a GFD, headaches and EEG abnormalities disappeared in most of the children in turn, resulting in them being negative for SBD. Asymptomatic children and adolescents manifested hyper-excitability and EEG abnormalities before a GFD. Adherence to a GFD has been shown to result in lighter headache symptoms reported by CD patients⁽ Reference Lerner, Makhoul and Eliakim ^{62 )}. Results of functional imaging studies such as single photon emission computed tomography were in favour of migraines, and a GFD could lead to an improvement of migraine in these patients⁽ Reference Gabrielli, Cremonini and Fiore ^{66 )}. Functional imaging studies revealed migraines present through single photon computed tomography with the result that a GFD could lead to an improvement. However, an association between CD and migraine headaches was not established when compared with the general population⁽ Reference Shahriar ^{67 )}.

Other common neurological symptoms of CD are ataxia and epilepsy. Cerebellar ataxia is one of the first symptoms⁽ Reference Cooke and Smith ^{68 )}, and one of the most frequently recognised neurological disturbances in CD⁽ Reference Fasano ^{69 )}. Its predominant clinical manifestations include dysarthria, dysphonia, pyramidal signs, abnormal movements of eyes and progressive ataxia of gait. Ataxia related to CD is not often associated with typical gastrointestinal symptoms or malabsorption signs. Ataxic symptom relief has been reported with the adherence to a GFD⁽ Reference Hadjivassiliou, Mäki and Sanders ^{70 )}. Regarding epilepsy, several studies have demonstrated a relationship between epilepsy and CD, with prevalence rates ranging from 3·5 to 7·2%⁽ Reference Zelnik, Pacht and Obeid ^{64 ,} Reference Fasano ^{69 )}. However, although epilepsy is considered in international studies as a condition associated with CD or an extra-intestinal manifestation of this disease, a recent study has not confirmed this association⁽ Reference Vieira, Jatobá and Matos ^{60 )}.

Recent data are less consistent and vary below these figures⁽ Reference Ludvigsson, Zingone and Tomson ^{71 )}. Peripheral neuropathy is the second most frequent neurological complication in CD patients and has been reported in up to 50% of cases⁽ Reference Parisi, Pietropaoli and Ferretti ^{61 ,} Reference Hadjivassiliou, Grünewald and Davies-Jones ^{72 )}. Neuropathy may precede a diagnosis of CD⁽ Reference Chin, Sander and Brannagan ^{73 )}. Research findings regarding the effect of a GFD on peripheral neuropathy have been mixed, with some reports indicating positive outcomes and others reporting no significant changes⁽ Reference Neto, Costa and Magalhaes ^{63 ,} Reference Luostarinen, Himanen and Luostarinen ^{74 )}.

A study which investigated neurological damage and gluten-free foods showed that neurological peripheral disorders, and autonomic dysfunctions with anti-neuronal antibodies in adults with CD did not disappear with a GFD⁽ Reference Tursi, Giorgetti and Iani ^{75 )}. On the contrary, important evidence comes from a case report of a 14-year-old patient with rare neurological symptoms⁽ Reference Uzma, Imdad and Beg ^{76 )}. The patient presented headaches and blurred vision for 1 year; she was diagnosed with papilledaema after an ophthalmic examination showing increased cerebrospinal fluid putting pressure on the backbone and was further diagnosed with pseudotumor cerebri. However, upper gastrointestinal endoscopy with duodenal biopsy confirmed the diagnosis of CD. The patient was put on a GFD, resolving the gastrointestinal symptoms and also reaching almost complete resolution of the pseudotumour cerebri symptoms.

Neurological signs are rare in children but as many as 36% of adult patients present neurological changes⁽ Reference Chaudhry and Ravich ^{77 )}. Other neurological manifestations are tremor, myelopathy, brainstem encephalitis, progressive leukoencephalopathy, vasculitis, occipital calcification and myoclonic syndrome. A myoclonic syndrome, often accompanied by ataxia, may occur in CD. Myoclonus may be present as focal, multifocal or generalised convulsions. They also include neuromuscular manifestation such as peripheral polyneuropathy, mono-neuropathy multiplex, dermatomyositis, polymyositis and inclusion body myositis⁽ Reference Shahriar ^{67 )}. Additionally, one study showed that there is no significant difference between the laboratory data of the coeliac patients with and without neurological manifestations⁽ Reference Işikay and Kocamaz ^{78 )}. The neurological symptoms are headaches, epilepsy, migraines, mental retardation, breath-holding spells, ataxia, cerebral palsy, attention-deficit/hyperactivity disorder, Down’s syndrome and Turner syndrome in order of frequency. Moreover, the 3a biopsy type was statistically more common among patients without neurological manifestations, while the 3b biopsy type was statistically and more common among patients with neurological manifestations. It is important to keep in mind that in the clinical course of CD, different neurological manifestations may be reported.

Although a range of neurological disorders are widely reported to be associated with coeliac patients, their pathogenesis remains unclear. Such disorders are believed to be secondary to vitamin deficiency due to malabsorption, and others to immune mechanisms. A further detailed study confirmed the role of hyperhomocysteinaemia for neurological features associated with CD⁽ Reference Ferretti, Parisi and Villa ^{79 )}.

Neurological conditions have been researched in detail as opposed to cognitive functioning. CD adult patients reported milder forms of cognitive impairment known as ‘brain fog’, a symptom which disappears after GFD treatment but re-presents itself again after inadvertent gluten exposure⁽ Reference Lichtwark, Newnham and Robinson ^{80 )}. Brain fog is characterised by the difficulty in concentrating, problems with attentiveness, short-term memory lapses, difficulties in word-finding, temporary loss in mental acuity and creativity as well as confusion and/or disorientation⁽ Reference Theoharides, Stewart and Hatziagelaki ^{81 )}.

A retrospective study on patients with a CD diagnosis after the age of 60 years presented evidence supporting the likelihood of such a link. Two patients out of seven presented a cognitive decline, initially attributed to Alzheimer’s disease, but they showed an improvement in their symptoms after the initiation of a GFD. A third of the patients suffered from a peripheral neuropathy, and completely recovered following a gluten-free regimen⁽ Reference Lurie, Landau and Pfeffer ^{82 )}. The level of cognitive function was believed to have improved together with mucosal healing, an hypothesis proposed by Lichtwark et al. ⁽ Reference Lichtwark, Newnham and Robinson ^{80 )} in their longitudinal pilot study which investigated the relationships between cognitive function and mucosal healing in individuals diagnosed with CD starting a GFD. The study tested eleven patients (eight females, three males), mean age 30 (range 22–39) years, on a battery of cognitive tests at 0, 12 and 52 weeks. The items under examination were information, processing efficacy, memory, visual–spatial ability, motoric function and attention. Researchers also collected small bowel biopsies via routine gastroscopy at 12 and 52 weeks so that cognitive performance could be compared with serum concentrations of tTG antibodies, with biopsy outcomes and with other biological markers. The results of the paper showed that tTG antibody concentrations decreased from a mean of 58·4 at baseline to 16·8 U/ml at the 52nd week, while four of the cognitive tests assessing verbal fluency, attention and motoric function reported significant improvement over the 12 weeks, besides confirming that improvement in cognitive performance was parallel to mucosal healing. The study reported an excellent adherence to the diet by all patients.

In addition, a study by Casella et al. ⁽ Reference Casella, Zanini and Lanzarotto ^{83 )} evaluated the functional and cognitive performance in CD patients diagnosed at the age of 65 years or older, compared with age- and sex-matched control patients using psychometric tests to obtain comprehensive information on functional performance, and general or more specific cognitive functions. The results evidenced how cognitive performance is worse in the elderly than in control patients, despite a longer time on a GFD⁽ Reference Casella, Zanini and Lanzarotto ^{83 )}.

Several studies have investigated the relationship between dementia and CD⁽ Reference Arnone and Conti ^{59 )}. Dementia develops as acalculia, confusion, amnesia and personality disorder⁽ Reference Lurie, Landau and Pfeffer ^{82 )}. However, the aetiology and specific treatment of this complication are not clearly known⁽ Reference Shahriar ^{67 )}. Collin et al. ⁽ Reference Collin, Pirttilä and Nurmikko ^{84 )} reported five cases of patients with CD who developed dementia before the age of 60 years. Four patients suffered intellectual deterioration ranging from moderate to severe. In addition to intellectual deterioration, one patient showed deficit in both verbal and visual memory. One had slow psychomotor functions, and the other showed severe memory deficit, constructional deficit and apraxia. The fifth patient had deficits in digit span, visual memory, and visual–motor constructional difficulties. Brain computed tomography revealed diffused cerebral or cerebellar atrophy in all patients⁽ Reference Collin, Pirttilä and Nurmikko ^{84 )}. Other studies have reported a link between dementia in individuals diagnosed with CD after the age of 60 years. A retrospective study in Israel examined seven patients diagnosed with CD after the age of 60 years. Of the seven, two female patients were initially diagnosed with dementia of the Alzheimer type due to a progressive cognitive decline. Compliance to a GFD ameliorated the cognitive decline in both patients⁽ Reference Lurie, Landau and Pfeffer ^{82 )}. However, in another study, adherence to a GFD resulted in no change in neurological symptoms in patients with CD who presented mild memory impairment⁽ Reference Luostarinen, Pirttilä and Collin ^{85 )}.

Psychiatric disorders and quality of life of coeliac disease patients

The association of CD with psychiatric disorders, including depression, has been identified for a long time. Several psychiatric symptoms have been reported as common complications in many patients suffering from CD, though the effects of diet on one’s mood and psychiatric symptoms remain largely unknown⁽ Reference Cicarelli, Della Rocca and Amboni ^{86 )}. Psychiatric symptoms usually described in CD patients include depressive symptoms, apathy, excessive anxiety, irritability⁽ Reference Bushara ^{65 )}, eating disorders⁽ Reference Karwautz, Wagner and Berger ^{87 )}, attention-deficit/hyperactivity disorder⁽ Reference Niederhofer and Pittschieler ^{88 )} and autism⁽ Reference Barcia, Posar, Santucci and Parmeggiani ^{89 )} as well as sleep disorders which are also common in CD. Sleep disorders are related to depression, anxiety and fatigue, and inversely related to QOL⁽ Reference Zingone, Siniscalchi and Capone ^{90 )}.

Carta et al. ⁽ Reference Carta, Hardoy and Boi ^{91 )} suggests that the possible causative factors are malabsorption and nutritional deficiencies (especially of vitamin B₆ and tryptophan) and the association with other autoimmune diseases such as thyroid disease. A study on untreated CD patients reported decreased plasma levels of tryptophan and other monoamine precursors and decreased cerebrospinal fluid levels of serotonin, dopamine and noradrenaline metabolites (5-hydroxyindoleacetic acid, homovanillic acid and 3-methoxy-4-hydroxyphenylglycol, respectively)⁽⁹²⁾. A cross-sectional, case–control study enrolling thirty-six CD patients used the Composite International Diagnostic Interview to assess lifetime psychopathology. The findings showed that the risks of major depression (41·7%), dysthymic disorder (8·3%), adjustment disorders (30·5%) and panic disorder (13·9%) are higher in CD⁽ Reference Carta, Hardoy and Boi ^{91 )}.

A meta-analysis on anxiety and depression in CD found that depression is more common and more severe in adults with CD compared with normal controls. However, depression in adults with CD did not differ from adults who had other physical illnesses and no differences in anxiety were found⁽ Reference Smith and Gerdes ^{93 )}. Additional studies have also found increased rates of depressive and anxiety symptoms in CD patients on a GFD⁽ Reference Addolorato, Mirijello and D’Angelo ^{94 ,} Reference Addolorato, Mirijello and D’Angelo ^{95 )}, though the prevalence of depressive symptoms in CD patients varies widely across studies ranging from 6 to 69% as shown by another large longitudinal population-based cohort study⁽ Reference Ludvigsson, Reutfors and Osby ^{96 )}, where CD patients were also reported to have an 80% increased risk of depression compared with controls. This variability in prevalence could be accounted for by differences in personal characteristics, cultural background and study design. The increased risk of depressive symptoms in CD patients could be explained by several mechanisms.

The first mechanism could be dietary non-compliance and sustained malabsorption, which could lead to sustained nutritional deficiencies (for example, vitamin B₆, vitamin B₁₂ and folic acid) producing the risk of depression⁽ Reference Hallert, Svensson and Tholstrup ^{97 )}. Second, a restrictive GFD could cause nutritional deficiencies. Even though these nutritional deficiencies contribute to the risks of depression, it is not established to date⁽ Reference Thompson, Dennis and Higgins ^{98 )}. Depression could also be induced by reductions in brain monoamine availability and metabolism⁽ Reference Fera, Cascio and Angelini ^{92 )} and regional cerebral hypoperfusion⁽ Reference Häuser, Stallmach and Caspary ^{99 )} in patients suffering from CD. Delgado et al. ⁽ Reference Delgado, Price and Miller ^{100 )} suggested excessive cytokine secretion due to chronic immune system activation as a fundamental pathology underlying depressive symptoms. Furthermore, there is an increased hypothalamic–pituitary–adrenal axis hyperactivity due to the cytokine activation associated with major depression⁽ Reference Kronfol and Remick ^{101 )}. Another reason can be found in the fact that, due to the strict dietary regimen, CD patients may avoid social situations involving food experiences. They may have higher levels of psychological distress because of daily difficulties, negative responses to the diet due to social surroundings and continuous worrying about dietary mistakes and negative results which could all lead to depression⁽ Reference Addolorato, Capristo and Ghittoni ^{102 )}. Finally, depression in CD patients may be a secondary condition resulting from the association between CD and other auto-immune diseases with a high risk of depression, such as thyroid disease and diabetes mellitus⁽ Reference Garud, Leffler and Dennis ^{103 )}.

Relationships between CD and psychiatric disorders such as anxiety and depression have been described especially when CD starts after 60 years of age⁽ Reference Shahriar ^{67 )}. It has been shown that children and adolescents with CD may have emotional and behavioural problems⁽ Reference Mazzone, Reale and Spina ^{104 )}. Most CD patients showed significantly higher scores of anxiety, harm avoidance, separation panic and somatic complaints, even after the introduction of dietary regimens. The introduction of a GFD results in a radical change in eating habits and lifestyle of CD children, and can be difficult to accept and stressful to follow. This induces a high level of anxiety, which may be evidenced in a different way according to gender susceptibility, resulting in depression in females and aggression and irritability in males. The acceptance of a GFD also depends on age. For example, adolescents aged between 12 and 17 years find it particularly difficult to adapt to their new dietary regimen. This is due to the fact that this age bracket already has to manage with social interactions with their peers and adults. Overall, reports highlight the fact of having a chronic condition during childhood and adolescence could prove difficult to manage. In this context, a strict food regimen can be considered a negative influence on their social life. On the whole, all these reports indicate that the impact of a chronic condition during childhood and adolescence may be difficult to manage⁽ Reference Mazzone, Reale and Spina ^{104 )}. On the other hand, another study demonstrated an association of increased depression and disruptive behavioural disorders in adolescents with untreated CD. This is evidence supporting the improvement in psychiatric symptoms after the initiation of a GFD⁽ Reference Pynnönen, Isometsä and Aronen ^{105 )}. A case-report also suggests that CD should be taken into consideration in children with psychiatric disorders, particularly if they are not responsive to psychotropic medication⁽ Reference Sharma, Kline and Shreeve ^{106 )}. Given that unrecognised CD may predispose the sufferer to serious psychiatric disorders and behavioural problems, it should be considered as a differential diagnosis in all age groups. A recent study aimed to establish whether long-term adherence to a GFD can be related to depressive symptoms in CD patients, given that lifetime depressive symptoms may be present in at least one-third of CD patients on a GFD. The results of a recent study on long-term adherence to a GFD (5 years) evidenced a decrease in depressive symptoms producing relief of the symptoms as opposed to a short-term diet of less than 2 years⁽ Reference van Hees, van der Does and Giltay ^{107 )}. It is worth noting that the elimination of gluten in the case of a patient suffering from chronic treatment-resistant symptoms of depression and anxiety showed significant improvement in the mental state and in routine activities. When anxiety and depressive symptoms persist even after an unsatisfactory reaction to pharmacological treatment, it indicates the need to identify the somatic reasons for the underlying condition⁽ Reference Urban-Kowalczyk, Œmigielski and Gmitrowicz ^{108 )}. Interestingly, a reduced QOL was highlighted in CD patients as compared with healthy control participants⁽ Reference Lee and Newman ^{109 )}.

Recent epidemiological data highlight the association between schizophrenia (SCZ) and several autoimmune diseases⁽ Reference Eaton, Byrne and Ewald ^{110 ,} Reference Chen, Chao and Chen ^{111 )}, CD being one found to be in association with SCZ since the 1950s⁽ Reference Singh and Kay ^{112 )}. Studies on the effects of the elimination of gluten from the diet of SCZ patients have further strengthened the existence of an association between gluten and SCZ. In fact, SCZ patients whose symptoms improved after the introduction of a cereal- and milk-free diet showed an interruption or reversal of clinical improvement towards wheat⁽ Reference Kalaydjian, Eaton and Cascella ^{113 ,} Reference Jackson, Eaton and Cascella ^{114 )}. A few studies have suggested that SCZ and CD may be associated with similar or adjacent genes⁽ Reference Zhong, McCombs and Olson ^{115 ,} Reference Straub, MacLean and O’Neill ^{116 )}. It has been reported that genetic susceptibility in SCZ lies in the HLA DQ, similarly to autoimmune disorders such as CD⁽ Reference Li, Underhill and Liu ^{117 )}. By contrast, a recent study showed no such HLA association in SCZ⁽ Reference Samaroo, Dickerson and Kasarda ^{118 )}.

The subsequent observations provided contrasting results. Epidemiological studies, for example the National Danish Register⁽ Reference Eaton, Mortensen and Agerbo ^{119 )}, found that CD occurred before the onset of SCZ and that antibody-based diagnosis (above all anti-gliadin) was a risk factor for SCZ⁽ Reference Samaroo, Dickerson and Kasarda ^{118 ,} Reference Karlsson, Blomström and Wicks ^{120 )}. A study observed that anti-gliadin antibodies have a role in the aetiopathogenesis of SCZ⁽ Reference Samaroo, Dickerson and Kasarda ^{118 )}. An increasing number of studies suggest that the immune mechanisms are partially responsible for SCZ. Similarly to CD, an aberrant Th1 immune reaction has been connected with the development of SCZ. The study suggests a causal link between CD and SCZ: the risk for SCZ in CD patients may be dependent on the interplay between IFN-γ and the transcription factor STAT1 (signal transducer and activator 1)⁽ Reference Mormile ^{121 )}.

A recent study showed that bacterial compositions could explain the inefficient gluten digestion and how in certain situations can be a risk factor for SCZ because the gut microbiota contributes to digestion, inflammation, gut permeability and behaviour⁽ Reference Severance, Yolken and Eaton ^{122 )}. It is also significantly recognised that bidirectional communication exists between the brain and the gut that uses neural, hormonal and immunological routes. An increased incidence of gastrointestinal barrier dysfunction, food antigen sensitivity, inflammation and the metabolic syndrome is seen in SCZ⁽ Reference Nemani, Hosseini Ghomi and McCormick ^{123 )}. As demonstrated, these symptoms can be influenced by the composition of the gut microbiota.

Another theoretical framework suggests that inappropriate oestrogen exposure occurring in the brain could also be occurring in the colon so that an association of CD or some other inflammation and SCZ may be observable not from a genetic link, but rather from a transgenerational effect of prenatal oestrogen exposure⁽ Reference Karlsson, Blomström and Wicks ^{120 )}.

There have been studies and case reports of a dramatic recovery from SCZ associated with the implementation of a GFD. A case report shows that there is a improvement in psychotic symptoms after a GFD in a young man with complex autoimmune illness⁽ Reference Eaton, Chen and Dohan ^{124 )}. The remission of psychotic symptoms in this patient was associated with the adherence to the diet. Regardless of the exact mechanism involved, the marked improvement in this patient’s SCZ symptoms after the implementation of a GFD highlights the need for further research on the role of the diet in SCZ.

Another research group reported a case of brain perfusion abnormalities, assessed by single photon emission computed tomography examination, in a 33-year-old CD patient with SCZ, with the regression of both cerebral hypoperfusion and SCZ symptoms observed after 6 months of a GFD⁽ Reference Cakir, Tosun and Polat ^{125 )}. These findings may have potential implications for the treatment of these subjects given that a GFD can contribute to the improvement of their symptoms. In another case report, the symptoms of SCZ were improved in a coeliac patient after the introduction of a GFD⁽ Reference De Santis, Addolorato and Romito ^{126 )}.

To date, CD adversely affects the QOL of individuals because of several factors such as its chronic nature, the impact on health, psychological distress, social and family connotations, and the need for lifelong treatment. While these factors are important for QOL, one area that has received less attention are the psychological symptoms and how to cope, despite the higher rates of psychological symptoms within CD patients compared with the general population.

There is proven evidence showing that when one suffers from CD it affects the general perception of their QOL and well-being and a GFD generates difficulties and limitations in the life of patients under treatment⁽ Reference Casellas, Rodrigo and López Vivancos ^{127 )}. Even in the case of a considerable improvement in the symptoms, adhering to a GFD can be difficult for many individuals because of poor palatability and poor availability of GF products, thus resulting in a condition that can have serious repercussions on the QOL⁽ Reference Khoshbaten, Rostami Nejad and Sharifi ^{128 )}. Casellas et al. ⁽ Reference Casellas, Rodrigo and Lucendo ^{129 )} have recently reported that good adherence to a GFD resulted in an improved QOL using CD-QOL compared with patients with the intention of not complying. It could be affirmed that it is only with a complete adherence to a GFD that brings significant benefits for the health and QOL of coeliac patients in order that its drawbacks can be counterbalanced. In conclusion, the results of this study suggest that most coeliac patients who followed a GFD correctly showed a better QOL, measured by a specific instrument for coeliac patients and this was also associated with a good control of the symptoms⁽ Reference Casellas, Rodrigo and Lucendo ^{129 )}. It has been demonstrated that there is a direct link between the severity of gastrointestinal and psychological symptoms in coeliac patients and how their symptoms both have an impact on QOL⁽ Reference Sainsbury, Mullan and Sharpe ^{130 )}. This research is the first which investigates the medical impact of the disease and its psychological effects and how adherence to a GFD has effects on the QOL in CD. This study shows how poor adherence to a GFD reduces the QOL which in turn increases the psychological symptoms as well as severe gastrointestinal symptoms and difficulty in coping. These results represent major threats in achieving an adequate QOL. Early diagnosis and treatment of this disease could alleviate the symptoms which in turn could lead to a better QOL.

Potential link between the intestine and the brain: the role of a gluten-free diet

Mental disorders that accompany digestive diseases constitute an interdisciplinary aspect to date not fully recognised and considered a diagnostic and therapeutic problem. The most recognised is CD in which patients suffer from a wide range of neuropsychiatric symptoms. It has not been fully explained how the pathogenic mechanism of CD affects the patient’s mental health, but one hypothesis suggests that it is due to serotonin imbalance or opioid neurotransmission caused by the effect of gluten and gluten metabolites on the central nervous system (CNS)⁽ Reference Kukla ^{131 )}.

Given that the gastrointestinal tract is connected to the CNS means that the communication involves neural pathways and immune and endocrine mechanisms. The intestinal barrier prevents toxins, pathogens and antigens in altering the various neuroactive compounds⁽ Reference González-Arancibia, Escobar-Luna and Barrera-Bugueño ^{132 )}.

The existence of a rich gut-to-brain communication raises the possibility that intestinal barrier alterations may take part in the pathophysiology of CNS disorders and determine neuropsychiatric symptoms⁽ Reference Julio-Pieper, Bravo and Aliaga ^{133 )}. To date there have been neurophysiological studies aiming to evaluate the gut–microbiota–brain axis⁽ Reference Petra, Panagiotidou and Hatziagelaki ^{134 ,} Reference Liu, Cao and Zhang ^{135 )} but these unfortunately have not yet involved coeliac patients. A study suggests that modulation of the gut microbiota may provide a novel therapeutic target for the treatment and/or prevention of mood and anxiety disorders⁽ Reference Slyepchenko, Carvalho and Cha ^{136 )}. Alterations in gut microbial composition is associated with marked changes in behaviours relevant to mood, anxiety and cognition, establishing the critical importance of the bi-directional pathway of communication between the microbiota and the brain in health and disease. Dysfunction of the gut–microbiota–brain axis has been implicated in stress-related disorders such as depression, anxiety and neurodevelopmental disorders such as autism and SCZ⁽ Reference Sherwin, Sandhu and Dinan ^{137 )}.

Although communication between gut microbiota and the CNS are not fully elucidated, neural, hormonal, immune and metabolic pathways have been suggested. The concept of a gut–microbiota–brain axis is emerging, suggesting that microbiota-modulating strategies may be a tractable therapeutic approach for developing new treatments for CNS disorders and for neurological and psychiatric symptoms⁽ Reference Moos, Faller and Harpp ^{138 )}. Several studies have reported the effect of a GFD on the composition of the gut microbiome in CD patients⁽ Reference Collado, Donat and Ribes-Koninckx ^{139 ,} Reference Nistal, Caminero and Vivas ^{140 )}, Patients with CD have a reduction in beneficial species and an increase in those potentially pathogenic as compared with healthy subjects⁽ Reference Marasco, Di Biase and Schiumerini ^{141 )}. Gut microbes can produce hormones and neurotransmitters and the bacterial receptors for these hormones influence microbial growth and pathogenicity. Gut bacteria directly stimulate afferent neurons of the enteric nervous system, sending signals to the brain via the vagus nerve⁽ Reference Carabotti, Scirocco and Maselli ^{142 )}. Through these varied mechanisms, gut microbes induced reactivity of the hypothalamic–pituitary–adrenal axis which influence memory, mood and cognition and are clinically and therapeutically relevant to a range of disorders. In order to alter the gut microbiome therapeutically, changes in diet, probiotics and prebiotics are necessary⁽ Reference Galland ^{143 )}. Some reports show that in autism disorders, the use of diets such as gluten-free and casein-free diets may contribute to the improvement in behavioural symptoms following these dietary regimens⁽ Reference Julio-Pieper, Bravo and Aliaga ^{133 )}. In patients under a GFD, a global increase in cortical excitability was observed in one study, suggesting a glutamate-mediated functional reorganisation compensating for the progression of the disease⁽ Reference Bella, Lanza and Cantone ^{144 )}. It was hypothesised that glutamate receptor activation, probably triggered by CD related to immune system dysregulation, might result in a long-lasting motor cortex hyperexcitability with increased excitatory post-synaptic potentials, probably related to the phenomena of long-term plasticity. In this study, a certain degree of improvement of depressive symptoms was also observed, supporting the role of a GFD in the amelioration of psychiatric CD-related disorders. Another study reports that immune system dysregulation in patients with CD may play a central role in triggering changes in motor cortex excitability resulting in the manifestation of the symptoms⁽ Reference Pennisi, Lanza and Giuffrida ^{145 )}. This study suggested that cross-reaction between anti-gliadin antibodies and neuronal antigens, as well as altered levels of ions related to transglutaminase deposition 6-immunoglobulin, could affect the normal balance between excitatory and inhibitory synaptic excitability. To emphasise the importance of these links, psychiatric or neurological patients may benefit from starting a GFD stressing the importance that there is a two-way communication between the brain and the gut that uses neural, hormonal and immunological pathways. In the future, scientific researches could prove that there is a link between the intestine and the brain, and that GFD could exert a role for the treatment of neuropsychiatric symptoms.