**5.3 Phycological associations with the GI autoimmune diseases**

Many of the patients who have GI autoimmune diseases suffer from psychiatric comorbidities such as anxiety, stress, and depression. The link between them could be bi-directional as anxiety, stress, and depression could be an etiology as well as comorbidities due to autoimmune diseases.

### *5.3.1 Psychological association with achalasia*

It was noted that achalasia can occur after a long episode of chronic stress. Since achalasia is a rare disorder, not so many studies try to research the relationship between stress and anxiety and achalasia. In 2020, Kalantari et al. conducted a study that maps the experience of achalasia patients from initial symptoms to management of symptoms. In their findings, they found that people who had achalasia before the diagnosis had anxiety due to the uncertainty about their diagnosis [218]. According to a study from Germany, after the diagnosis of achalasia, patients were more likely to develop depression at significantly higher rates than those without the condition. Regardless of other comorbidities and the clinical characteristics of the patients, achalasia is associated with an increased incidence of depression according to their study [219]. The question whether stress, anxiety, or depression are a contributor or trigger for achalasia, or they are a secondary outcome of achalasia yet needs to be further studied.

### *5.3.2 AAG*

It was also reported that acute stress can be a cause for AAG [220]. There is more evidence that AAG may lead to vitamin B12 deficiency, which may manifest as neuropsychiatric disorders, such as emotional instability, cognitive deficits, depression, and personality change [221]. In 2015, Tenca et al. found that the psychopathological profile has a role in symptoms occurrence in AAG [222]. It was also reported that those with AG have a significantly higher risk of experiencing psychological distress, with younger females (<50 years) displaying the highest risk, regardless of whether they have an infection with *H. pylori* (HP) [223]. Zhao et al. found that chronic atrophic gastritis patients were 54.5% likely to experience depression, as the regression analysis indicated that interpersonal sensitivity correlated positively with depression [224].

### *5.3.3 Celiac disease*

In CD, there is a clear relationship that associates celiac diseases with stress, anxiety, and depression. Just like the other autoimmune GI diseases, the debate is not yet settled. However, it is suggested that CD has a role in these manifestations [225]. CD presents in many clinical presentations that are poorly understood such as changes in behavior are evident in cases of anxiety, depression, short-term memory loss, sleep disturbances, cognitive impairment, psychosis, and attention deficit disorder [226]. In CD, many patients have reported the symptoms of CD after stressful life events [227]. Addolorato et al. reported in a longitudinal study that 71% of people with celiac disease suffered from high levels of anxiety, the levels of anxiety were high in 24% of the control subjects, and 26% of the newly diagnosed celiac patients demonstrated anxiety [228]. In a Swedish study that evaluated patients with CD between 1973 and 2016, they concluded that children with CD have an increased risk of developing psychiatric disorders in adulthood [229]. According to Wahab et al., CD is associated with anxiety and oppositional defiant behavior when it is combined with HLA-DQ2 or HLA-DQ8 risk alleles [230] as a conclusion for their study on CD Autoimmunity and Emotional and Behavioral Problems in Childhood. Depression has been reported

in association with CD since 1951 [231]. Several studies have shown that people with CD are more likely to suffer from depression than people without CD [232–239].

Butwicka et al. found that children with CD had a 1.4-fold greater risk of developing mental disorders compared with the general population. Childhood CD was identified as a risk factor for mood disorders, anxiety disorders, eating disorders, behavioral disorders, ADHD, ASD, and intellectual disabilities in their study. Moreover, mood, eating, or behavioral disorders were more common before celiac disease diagnosis [240]. Individuals with CD have an increased risk of anxiety disorders, according to several studies [228, 241, 242]. These come in agreement with Clappison's systematic review and meta-analysis on the psychiatric disorders association with CD [243]. Psychological symptoms before diagnosis could be caused by the general health of the patient, or by hypoperfusion of the brain in certain regions, a result of vitamin deficiency due to malabsorption. Also, Hyperphomocysteiemia can damage the blood-brain barrier, exposing the neuronal tissue to neuro-irritative substances [226]. Additionally, they may be associated with Ads such as thyroid disease, a risk factor for depression, panic disorder, and type 1 diabetes. There is speculation that one of the possible explanations could be due to the cytokines that are produced by the immune reactions, which can affect the brain circuits that control mood [226].

## **5.4 EoE**

There is some evidence that EoE and its treatments can significantly reduce psychological functioning, resulting in increased anxiety and depression [244]. Mental distress is a common problem among adult EoE patients, with an increased risk of significant anxiety among those younger than 35 years of age [245]. Mechanistically speaking, the protein Eotaxin-1/CCL11 which is involved in Eosinophil Recruitment could be the reason for the pathopsychological involvement in EoE patients. There has been evidence that eotaxin affects the central nervous system, and it was noted that eotaxin-1/CCL11 crosses the blood-brain barrier unaltered [246]. Eotaxin-1/ CCL11 inhibits neural progenitor cell proliferation in isolated neurons and neurons derived from neurospheres, as well as in hippocampal slices without affecting their ability to form neurons or astrocytes in vitro [247]. Neurons were not directly affected by eotaxin-1/CCL11. However, related chemokines were able to promote microglial migration and activation, producing reactive oxygen species, which exacerbated glutamate-induced neurodegeneration [248]. The serum levels of 22 cytokines/ chemokines, including eotaxin-1 and CCL11, were assessed in 49 patients with major depression, and 49 matched controls reported increased levels of the molecule in an inflammatory context [249].
