Depression is an etiologically and clinically heterogeneous psychiatric disorder [1
] which affects more than 300 million people worldwide [2
]. Its development is connected with both genetic determinants and environmental factors [3
]. In 1991, Smith formulated the macrophage theory of depression which suggested that mechanisms involved in the pathogenesis of the disease are macrophage activation and excessive secretion of pro-inflammatory cytokines. Pro-inflammatory cytokines, due to their ability to penetrate the blood–brain barrier (BBB), may influence the metabolism and secretion of neurotransmitters which, consequently, leads to dysregulation of Central Nervous System (CNS) homeostasis [5
]. There is a vast body of evidence in support of this theory: (1) the imbalance of pro-inflammatory and anti-inflammatory mediators is observed before the onset of the illness [6
]; (2) significantly higher levels of pro-inflammatory cytokines are observed in the acute phase of depression [7
]; (3) higher levels of inflammation markers are linked to a higher risk of recurrence of the next depressive episode [8
]; (4) higher concentrations of markers of inflammation are connected with progression of the illness [9
]; (5) a wide range of anti-inflammatory agents have been successfully tested in patients suffering from major depressive disorder (MDD) [10
Factors related to systemic inflammation include i.a. excessive stress, environmental pollution, stimulants (cigarettes, alcohol), excessive body weight, poor diet [11
] and leaky gut syndrome [12
]. An increasing number of studies show a probable relationship between systemic inflammation and gut permeability in such conditions as: coeliac disease [14
], autoimmune hepatitis [15
], Parkinson’s disease [16
], autism spectrum disorders [17
]. In 2017, Karakula-Juchnowicz et al. suggested that IgG food hypersensitivity could lead to systemic inflammation and be a trigger factor for the development of MDD. Proteins that occur in food and protein-derived compounds may modulate the immune response of the body. Increased gut permeability may lead to translocation of food-borne components into blood circulation, resulting in an abnormal immune response and increased levels of circulating pro-inflammatory cytokines, and thus, the development or maintenance of MDD. Elimination of trigger foods may inhibit the pathological response of the immune system and restore the pro/anti-inflammatory balance of the body [19
] (see Figure 1
for an overview).
There is growing evidence that one of the most visible manifestations of gut permeability is irritable bowel syndrome (IBS) which affects 10–13% people around the world [20
]. What is more, it is documented that individuals with IBS present low-grade intestinal inflammatory process [21
], which is not always connected with a history of a gastrointestinal infection [22
]. Irritable bowel syndrome, the most common group of gastrointestinal symptoms characterized by diarrhoea, constipation and bloating, can affect quality of life in those patients [23
]. Abdominal pain or discomfort associated with IBS is relieved by defecation. Subtypes of IBS are distinguished based on the manifested symptoms: IBS with constipation (IBS-C), IBS with diarrhoea (IBS-D), mixed IBS (IBS-M), unsubtyped IBS [24
The etiology of IBS has not been fully elucidated. However, some determinants known as gut-permeability-inducers (e.g., microbiota alternation and diet), have been suggested to play a role in pathophysiology of IBS [25
]. Due to the characteristics of IBS (no organic changes), the treatment is based on changes of lifestyle, dietary interventions, counselling, psychological therapies, and dealing with symptoms [26
]. Pharmacological therapies that target IBS symptoms include: antispasmodic medication with laxative or anti-diarrhoeal therapies; antibiotics, probiotics, bulking agents, stool softeners or stimulant laxatives [27
]. Elimination diets are key to reducing IBS symptoms like bloating, gas and pain. The most recommended one is a low FODMAP diet (eliminating fermentable oligosaccharides, disaccharides, monosaccharides and polyols) [29
] which is followed by a gluten-free diet according to non-celiac gluten sensitivity (NCGS) [31
], a lactose-free diet [33
] or a diet based on measurements of individual levels of IgG antibodies to food antigens in patients [34
]. The efficacy of a low FODMAP diet is around 75% in patients with visceral hypersensitivity [35
], but on the other hand, a low FODMAP diet might alter gut microbiota. FODMAPs belong to foods that have prebiotic functions, therefore their restriction may lead to reduction in beneficial bacteria in faeces (Bifidobacteria
An elimination diet based on specific IgG antibodies against food has been shown to improve symptoms in patients with IBS [27
]. In 2006, Monsbakken suggested that food hyperreactivity can affect up to 70% of IBS patients [39
] and the number of studies confirming this finding is still growing [40
Given that there is:
increasing evidence linking IBS and food IgG hyperreactivity, and
a suggested relationship between food IgG reactivity and MDD.
We decided to compare IgG reactions to food proteins in the serum of patients with IBS, MDD and healthy controls.
There are numerous studies which confirm IgG hyperreactivity to food antigens in patients with IBS [27
Due to this substantial amount of evidence and an unclear association between MDD and IgG hyperreactivity, we decided to compare levels of IgG antibodies against food between IBS, MDD patients and healthy controls.
The results of our study indicate differences between the examined groups in the proportion of people whose total IgG values exceeded the cut off level (>7.5 µg/mL). Unusually, most cases of hyperreactivity were found in MDD (64%) group and the least number in HC (19%) group. As revealed by the post-hoc comparisons of the paired groups, total IgG in the examined groups showed differences between MDD patients and healthy controls, no such dissimilarity was found between the IBS group and HC group. It was the application of ex-Gaussian modelling (due to substantially skewed data with increased exponential part of distribution) that revealed differences in tau (τ) (which displays the extremes in IgG results) between MDD and HC groups and also between the IBS and HC groups.
Further analysis demonstrated the presence of many distinctions in individual levels of IgG depending on the type of illness. There were differences in levels of IgG against celery, garlic and gluten between MDD and HC groups and levels of IgG against gluten between the IBS and MDD groups.
Our results indicate a dissimilarity in the immune response to food antigens among the three studied groups, surprisingly, with the highest immunoreactivity in patients suffering from MDD compared with healthy controls. A possible mechanism of the phenomenon remains obscure.
On the one hand, a possible cause of the hyperreactivity among patients with MDD may be disruption of gut-microbiome-brain axis, which is related to low-grade inflammation occurring peripherally and in the CNS [19
]. It is suggested that altered gut microbiota could be responsible for increased gut permeability.
Evidence from model studies confirms that intragastric administration of Clostridium butyricum
contributes to improvements in mucosa and BBB integrity and inhibition of neuroinflammation processes [60
]. What is more, one recent study on patients with mood disorders revealed that the disruption of gut barrier integrity could be a result of gut dysbiosis. Based on the analysis of fecal microbiota, researchers demonstrated that patients with MDD and anxiety were characterized by over-representation of genes involved in LPS biosynthesis and deleterious metabolism of mood neurotransmitter pathways. The patients with mood disorders had also higher levels of plasma LPS, zonulin and fatty-acid binding protein 2 (FABP2) which reflected gut permeability [61
]. However, it is still poorly understood whether intestinal barrier dysfunction is a cause or a consequence of MDD or it exists merely in some group of patients regardless of the disease.
On the other hand, there is some evidence that due to gut-brain signaling, inflammation of CNS could lead to secondary disruptions of the digestive tract. More and more studies show that neuroinflammation is a cause of chronic mucosal damage in the gut and hyperreactivity of enteric glial cells. The intestinal barrier disruptions manifest themselves by long-term neurobehavioral changes [62
]. Post-mortem studies demonstrated that neuroinflammation was involved in pathophysiology of depression [64
A scenario proposed by Karakula-Juchnowicz et al. that links the inflammatory theory of depression with IgG food hypersensitivity and leaky gut syndrome assumes that loss of integrity of the tight-junction barrier could be caused by food antigens [19
]. Overproduction of zonulin triggered, for example, by gliadin through activation of the epidermal growth factor receptor and protease-activated receptor causes loosening of the tight junction barrier and an increase in permeability of the gut wall. Afterwards, intestinal permeability allows food-derived compounds cross into bloodstream and activate the immune response which is involved in overproduction of proinflammatory cytokines, their transport across BBB and, consequently, the presence of clinical manifestation of depression [19
]. There is a substantial body of evidence that there is a link between food-derived antigens and other psychiatric disorders with the suggested role of inflammation in their pathogenesis [66
]. Okusaga et al. revealed a possible relationship between non-celiac gluten sensitivity dependent on IgG antibodies and inflammatory pathways. In the mentioned study, schizophrenic patients with elevated anti-gliadin IgG had increased serum kynurenine levels and kynurenine to tryptophan ratio compared with patients without increased anti-gliadin IgG. Tryptophan to kynurenine conversion is linked with inflammation and raised cortisol levels [67
]. Another study found that anti-casein IgG antibodies are linked with type I bipolar disorder, psychotic symptoms and mania severity [68
So far, the number of studies exploring seroreactivity to food antigens in patients with MDD has been insufficient. Only one observation has been made and its results remain inconclusive. The paper in question reports no differences in mean IgG concentrations between MDD patients and healthy persons. The researchers observed lower levels of IgG against dietary proteins in patients with MDD who had high exposure to milk proteins compared with the control group with high exposure. Surprisingly, the authors found lower levels of tumour necrosis factor-alpha (TNF-alpha) and higher levels of cortisol in sera of the patients relative to the control subjects [69
]. TNF-alpha and interleukin 6 (IL-6) are considered to be well-known inflammatory factors involved in pathophysiology of depression, as supported by a meta-analysis done by Köhler et al. in 2017 [70
]. Also, the results of the studies on anti-inflammatory effects of cortisol [71
] have not been confirmed in MDD patients where excess cortisol secretion was associated with higher levels of proinflammatory cytokines [72
]. These findings confirmed the notion that glucocorticoid resistance, cortisol hypersecretion and increased inflammation are indeed coexistent and related biological abnormalities [73
]. An interesting observation made by Rudzki et al. [69
] is the link between TNF-alpha concentration and total food IgG level, indicating a potential relationship between IgG reactivity to dietary proteins and low-grade inflammation. Some explanation for the discrepant results obtained by Rudzki et al. [69
] may be provided by findings from the study by Lamers at al. [74
] pointing to a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. The proportion of 50% of patients with melancholic depression versus 11.76% of patients with atypical depression in the study by Rudzki et al. [69
] could have had a substantial influence on a lack of differences in IgG levels between the patients and the healthy controls. A relatively small size of the group of patients and statistical analysis conducted by means of classical methods may also have affected the validity of the observations.
Our results regarding differences between IBS and HC are partly consistent with findings from other studies and indicated that serum IgG antibody levels of some common foods are abnormally elevated in IBS patients [75
]. We did not find differences in total IgG levels between IBS and HC groups until we applied ex-Gaussian modelling which allowed us find differences in the extreme results (τ) of IgG levels between these two groups. Based on elevated IgG above the cut-off point we detected dissimilarity between IBS (46%) and HC (19%). However, we did not find differences in individual levels of IgG.
This lack of consistency with findings from other studies could be a consequence of a relatively small size of the group. On the other hand, this may be explained by attempts of IBS patients to cut down on foods aggravating their symptoms such as bloating or constipation. Taking into account that gastrointestinal complaints are the core of IBS [77
], patients suffering from this disorder might intuitively cut down on the food products that, in their opinion, worsen the symptoms [39
], yet without calling this practice “following a diet”. From a clinical perspective, such behaviour is not tantamount to an elimination diet, which was an exclusion criterion from our study. However, it might lead to decreased exposure to a specific food antigen, possibly affecting IgG levels. For this reason, further research aimed at finding differences in food IgG levels between the groups studied should determine food intake and eating frequency in order to evaluate exposure to the food products studied. It is worth mentioning that an elimination diet is a method used to reduce IgG antibodies in the case of high concentrations of IgG against food proteins [78
]. On the other hand, results of studies concentrated on the relationship between food-IgG exposure and dietary habits are contradictory [69
], so research aimed at assessing differences in IgG antibodies against food, especially food with high FODMAP concentration levels (e.g., garlic, gluten, broccoli), between healthy controls and IBS patients should strictly determine the time between the discontinuation of the diet and IgG examination.
A positive response to a diet based on IgG antibodies against food has been reported in several different diseases, such as migraine [49
], obesity [81
], Crohn disease [82
]. A common thread of all above cases is inflammation. Recent data provide evidence that inflammatory processes are considered to be an important factor for the development of both depression and IBS [12
]. To our knowledge, there are no randomized control trials supporting potential utility of an elimination diet in patients with MDD, however, it has been shown that an elimination diet based on specific IgG antibodies against food may alleviate symptoms in patients suffering from IBS [27
In a double blind, randomized, controlled, parallel study, Atkinson et al. [27
] showed significant reduction in severity of symptoms in patients with IBS due to an elimination diet based on a IgG test compared to a sham diet (not based on increased quantities of IgG-antibodies). The quality of life also improved after following an IgG-based diet. The authors calculated that three patients out of four should be treated with this approach. After reintroduction of the respective foods the researchers observed the reverse response in the patients. Those findings are consistent with a study by Drisko et al. [38
]. They also show a significant improvement of symptoms in patients with IBS. The researchers demonstrated increased titres of specific IgG antibodies for selected food in this group of patients. After 6 months on a diet without products with increased IgG concentration, patients with IBS demonstrated improvement in stool frequency, pain relief and the quality of life.
In turn, Zuo et al. [52
] analysed patients with IBS and FD (functional dyspepsia) in comparison to the control group in terms of specific IgG, IgE antibody and total IgE antibody titres. They demonstrated that IBS patients had significantly higher titres of IgG antibody to crab, egg, shrimp, soybean and wheat than controls. FD patients had significantly higher titres of IgG antibody to egg and soybean than controls. Interestingly, there was no correlation in percent of patients with positive specific IgE antibodies in the three groups. There were no significant differences between IBS patients, FD patients and controls in the serum total IgE antibody levels. Guo et al. [57
] evaluated the benefit of an IgG-based diet in patients with IBS with diarrhoea form (IBS-D) of the disease. The phase of 12-week elimination of food products with increased IgG resulted in improvement in IBS-D participants compared with the baseline. The researchers showed amelioration in abdominal pain (bloating level and frequency), diarrhoea frequency, abdominal distension, stool shape, general feelings of distress and total symptom score.
An interesting study was conducted by Aydinlar et al. [56
]. In this double-blind, randomized, controlled, cross-over clinical trial individuals suffering from both migraine and IBS could take advantage of IgG-based elimination diet. An individual diet approach may effectively alleviate conditions such as migraine attack, maximum attack duration, mean attack duration, maximum attack severity and number of attacks with acute medication, as well as abdominal symptoms: pain-bloating severity, pain-bloating within the last 10 days, and also improvement in quality of life. Nonetheless, the small sample (21 patients) and funding bias of the examination should be pointed out as a weakness of the study.
Despite many results confirming the clinical manifestation of elevated levels of IgG antibodies against food antigens, the diagnosis based on their elimination is controversial. Numerous allergy societies question the usefulness of IgG antibodies tests as a diagnostic method for assessing adverse reactions to food intake [85
], nevertheless, some recommend using IgG antibodies tests for research purposes [88
]. It is known that IgG4 is an antibody involved in the desensitization of type I allergies (IgE-dependent) [89
]. There is some new evidence that patients with IBS my present increased IgG4 titres [76
], but this still needs clarification. It is worth mentioning that not all subclasses of IgG are involved in desensitization. Furthermore, they are able to form an immune complex with bounded food antigens. Such complexes are destroyed by pathogenic cells which leads to the release of proinflammatory cytokines. Aljada et al. showed that food intake is able to induce significant inflammatory changes, which has been characterized by a decrease in IkappaBalpha and an increase in NF-kappaB binding, plasma C-reactive protein (CRP), and the expression of IKKalpha, IKKbeta as well as p47 (phox) subunit [90
]. This state induces a low-grade inflammation condition which may be aggravating for the body. It is documented that individuals with IBS may present low-grade inflammatory process in the gut mucosa which is not always connected with a history of a gastrointestinal infection [22
]. Therefore, testing IgG against food could be one of the novel diagnostic approach to identify triggers leading to inflammation in these conditions, and administration of diet based on concentration of specific IgG may exert a beneficial effect in patients with IBS and depression.