Team:Thessaly/Excellence
Jacka
Overview
The Microbiome-Gut-Brain axis plays a key role both in the establishment and the perturbation of the
balance between the gut microbiome metabolites and the host’s biochemical composition.
Thus, gut dysbiosis can participate in the manifestation of mental disorders.
For that reason, AMALTHEA deploys its core products, the bio-electronic capsule and the genetically
engineered probiotic, to tackle serious problems related to the comorbidity of gut and mental diseases.
AMALTHEA aims for the functional evaluation of the gut microbiome and the amelioration of
gastrointestinal symptoms related to dysbiosis. Through our bibliographic research we came
across a considerable amount of literature concerning the role that gut microbes play in our
general wellbeing, including both our somatic and mental health. In parallel with this
research, we contacted various stakeholders in order to get their feedback regarding the
main aspects of our project. During these conversations, and in spite of many specialists
having very divergent backgrounds, we repeatedly received a prompting, towards the
consideration of mental health in the evaluation of the general impact that gut microbiota
imbalances inflict on the human body. Eventually we decided to investigate this issue more
thoroughly, starting by asking two basic questions: What kind of relationship is established
between the gut microbiome and the Central Nervous System (CNS) -especially the brain- and at
what degree is this relationship able to interfere/cause mental health disorders? Aiming to
shed light on this perspective and due to our partnership with team Aalto-Helsinki, we
elaborated on these topics. As the time passed and the points of intersection between our
main project and the mental health perspective increased, we decided to take this research a
step further and start acting upon related issues that emerge at the individual, as well as at
the societal level. Our starting point was the inadequately investigated, often
non-communicable and always extremely costly issue of comorbidity of enteric and mental disorders.
Microbiome -Gut-Brain axis:
interplay of Gut & Mental disorders
The large community of microbiota that resides in the human and animal gastrointestinal tract, has been shown to
play a crucial role in the function of the nervous system, mostly through endocrine and neurocrine pathways.
The gut microbiome appears to influence the development of emotional behavior, stress- and pain-modulation systems,
and brain neurotransmitter systems. The brain in turn, alters microbial composition and behavior via the autonomic nervous system
(Mayer E.A et al., 2014).
The vagus nerve is involved in the direct communication between the gut bacteria and the brain, supporting the important role of GABA-mediated signaling pathway in the bidirectional communication of the GBA (Liu, X. et al., 2015). Vagal efferent fibers carry impulses of cholinergic anti-inflammatory reflex, thus controlling immune homeostasis of the gut (Nowakowski J.et al., 2016), while visceral signals derived from bacterial colonization can be transmitted back to the brain.
Crohn’s disease (CD) and Ulcerative Colitis (UC) are currently viewed as multifactorial diseases with
complex pathogenesis involving abnormal immune response, impairment of anti-inflammatory pathways,
interactions with intestinal microbiota, and disturbances in the GBA. In case of gut diseases like IBD,
persistent inflammatory state and diet dependent symptoms such as malnutrition and malabsorption,
makes the patients more prone to depression. Impaired intestinal barrier is an essential aspect of
IBD pathogenesis which may contribute to vulnerability to depression in this group of patients,
through an LPS-dependent pathway (Nowakowski J., 2016). Given the suggestion that LPS-dependent pathway with its potential
to induce neuroinflammation is involved in the development of depression, chronic exposition to gut
microbiota antigens occurring in IBD may help explain the high comorbidity of IBD and depression.
At the same time, production of reactive oxygen and nitrogen species (O&NS),
might bridge autoimmune phenomena reported in both IBD and depression. Considering the fact that
mood disorders are accompanied by significantly increased O&NS, it cannot be ruled out that O&NS,
taking part in the development of IBD, eventually facilitate the development of depression.
Preliminary evidence also supports the existence of association between GI inflammation and
bipolar disorder. A relative study showed elevated levels of a marker helpful in making CD diagnosis
in the blood of patients with bipolar disorder, which indicates enhanced immune response against
antigens of gut origin (Pillay B. 2017). Furthermore, IBDs may affect mental health because of their impact on the
serotonergic system.
Many studies have shown the correlation and, sometimes, even the causality between diet and mental
health. Studies have reported that mental illnesses like depression, schizophrenia and ASD, are among
many that present this type of correlation. Based on the extensively investigated relationship between
diet and gut microbiota, one can easily come to the conclusion that the gut microflora itself,
participates -both through diet and independently- to the manifestation of symptoms in those
psychiatric disorders.
The correlation between depression and diet has also been shown through studies that tested the mean depressive symptom scores in relation with a healthy diet in Greece (Chatzi L.et al., 2011) and other countries (Park J-Y.et al., 2010), (Tangney CC.et al, 2002) with each of these studies, having different adjusted variables. Moreover, increased adherence to whole food dietary patterns (Tangney CC.et al, 2002) and healthy diet quality (Kuczmarski MF.et al., 2010), has been associated with reduced odds of depressive symptoms. Increased consumption of fast foods has also been associated with increased odds of depressive symptoms (Sanchez-Villegas A.et al, 2009), (Fowles ER.et al., 2011), while decreased consumption of snack food (Liu C.et al., 2007) and decreased consumption of high calorie sweet foods (Jeffery RW., 2009), were associated with reduced odds of depressive symptoms by different studies.
Developing of depression in offspring has also been associated with dietary factors, this time concerning the pregnant mother (Peretti, S.et al., 2018).
Maternal diet during pregnancy determines the development of the neural circuitry that regulates behavior, thus determining persistent behavioral effects in offspring (Peretti, S.el at, 2018). High concentration of some nutrients (e.g. high-fat diets (Sullivan EL, 2014)) has been associated with an increase or reduction in the risk of the offspring developing ASD (Peretti, S.el at, 2018).
ASD patients’ diet has been associated with worsening of the ASD symptoms. A factor that makes the situation even more complicated, is that ASD patients present food refusal, feeding selectivity, strong preferences for some foods and aversions to others, with the phenomenon being even more serious in children. Gluten-free and casein-free diets, ketogenic diets, and the intake of vitamin D and folic acid have a beneficial role in improving the general condition of children with ASD. These elements improve the characteristic autist traits, such as the social, cognitive, motor, and communicative skills that are strongly impaired in the autistic population (Peretti, S.el at, 2018).
Existing problems and our way of
The worldwide society suffers heavy consequences because of the inadequate knowledge and unsuccessful
treatments regarding mental and gastrointestinal pathogenies. For that reason, a dire need for
solutions that tackle those problems both separately and simultaneously has emerged. AMALTHEA
concentrates on this open call, and makes a number of attempts to include more patients to the group
of those receiving a proper diagnosis -and consequently a treatment-, increase the amount of data
available for researchers, contribute to the alleviation of symptoms in schizophrenics and conduce
to the global effort of decongesting the public health facilities.
Figure 5:Three potential mechanisms of explaining the Association between Psycological and Physical Symptoms.
We started by contacting Paraskevi Angelopoulou, a Health psychologist and researcher, with years of working experience at Greek health facilities. We were informed that no medical school in Greece, except for one, has any subject related to the patient’s psychology, or even the proposed way in which a doctor should engage in a difficult conversation, e.g., announcing bad news about the patient’s health. This inevitably leads to serious communication problems between the doctor and the patient, which in turn, leads to decreased compliance to treatment. Lack of proper training around mental health issues, also points to an increased chance (by 15%) of a doctor describing a patient’s visit as “difficult”, which leads to a bad attitude towards the patients (Kroenke K.et al., 2003). On the top of that, the following phenomena, also play a crucial role in the formulation of the current regime:
Figure 6: 29% of the gastroenterologist's patients fulfill the criteria for depression
All these factors combined often lead to medical errors, mistakes in prescription and incorrect risk management.
In order to tackle these issues, we decided to get in contact with as many gastroenterologists as we could, talk with them about the way they are approaching their patients and ask them whether they take into consideration their patients’ mental state. We then offered them our booklet which contained basic data about the above-described issues and information about the ways they can actively help their patients or get further informed. Gastroenterologists are actuated to encourage their patients to visit a mental health expert, as psychotherapy (e.g., Short Term Psychodynamic Psychotherapy (STPP)) has been shown to have beneficial effects on patients with GI disorders:
Figure 7: 91,3% of the those who were subjected to STPP reported inmrovement to their mental state.
Based on the gastroenterologist’s feedback:
Based on the psychiatrists’ feedback:
Based on the health psychologist’s feedback:
After integrating the specialists’ advice in our work, we ended up with two new booklets: A brand new one for gastroenterologists and a second one for gastroenterology patients, closer on the old one. Here you can check the old and the new versions and see for yourself the changes on the layout and content.
Our work, however, did not stop there, as we concluded that tackling a problem of comorbidity -enteric and mental health disorders- requires an approach that focuses on both gastroenterology and mental health experts. Therefore, our next step was to talk with a psychiatrist, Dr. Agorastos, and get his feedback on the topic. He told us that engaging with gastroenterologists is a good decision as, 80% of chronic diseases -many of which are related to the gut- are stress related, and thus informing the gastroenterologists about it is a first step towards improving the quality of provided services. He also informed us that gastroenterologists often prescribe psychiatric drugs to treat gut related symptoms without knowing their effects on the patient’s mental state.
Why try to convince psychiatrists to suggest our capsule, “AMALTHEA” to their patients?
Stress and depression are related to various, often non-communicable, digestive diseases, and they may be predisposing factors for functional dyspepsia and IBS. Chronic depression may also be linked with elevated cancer risk (Lee S., 2015). Studies concerning IBD, show that IBD diagnosis and gastrointestinal symptoms tend to occur earlier in life in patients with depression/anxiety and, at the same time, nearly two-third of patients with anxiety and more than a half with depression encounters first episode of mentioned psychiatric disorders up to two years before IBD diagnosis (Nowakowski J., 2016). For that reason, targeting psychiatric disorders can not only improve the patient's health from a mental health point of view, but it can also contribute to the prevention of a possible manifestation of gut disorders in the future
We asked for Dr. Agorastos’ opinion on whether psychiatrists and their patients would be positive towards our microbiome evaluating capsule. His response was very positive for both doctors and their patients. He noted that even though some patient groups would be harder to convince, such as schizophrenics, he thinks that most patients especially those suffering from stress spectrum disorders (e.g. depression) would be open to utilize the capsule and also share the data concerning their clinical image in case we use the capsule as a research tool. The fact that the measurements are going to be taken in a non-invasive manner, plays a major role in the inclination of patients to take the capsule.
Microbiota imbalances reported by the capsule can lead psychiatrists to the conclusion that tackling the problem with diet modifications might be a partial solution. Studies have shown that targeting the microbiota by probiotic supplementation could alleviate psychological distress including an index of depression (Raypole, C., 2019). At this point a patient warned by the doctor, can alter their diet either using our application, or directly consuming our probiotic, as it is a product personalized and safe for general use at the same time. The probiotic can be proposed by the doctor even without the patient using the capsule, as it is a product that can be used only as a prevention measure.
To validate our hypothesis, we turned again to Dr. Agorastos’ , this time to ask about the psychiatrists’ and psychiatric patients’ attitude towards our engineered probiotic. He replied that although the average psychiatrist does not tend to give dietary advice -or propose probiotic consumption to their patients-, they would be positive towards the introduction of such an approach to their practice. He also added that patients would probably be very positive to the idea of improving their mental state by integrating a probiotic-containing product to their diet.
Figure 8: The above cycle can either begin from a psychologist’s/psychiatrist’s patient, or from a gastroenterologist’s patient, tackling the problem from both directions. The first one is already in psychotherapy or on psychotropic medication, and through their mental professional’s guidance can use AMALTHEA to detect a coexisting gut dysbiosis or gut related disease. The capsule’s results are evaluated by a gastroenterologist, thus making the individual, a gastroenterologist’s patient. The mental health professional can also point their patient towards a gastroenterologist skipping the step of capsule utilization. In turn, the gastroenterologist can propose the capsule, making again the former psychiatric patient, a gastroenterologist’s one. If we start from the point of an individual with an already diagnosed gut related disease, a well-informed gastroenterologist can point out some indications of an underlying mental disorder, promoting their patient to a mental health expert. If that expert diagnoses a mental disorder, the former gastroenterologist’s patient now becomes also, a psychologist’s/psychiatrist’s patient.
How did we contribute to the confrontation of the above issues?
The determination of whether correlation between stress and relapse in IBD, actually exists, is very hard to make. This phenomenon takes place due to various reasons, like difficulty in performing perspective analyses of the above-mentioned relationship (Lee, S. P., 2015) and defining the relapse itself. Concerning the perspective analyses, stress can be measured in a variety of ways from adverse life event scales through diary records of daily stress to various tools to measure chronic stress. One of the biggest problems with event scales is that they take little account of how stressful each individual might find the same event, thus making it hard to determine the exact psychological condition of every subject participating in the research. On the other hand, when trying to measure disease activity in IBD patients, a common practice is to utilize standardized scoring systems, such as the CD Activity Index (CDAI) and the Simple Clinical Colitis Activity Index (SCCAI). However, that most of them include self-reported symptoms and variables such as stool frequency which are known to be adversely affected by stress, but which do not necessarily reflect a worsening of disease activity (Lee, S. P., 2015). This phenomenon is translated into a requirement of high degree of compliance by the patient for the collection of detailed data relating both to stress and GI symptoms. On top of all the aforementioned obstacles, researches that aim to test the correlation between stress and disease activity require a long study time, during which, confounding factors such as medication, can change, thus interfering with the results.
The above issues are reflected upon the amount of evidence concerning this topic. There are statistical reports related to the Greek population, which show that GI disorders (duodenal ulcer, colitis) have a certain prevalence (males: 3,1%, females: 4,4%, Sum: 3,8%) but there is no data about their correlation with mental disorders. Our conversation with the health psychologist Ms. Angelopoulou, confirmed to us that another issue that makes the prosecution of research on this topic, is the lack of patients with GI disorders that volunteer to engage in studies, mostly because of the surrounding stigma.
How did we contribute to the confrontation of the aforementioned issues?
Schizophrenia is a common, severe mental illness. Clinicians still engage in a slow trial-and-error process with each patient, in order to identify the most efficacious drug(s) with the fewest side effects; notably, 30% of cases show little response to first-line antipsychotics (Seah, C., & Brennand, K. J., 2020).
AMALTHEA does not claim that it makes a proposal with a huge impact on this complex disorder. What it does aim for, is approaching the matter in an innovating way that could possibly alleviate the symptoms of diseases that cooccur with schizophrenia, and thus make the lives of schizophrenic patients slightly easier. AMALTHEA’s approach is based on the facts mentioned above, at the Mental health and Diet section: occurrence of nutritional deficiencies is very common in schizophrenic patients, SCFAs can contribute to the patients’ wellbeing and multidisciplinary teams of experts constitute an arising proposal for the patients’ management.
How did we contribute to the confrontation of the aforementioned issue?
There are efforts to tackle the Hospital congestion issue worldwide (Seah, C., & Brennand, K. J., 2020). 1/3 of patients presenting in clinics, fulfil the criteria for mental disorders (Abbass A.et al., 2009) and 73% of primary care patients with depressive or anxiety disorders presented exclusively with somatic symptoms (Kroenke K., 2003). These phenomena cause confusion, discomfort and stigmatization for the patients, along with hospital congestion. In turn, hospital congestion leads to problems such as:
Figure 9: From all primary care patients that fulfil the criteria for a phsychiatric disorder, 56% present only with somatic symptoms (Abbass A., 2009)
How did we contribute to the confrontation of the aforementioned issue?
✔Prevention and Indication of existing gut disease
Early microbiome functionality assessment performed by our capsule can lead to early GI disorder detection, and thus reduced probability for hospitalization. On the top of that, this assessment can also be performed remotely: the capsule can be used as a bridge between the doctor and a remote patient, benefiting from the digital health services provided by our mobile application.
Our mobile application, e-AMALTHEA, is on the roots of combating mental health disorders. Its features
cover two main aspects: the safe, anonymized collection of the user’s data for research purposes and
the interconnection of users and health specialists.
Data from users are collected anonymously and stored in a database. This source of these data can be useful for research for reasons described above.
The data collection is accomplished through a series of questions related to the user’s state of gut and mental health. The researcher can study the results and find useful correlations between enteric and mental disorders, thus overcoming the problem of uncertainty that comes from insufficient data concerning one or both those aspects, the issue of high compliance from the patient and the problem of dearth of participants. The users will monitor and improve their own health in a friendly and reassuring environment, while providing data for researchers.
The provision of these data is made through weekly questionnaires that cover some topics that Ms. Angelopoulou and Dr. Agorastos, prompted us towards. Namely, these topics are: mood, anxiety, stress, sleep, functionality and social interactions. The selection of the questions has been made through our conversations with Ms. Angelopoulou and the review of preexisting, certified questionnaires such as the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (PRIME-MD-PHQ), the PHQ-9 and the Perceived Stress Questionnaire (PSQ).
For more information about the app's use as a research tool, visit the application page.
We recognize the universal problem of the absence of interdisciplinary teams of experts, that is even more intense in Greece. For that reason, our application can also be used as a platform at which gastroenterologists, dietitians and mental health experts (psychologists or psychiatrists) can have access to certain information that the user provides (each specialist has access to information relevant to their field) while ensuring that the personal information of the user is not shared to more people than necessary). This way, the specialists can give their advice in response to the user’s data.
How does the microbiome affect the brain?
The microbiome-gut-brain axis comprises several fundamental elements including the CNS,
the neuroendocrine and neuroimmune systems, both the sympathetic and parasympathetic limbs of
the autonomic nervous system, the enteric nervous system (ENS) and, of course,
the gut microbiome (Kennedy, P. J, et al., 2014). An important interaction that indirectly affects the brain function
and subsequently, one’s mental state, is the release of biologically active peptides from
enteroendocrine cells. The alterations in the amount of peptides being released,
are a result of the alteration of nutrient availability that gut microbiota inflict
upon the host. Given the close relationship between nutrient sensing and peptide secretion
by enteroendocrine cells, this particular ability of microbiota, manages to affect
the Gut-Brain Axis (GBA) (Carabotti, M. et al., 2015).
The vagus nerve is involved in the direct communication between the gut bacteria and the brain, supporting the important role of GABA-mediated signaling pathway in the bidirectional communication of the GBA (Liu, X. et al., 2015). Vagal efferent fibers carry impulses of cholinergic anti-inflammatory reflex, thus controlling immune homeostasis of the gut (Nowakowski J.et al., 2016), while visceral signals derived from bacterial colonization can be transmitted back to the brain.
Gut and mental pathogenesis mediated by gut microbiota
Disturbances of the gut microbiota have been implicated in functional disorders of the GBA,
such as irritable bowel syndrome (IBS) and neuropsychiatric disorders, like autism spectrum
disorder (ASD) and major depression. Therefore, gut microbiota end up playing the role of the brain’s
peacekeeper (Gao K.et al., 2020).
Figure 1: Schematic representation of the basic components that comprise the network of the microbiota-gut-brain interactions, as well as some potential pathological outcomes (Chidambaram S.B., 2020).
Anxiety and Depression
It is noted that anxiety and depression are generally considered to be correlated with
stress. Increasing data show that stress has also been associated with changes in the GI
microbiota (e.g., low levels of Lactobacilli) via the sympathetic nervous system and
adrenergic response. These findings suggest that stress leads to anxiety/depression by
altering the gut microbiota and that anxiety/depression influences the gut microbiota,
which also affects the development and/or progress of these mental disorders
(Liu, X.el at, 2015). Depression and anxiety are the most common psychiatric disorders in IBD.
Biological mechanisms
concerning both IBDs and depression/anxiety explain susceptibility
to developing mental disorders in IBD (Liu C.et al, 2007). There is also evidence, suggesting that children
with Crohn's disease and ulcerative colitis are more depressed (12% prevalence) than
a healthy control group (Bennett, D. S.et al.,1994).
Figure 2: Prevalence of depression and anxiety disorders (adults 15+) in Greece, in 2019 (Hellenic Statistical Authority, 2020).
Figure 3: Prevalence of depression and mental disorders in IBD (Nowakowski J., 2016).
Figure 4: Affective disorders and Gastrointestinal (GI) Symptoms in a Population-Based Sample (Kroenke K., 2003).
Figure 2: Prevalence of depression and anxiety disorders (adults 15+) in Greece, in 2019 (Hellenic Statistical Authority, 2020).
Figure 3: Prevalence of depression and mental disorders in IBD (Nowakowski J., 2016).
Figure 4: Affective disorders and Gastrointestinal (GI) Symptoms in a Population-Based Sample (Kroenke K., 2003).
Schizophrenia
Schizophrenia has a complex manifestation, a multifactorial cause and a lifetime
prevalence of 1%. (McCutcheon, R. A et al., 2019). A large portion of schizophrenic patients present with numerous
cooccurring disorders. Most recent studies suggest that cardiovascular disease, type II
diabetes mellitus, sepsis, gastrointestinal or digestive disease, autoimmune disorders,
influenza and pneumonia are the major causes of mortality in schizophrenia. Notably, the
gut is the key functional organ for many of these disorders (McCutcheon, R. A et al., 2019). Inflammatory GI diseases,
especially colitis, are thought to be highly prevalent (in over 90% of samples) in
schizophrenia. At the same time, butyrate (a crucial product of the gut microbiome) has
been shown to decrease metabolic impairments in pregnant mice. The potential fetal
neuroprotective effects of SCFA (Short Chain Fatty Acids) in models of maternal diabetes and
risk for psychosis, are a very appealing topic for future studies, and a target group like
this -although being rare- can be possibly benefited from both our capsule and our probiotic
consumption.
Autism Spectrum Disorder (ASD)
The pathogenesis of ASD, is a complex phenomenon in which both genetic and environmental
factors have appeared to be involved. GI syndromes, include increased constipation (20%)
and diarrhea (19%) in children with ASD, in comparison with their unaffected siblings
(42 vs. 23%, respectively). Patients with ASD who present GI symptoms might display
significant behavioral manifestations, such as anxiety, self-injury and aggression.
Accumulating evidence demonstrates that the gut microbiota is directly or indirectly associated with ASD symptoms, in part by influencing the immune system and metabolism. Alterations in the composition of the gut microbiota and their metabolic products, as well as increased intestinal permeability, are commonly observed in patients with ASD. For example, LPS is increased in the serum of ASD compared with healthy individuals and is associated with impaired social behavioral scores (Li Q.et al., 2017).
Accumulating evidence demonstrates that the gut microbiota is directly or indirectly associated with ASD symptoms, in part by influencing the immune system and metabolism. Alterations in the composition of the gut microbiota and their metabolic products, as well as increased intestinal permeability, are commonly observed in patients with ASD. For example, LPS is increased in the serum of ASD compared with healthy individuals and is associated with impaired social behavioral scores (Li Q.et al., 2017).
Mental Health and Diet
Depression
Multiple studies have shown correlation between diet and depression prevalence. Studies performed with
depression as exposure of interest, show that depressive symptoms were associated with reduced
likelihood of healthy eating (Pagato S.L. et al., 2009), (Beydoun MA, 2009) while they were positively correlated with greater fast-food
consumption (Crawford GB el at., 2011). More specifically, it has been reported that increased adherence to Mediterranean (Sanchez-Villegas A.et al., 2009)
and Japanese (Nanri A.et al., 2010) diet is associated with reduced odds of self-reported depression in both sexes, while
the Norwegian diet showed the same results only for males (Jacka FN.et al., 2011).The correlation between depression and diet has also been shown through studies that tested the mean depressive symptom scores in relation with a healthy diet in Greece (Chatzi L.et al., 2011) and other countries (Park J-Y.et al., 2010), (Tangney CC.et al, 2002) with each of these studies, having different adjusted variables. Moreover, increased adherence to whole food dietary patterns (Tangney CC.et al, 2002) and healthy diet quality (Kuczmarski MF.et al., 2010), has been associated with reduced odds of depressive symptoms. Increased consumption of fast foods has also been associated with increased odds of depressive symptoms (Sanchez-Villegas A.et al, 2009), (Fowles ER.et al., 2011), while decreased consumption of snack food (Liu C.et al., 2007) and decreased consumption of high calorie sweet foods (Jeffery RW., 2009), were associated with reduced odds of depressive symptoms by different studies.
Developing of depression in offspring has also been associated with dietary factors, this time concerning the pregnant mother (Peretti, S.et al., 2018).
Schizophrenia
Schizophrenia patients often present with co-occurring nutritional deficiencies. Due to this fact,
they are most likely to benefit from the implementation of individualized dietary interventions (Joseph, J.et al., 2017).
“For dietary interventions in schizophrenia patient populations to be successful, the combined
support from scientists, dieticians, family members, and neuropsychiatric clinicians who have been
successful in implementing behavioral modifications will be necessary”
(Paul J Kennedy, 2014)
Gluten free diets in schizophrenia
The incidence of celiac disease and non-celiac gluten sensitivity is higher in schizophrenia.
Studies indicate that a diet avoiding gluten benefits a limited subset of patients. Consumption of a
gluten free diet in individuals who did not have a diagnosis of celiac disease or non-celiac gluten
sensitivity leads to lower butyrate levels, reductions in beneficial gut microbial species, and
increased host immune activation. Thus, determination of whether one of these disorders exists, is
important for concluding to a curtain diet.
SCFAs in schizophrenia
Multiple studies have reported the beneficial effect of SCFAs in the schizophrenic patient’ health
status. The beneficial effects of SCFAs are mediated in two main ways:
The downregulation of NF-κB-binding capacity induced by LPS and the modulation of multiple immune
and epigenetic pathways including obesity induced inflammation (Joseph, J.el at., 2017).
Autism Spectrum disorder
Several studies have tried to show a possible relationship between nutritional status and autism.
Diet plays a key role in ASD in two independent ways: Maternal diet during pregnancy determines the development of the neural circuitry that regulates behavior, thus determining persistent behavioral effects in offspring (Peretti, S.el at, 2018). High concentration of some nutrients (e.g. high-fat diets (Sullivan EL, 2014)) has been associated with an increase or reduction in the risk of the offspring developing ASD (Peretti, S.el at, 2018).
ASD patients’ diet has been associated with worsening of the ASD symptoms. A factor that makes the situation even more complicated, is that ASD patients present food refusal, feeding selectivity, strong preferences for some foods and aversions to others, with the phenomenon being even more serious in children. Gluten-free and casein-free diets, ketogenic diets, and the intake of vitamin D and folic acid have a beneficial role in improving the general condition of children with ASD. These elements improve the characteristic autist traits, such as the social, cognitive, motor, and communicative skills that are strongly impaired in the autistic population (Peretti, S.el at, 2018).
Existing problems and our way of
tackling them
Prblem 1#: Undiagnosed patients with enteric and/or mental disorders
Identification of the problem
Figure 5:Three potential mechanisms of explaining the Association between Psycological and Physical Symptoms.
Somatic symptoms and psychological disorders are known to interplay in a variety of different
situations. The exact incidences of comorbidity, though, as well as the degree to which each one
of them -somatic and psychological symptoms- is contributing to the overall clinical picture, is
very difficult to determine and depends to a variety of factors, such as the type of medical and
psychological disorder/symptom, the number and duration of symptoms, environmental factors (e.g.,
lifestyle) and the genetic background. Indeed, it has been shown, that disease-specific somatic
symptoms in patients with a variety of medical disorders are influenced as much by psychological
factors as by the severity of the underlying medical disorder (Abbass A.et al, 2009). In light of this phenomenon, we
wandered, whether this high prevalence of comorbidity is taken into consideration by doctors, when
examining their patients for medical symptoms.
We started by contacting Paraskevi Angelopoulou, a Health psychologist and researcher, with years of working experience at Greek health facilities. We were informed that no medical school in Greece, except for one, has any subject related to the patient’s psychology, or even the proposed way in which a doctor should engage in a difficult conversation, e.g., announcing bad news about the patient’s health. This inevitably leads to serious communication problems between the doctor and the patient, which in turn, leads to decreased compliance to treatment. Lack of proper training around mental health issues, also points to an increased chance (by 15%) of a doctor describing a patient’s visit as “difficult”, which leads to a bad attitude towards the patients (Kroenke K.et al., 2003). On the top of that, the following phenomena, also play a crucial role in the formulation of the current regime:
All these factors combined often lead to medical errors, mistakes in prescription and incorrect risk management.
“Patients need reassurance that they will be believed, respected, and supported, and not blamed
if a treatment does not work. Language is a powerful tool to enable and encourage”
(The Lancet, 2021)
In order to tackle these issues, we decided to get in contact with as many gastroenterologists as we could, talk with them about the way they are approaching their patients and ask them whether they take into consideration their patients’ mental state. We then offered them our booklet which contained basic data about the above-described issues and information about the ways they can actively help their patients or get further informed. Gastroenterologists are actuated to encourage their patients to visit a mental health expert, as psychotherapy (e.g., Short Term Psychodynamic Psychotherapy (STPP)) has been shown to have beneficial effects on patients with GI disorders:
Our Set of Booklets
Recognizing the above mentioned issues, we developed a booklet that addressed gastroenterologists
as its target audience, to inform them about the importance of their patients’ mental state when
making an evaluation of their health. We presented it to a health psychologist Ms. Angelopoulou,
a gastroenterologist Dr. Taloumtzis and a psychiatrist, Dr. Agorastos to get their feedback.
They were concerned about both its scientific and its practical aspects.
We took their recommendations very seriously and made the following changes:
Based on the gastroenterologist’s feedback:
- The initial twenty five-pages long booklet for gastroenterologists was reduced to nine-pages long one, because doctors are usually too busy to spend that much time in order to turn all those pages, although the overall amount of information was small and spread.
- The information needed to be more concentrated in practical advice that a gastroenterologist can implement into their everyday practice, instead of statistics that concern the general population or irrelevant groups of people.
- The bibliography needed to be revised because revolutionary drugs, like biological factors, used in the treatment of gastroenterology patients in the last years, reduced significantly the necessity of surgery. The prescription of those drugs lead to the shrinking of the group of patients eligible for operation, leading in turn to a different statistical sample. Thus, the current situation disallows the utilization of the data we had previously found, concerning the reduction of the need for surgery in patients with Crohn, after doing psychotherapy.
Based on the psychiatrists’ feedback:
- The images used in the booklet should be very carefully selected, in order not to enhance, but alleviate the stigma and discrimination against individuals with mental health disorders.
- The phraseology should also be chosen very carefully. For example, he proposed changing the title: “What is a mental disorder?” into “How to you conceive the concept of mental health?”.
- He encouraged us to design a booklet for gastroenterology patients, in order to inform them on basic concepts concerning their mental health.
Based on the health psychologist’s feedback:
- The content should include epidemiological data about the prevalence of different GI disorders to link the rest of the information -which concerned almost exclusively the mental health perspective- with the gastroenterologists’ main subject.
- We could also prepare a booklet for patients to familiarize them with the extremely high prevalence of comorbidity between enteric and mental health disorders.
After integrating the specialists’ advice in our work, we ended up with two new booklets: A brand new one for gastroenterologists and a second one for gastroenterology patients, closer on the old one. Here you can check the old and the new versions and see for yourself the changes on the layout and content.
Our work, however, did not stop there, as we concluded that tackling a problem of comorbidity -enteric and mental health disorders- requires an approach that focuses on both gastroenterology and mental health experts. Therefore, our next step was to talk with a psychiatrist, Dr. Agorastos, and get his feedback on the topic. He told us that engaging with gastroenterologists is a good decision as, 80% of chronic diseases -many of which are related to the gut- are stress related, and thus informing the gastroenterologists about it is a first step towards improving the quality of provided services. He also informed us that gastroenterologists often prescribe psychiatric drugs to treat gut related symptoms without knowing their effects on the patient’s mental state.
“Screening patients with CD and UC for mental disorders should become element of clinical approach
in case of IBD. Achieving psychological remission, next to the remission of somatic symptoms,
appears to be a promising endpoint in the treatment of IBD”
(M. Barreiro-de Acosta & J. P. Gisbert, 2014)
Why try to convince psychiatrists to suggest our capsule, “AMALTHEA” to their patients?
Stress and depression are related to various, often non-communicable, digestive diseases, and they may be predisposing factors for functional dyspepsia and IBS. Chronic depression may also be linked with elevated cancer risk (Lee S., 2015). Studies concerning IBD, show that IBD diagnosis and gastrointestinal symptoms tend to occur earlier in life in patients with depression/anxiety and, at the same time, nearly two-third of patients with anxiety and more than a half with depression encounters first episode of mentioned psychiatric disorders up to two years before IBD diagnosis (Nowakowski J., 2016). For that reason, targeting psychiatric disorders can not only improve the patient's health from a mental health point of view, but it can also contribute to the prevention of a possible manifestation of gut disorders in the future
We asked for Dr. Agorastos’ opinion on whether psychiatrists and their patients would be positive towards our microbiome evaluating capsule. His response was very positive for both doctors and their patients. He noted that even though some patient groups would be harder to convince, such as schizophrenics, he thinks that most patients especially those suffering from stress spectrum disorders (e.g. depression) would be open to utilize the capsule and also share the data concerning their clinical image in case we use the capsule as a research tool. The fact that the measurements are going to be taken in a non-invasive manner, plays a major role in the inclination of patients to take the capsule.
Microbiota imbalances reported by the capsule can lead psychiatrists to the conclusion that tackling the problem with diet modifications might be a partial solution. Studies have shown that targeting the microbiota by probiotic supplementation could alleviate psychological distress including an index of depression (Raypole, C., 2019). At this point a patient warned by the doctor, can alter their diet either using our application, or directly consuming our probiotic, as it is a product personalized and safe for general use at the same time. The probiotic can be proposed by the doctor even without the patient using the capsule, as it is a product that can be used only as a prevention measure.
To validate our hypothesis, we turned again to Dr. Agorastos’ , this time to ask about the psychiatrists’ and psychiatric patients’ attitude towards our engineered probiotic. He replied that although the average psychiatrist does not tend to give dietary advice -or propose probiotic consumption to their patients-, they would be positive towards the introduction of such an approach to their practice. He also added that patients would probably be very positive to the idea of improving their mental state by integrating a probiotic-containing product to their diet.
How did we contribute to the confrontation of the above issues?
✔ Improving the quality of provided help by gastroenterologists. We achieved it by informing doctors
about the prevalence of psychological disorder comorbidity in their patients and the developing a
comprehensive booklet
✔Broadening the spectrum of people receiving an enteric disorder diagnosis. We achieved it by including psychiatric patients as users of our capsule, facing the problem of comorbidity of psychiatric and gut disorders, but inability of psychiatrists to order colonoscopies.
✔Broadening the spectrum of people receiving an enteric disorder diagnosis. We achieved it by including psychiatric patients as users of our capsule, facing the problem of comorbidity of psychiatric and gut disorders, but inability of psychiatrists to order colonoscopies.
Problem #2: Lack of data concerning the comorbidity and correlation of gut and mental disorders
Identification of the problem
The determination of whether correlation between stress and relapse in IBD, actually exists, is very hard to make. This phenomenon takes place due to various reasons, like difficulty in performing perspective analyses of the above-mentioned relationship (Lee, S. P., 2015) and defining the relapse itself. Concerning the perspective analyses, stress can be measured in a variety of ways from adverse life event scales through diary records of daily stress to various tools to measure chronic stress. One of the biggest problems with event scales is that they take little account of how stressful each individual might find the same event, thus making it hard to determine the exact psychological condition of every subject participating in the research. On the other hand, when trying to measure disease activity in IBD patients, a common practice is to utilize standardized scoring systems, such as the CD Activity Index (CDAI) and the Simple Clinical Colitis Activity Index (SCCAI). However, that most of them include self-reported symptoms and variables such as stool frequency which are known to be adversely affected by stress, but which do not necessarily reflect a worsening of disease activity (Lee, S. P., 2015). This phenomenon is translated into a requirement of high degree of compliance by the patient for the collection of detailed data relating both to stress and GI symptoms. On top of all the aforementioned obstacles, researches that aim to test the correlation between stress and disease activity require a long study time, during which, confounding factors such as medication, can change, thus interfering with the results.
“Given the state of current evidence for a modest role for stress as a contributing factor in IBD
and the largely disappointing results of controlled intervention trials, further trials of
psychosocial intervention should target high-risk patients with IBD rather than being applied
without selection criteria”
(Mawdsley J. E. et al., 2016)
The above issues are reflected upon the amount of evidence concerning this topic. There are statistical reports related to the Greek population, which show that GI disorders (duodenal ulcer, colitis) have a certain prevalence (males: 3,1%, females: 4,4%, Sum: 3,8%) but there is no data about their correlation with mental disorders. Our conversation with the health psychologist Ms. Angelopoulou, confirmed to us that another issue that makes the prosecution of research on this topic, is the lack of patients with GI disorders that volunteer to engage in studies, mostly because of the surrounding stigma.
“There is a general need for further research into the incidence, prognosis and public health
burden of many gastrointestinal disorders across Europe, and a particular need for more studies
from eastern Europe…”
(Farthing M et al., 2014)
How did we contribute to the confrontation of the aforementioned issues?
✔Developing a research tool
Aiming to combat the lack of reliable data, we decided to utilise e-AMALTHEA, our
mobile application as a research tool. Through e-AMALTHEA, researchers will be able to collect the
user's data, anonymously and correlate gut and mental health disorders.
A special application of the capsule:
Individual and mass scale research on the effect that food inflicts on the consumer’s health and correlation of these data with mental health disorders. The invention of tools for better understanding of this relationship is very important, as for example, research on the effect the Mediterranean diet inflicts on schizophrenia, has not yet been conducted (Joseph, J et al., 2017).
Individual and mass scale research on the effect that food inflicts on the consumer’s health and correlation of these data with mental health disorders. The invention of tools for better understanding of this relationship is very important, as for example, research on the effect the Mediterranean diet inflicts on schizophrenia, has not yet been conducted (Joseph, J et al., 2017).
Problem #3: Lack of successful diet-oriented treatments in schizophrenia
Identification of the problem
Schizophrenia is a common, severe mental illness. Clinicians still engage in a slow trial-and-error process with each patient, in order to identify the most efficacious drug(s) with the fewest side effects; notably, 30% of cases show little response to first-line antipsychotics (Seah, C., & Brennand, K. J., 2020).
AMALTHEA does not claim that it makes a proposal with a huge impact on this complex disorder. What it does aim for, is approaching the matter in an innovating way that could possibly alleviate the symptoms of diseases that cooccur with schizophrenia, and thus make the lives of schizophrenic patients slightly easier. AMALTHEA’s approach is based on the facts mentioned above, at the Mental health and Diet section: occurrence of nutritional deficiencies is very common in schizophrenic patients, SCFAs can contribute to the patients’ wellbeing and multidisciplinary teams of experts constitute an arising proposal for the patients’ management.
How did we contribute to the confrontation of the aforementioned issue?
✔SCFAs supplementation with our probiotic
Supplementation of SCFAs can lower risk of cardiovascular disease, type II diabetes, and systemic inflammation, leading to a bigger lifespan in schizophrenics.
✔Utilization of capsule
Concerning the mothers with diabetes and risk for psychosis, utilization of our capsule can help to the determination of SCFAs deficiency in the gut. SCFA supplementation in this case, either performed through our probiotic or not, can play a neuroprotective role for fetus (Joseph, J. el at, 2017).
Supplementation of SCFAs can lower risk of cardiovascular disease, type II diabetes, and systemic inflammation, leading to a bigger lifespan in schizophrenics.
✔Utilization of capsule
Concerning the mothers with diabetes and risk for psychosis, utilization of our capsule can help to the determination of SCFAs deficiency in the gut. SCFA supplementation in this case, either performed through our probiotic or not, can play a neuroprotective role for fetus (Joseph, J. el at, 2017).
Problem #4: Hospital congestion
Identification of the problem
There are efforts to tackle the Hospital congestion issue worldwide (Seah, C., & Brennand, K. J., 2020). 1/3 of patients presenting in clinics, fulfil the criteria for mental disorders (Abbass A.et al., 2009) and 73% of primary care patients with depressive or anxiety disorders presented exclusively with somatic symptoms (Kroenke K., 2003). These phenomena cause confusion, discomfort and stigmatization for the patients, along with hospital congestion. In turn, hospital congestion leads to problems such as:
- Large expenses for the state (The National Mental Health Development Unit., 2010), (Expert Panel on ED Decongestion, 2009).
- Overworking of nurses -and other health professionals in public hospitals (Sung-hun Park el at., 2019).
- Patient dissatisfaction (Pashardes P.el at., 2016).
Figure 9: From all primary care patients that fulfil the criteria for a phsychiatric disorder, 56% present only with somatic symptoms (Abbass A., 2009)
How did we contribute to the confrontation of the aforementioned issue?
✔Prevention and Indication of existing gut disease
Early microbiome functionality assessment performed by our capsule can lead to early GI disorder detection, and thus reduced probability for hospitalization. On the top of that, this assessment can also be performed remotely: the capsule can be used as a bridge between the doctor and a remote patient, benefiting from the digital health services provided by our mobile application.
e-AMALTHEA
Research tool
Data from users are collected anonymously and stored in a database. This source of these data can be useful for research for reasons described above.
The data collection is accomplished through a series of questions related to the user’s state of gut and mental health. The researcher can study the results and find useful correlations between enteric and mental disorders, thus overcoming the problem of uncertainty that comes from insufficient data concerning one or both those aspects, the issue of high compliance from the patient and the problem of dearth of participants. The users will monitor and improve their own health in a friendly and reassuring environment, while providing data for researchers.
The provision of these data is made through weekly questionnaires that cover some topics that Ms. Angelopoulou and Dr. Agorastos, prompted us towards. Namely, these topics are: mood, anxiety, stress, sleep, functionality and social interactions. The selection of the questions has been made through our conversations with Ms. Angelopoulou and the review of preexisting, certified questionnaires such as the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (PRIME-MD-PHQ), the PHQ-9 and the Perceived Stress Questionnaire (PSQ).
For more information about the app's use as a research tool, visit the application page.
Mental Health Questionnaire
Taking into consideration the advice Ms. Angelopoulou gave us, we performed the iterations below:
Here you can find a draft of the questionnaire's content
Future vision:
- The questions related to somatic symptoms were kept separate from the mood-related ones. We don’t want the users to make the connection themselves and thus, self-diagnosing.
- The functionality-related questions remained as few as possible. Too many questions on this topic, can stress the user.
- Under the functionality section, we chose to address the matter of control (over somatic symptoms). Generally speaking, this issue puts pressure on people with GI disorders and although it is important to be addressed, one should not elaborate too much.
Here you can find a draft of the questionnaire's content
Future vision:
- Personalization of the app’s interface: For example, If the user answers "Yes" to the question about self-harm when first opening the application, the algorithm sends positive messages to the user. This way, it promotes the feeling that the user is not alone, thus customizing the experience to each user’s special needs.
Connection with experts
We recognize the universal problem of the absence of interdisciplinary teams of experts, that is even more intense in Greece. For that reason, our application can also be used as a platform at which gastroenterologists, dietitians and mental health experts (psychologists or psychiatrists) can have access to certain information that the user provides (each specialist has access to information relevant to their field) while ensuring that the personal information of the user is not shared to more people than necessary). This way, the specialists can give their advice in response to the user’s data.
“Over-reliance on drugs or devices may be spurred on by aggressive industry marketing, lack of
access to multidisciplinary services, such as physiotherapy or psychology…”
(The Lancet, 2021)
Gastroenterologist
- Retrieves data from the functional evaluation of the microbiome (if the user has used the capsule) and the user’s answers to the offered questionnaires.
- Provides advice and consults the user utilizing the application’s interactive interface.
Dietitian
- Retrieves data from the user’s answers to the questionnaire's questions that are related to their diet, their body’s response to different foods and the characteristics of their feaces (from the provided stool chart).
- Provides dietary advice utilizing the application’s interactive interface, possibly leading to a personalized dietary pattern that fits the user’s needs and preferences.
Psychologist/Psychiatrist
- Retrieves data from the user’s answers to questions related to their gut health and mental state.
- Provides feedback by utilizing the application’s interactive interface.
App’s friendly interface
Through our conversations with Ms. Angelopoulou, it became clear that it is important for the user
-especially when the prevalence of stress related disorders is high- to be in a calm, cozy and
welcoming environment. The interface should not make them feel like the process of symptom
reporting, diet consulting and questionnaire filling is mandatory or possesses a censorious
tone. We took special care of the mental health questionnaires, selecting southing colors for
the background and emojis as selection options when possible. When the questionnaire’s completion
is over, a couple of images pop up and the user chooses which one of them matches their mood the
best way. In the end, a mindfulness activity begins: The user looks at the selected image
(its theme is inspired from nature landscapes) for a minute. After that, they close their
eyes until the application tells them to open them (duration of 3 minutes). In the background
a calming music is playing. This exercise promotes relaxation and “psychological
rehabilitation” of the user. Activities like this, also function as a tool to connect an
experience (e.g. filling of a questionnaire) with emotions that attract the user to repeat the
experience and hence, be responsible towards the task.
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