Day 1 :
Chief Specialist Scientist
Keynote: Effects of Rooibos on microbiota dysbiosis: implications for diet-induced metabolic dysfunction
Time : 10:00AM
Prof Muller focuses his research on the potential role of phenolic compounds in the prevention and treatment of metabolic conditions such as insulin resistance, dysbiosis, obesity and type 2 diabetes. He is also involved with a proteomics study to identify early markers for type 2 diabetes. These markers are currently being tested in human subjects. He has 2 International patents (the USA and Europe) for the prevention of diabetes and has authored and co-authored 81 peer-reviewed articles and two book chapters.
Recent research indicates that the gut microbiota plays a crucial role in maintaining health or promoting metabolic diseases such as obesity and diabetes. Modulation of the gut microbiome composition by enhancing the polyphenol content of the diet has potentiality in health improvement and even disease prevention. Rooibos (Aspalathus linearis) is known to exhibit such preventive effects against metabolic diseases such as diabetes. We propose that a major factor mediating these effects is through the regulation of gut microbiota by Rooibos polyphenols. We used a high fat and sugar diet-induced non-human diabetic primate model (n=6) to elucidate the effects of Rooibos on GUT microbiota. In the study, we evaluated the effect of 4 weeks of supplementation (90 mg/kg body weight) with a pharmaceutical grade aspalathin-enriched green rooibos extract (Afriplex GRT) containing ca. 12.8% aspalathin, on the gut microbiota of high fat diet-induced diabetic and normal vervet monkeys (Chlorocebus aethiops). Stools collected before and during treatment were analyzed by Microbial DNA qPCR array. The 28-day treatment of the monkeys with GRT extract, improved glucose tolerance, lowered cholesterol, specifically LDL-cholesterol in the blood. In addition, Afriplex GRT significantly affected bacteria deemed to be characteristic of the microbiota phenotype harmful to the metabolism as seen in the shifts between normal monkeys on a maize diet compared to diabetic monkeys on a high fat and sugar diet. The Firmicutes to Bacteroidetes (F/B) ratio, increased in the diabetic monkeys, was reduced by the treatment, that correlated with improved blood glucose and lipid parameters. Key bacterial species increased by the GRT treatment, include: Akkermansia muciniphila, Bacteroides intestinalis, Desulfovibrio piger and Bifidobacterium adolescentis. Supplementation of the diabetic animals Afriplex GRT treatment improved several microbial species relevant to human metabolic diseases in high fat and sugar fed diabetic vervet monkeys.
Professor of Psychiatry NPIstanbul Brain Hospital Turkey
Keynote: METABOLİC SYNDROME as a MOOD DİSORDER / Metabolic syndrome and Bipolar Disorder/ Metabolic Syndrome and Psychotropic Drugs/ The mediator role of Childhood Trauma / Mediator role of Environmental Factors as climate, geographic factors, migration and changeable life styles / Mediator role of Affective Temperament between Childhood Trauma and Environmental Factors in MetS and/or BD
Time : 11:00AM
Born in Germany in 1972. He completed his specialist education at Ege University. During his professional life, she worked as a psychiatric specialist in a general medical hospital, as an associate professor of psychiatry in the second largest mental health hospital in the Turkey. Since 2014, as a professor of psychiatry, she has taught at Üsküdar University and has been working with bipolar disorder in NPIstanbul Brain Hospital. Another area of interest is psychoanalytic psychotherapies.
METABOLİC SYNDROME as a MOOD DİSORDER
Bipolar disorder (BD) is known to be associated with premature mortality (Evans et al. 2005). Excess mortality rates due to medical disorders are between 1.5-3 times higher in adults with BD compared to general population. There is increasing evidence that indicates an interrelationship between mood disorders and some physical disease: Obesity (waist circumference), hypertension, diabetes, dyslipidemia, cardiovascular and cerebrovascular disease (Fagiolini and Goracci 2009). Glucocorticoid/insulin signaling mechanisms and inflammatory effector systems are intersections pointing to pathophysiological relationships between BD and general medical conditions that are susceptible to stress as metabolic syndrome (MetS).
Metabolic syndrome and Bipolar Disorder
MetS is more prevalent in those with BD than in the general population (Kesebir et al. 2017). A subgroup of patients with BD have a higher risk of developing MetS based their habits, lifestyles, genetic susceptibility, and choices of treatment. A 35-50% prevalence of MetS has been reported in patients with BD, and the MetS includes obesity, hypertension, diabetes and dyslipidemia. Although they are not among the diagnostic criteria of MetS, the proinflammatory and prothrombotic states and purinerjic dysfunction are considered to be in framework of MetS (Turan et al. 2014, Kesebir et al. 2014a).
Bipolar patients with a MetS have a adverse course and outcome, less favorable response to treatment, a greater risk for suicidality, unemployment and thus higher cost (Kesebir et al. 2017). On the other hand, having a medical condition was associated with longer duration of untreated illness and female gender (Maina et al., 2013). In Perugi et al.’s (2015) study, length of pharmacological treatment and age at onset of first major episode were associated with the presence of comorbid MetS.
In our study that investigates MetS in patients with first manic episode which take into consideration of the presence of a previous depressive episode (Kesebir et al. 2016a). MetS was found to be more frequent in first manic episode (FME) with previous depressive episode (PDE) group than FME without PDE. Moreover, presence of PDE was found to be the strongest predictor of MetS in regression analysis. Obviously, individuals with depression have an elevated risk of MetS (Vancampfort et al. 2013a, 2013b). At the same time according to our results, four-fifths of the patients with PDE, had used a psychopharmacological treatment for their mentioned depressive disorders. As a result it is worth to ask whether depressive episode itself or the psychopharmacological agents used to treat it was the cause of the higher MetS in these FEM patients with PDE.
Metabolic Syndrome and Psychotropic Drugs
According to Vancampfort et al.’s meta-analysis, antipsychotic use significantly explained higher MetS prevalence estimates in major depressive disorder (MDD), (2013b). Differences in MetS prevalences were not mediated by age, gender, geographical area, smoking, antidepressant use, presence of psychiatric co-morbidity. In another study, there was some mediating role for tricyclic and non-selective serotonin-reuptake inhibitor antidepressant use but overall, the mediating role of clinical differences were limited (Luppino et al. 2014). When Margary et al. evaluated 83 psychiatric inpatients diagnosed with schizophrenia, bipolar disoreder and MDD they found a positive association between antidepressant drug treatment with triglycerides, and triglycerides/HDL ratio levels and antipsychotics drugs with the HOMA and Framingham index (2013). In Perugi et al.’s study, duration of pharmacological treatment and age at onset of first major episode were associated with the presence of comorbid MetS (2015).
Time of onset for affective disorders and medical conditions were relatively concurrent. When comorbidity of medical conditions were evaluated in terms of phases of bipolar disorder, possibly they are more prevalent at onset and earlier episodes. This is because early mortality is observed more in patients with earlier onset (Goldstein et al. 2009). Comorbid medical conditions that emerge in middle stages of bipolar disorder would possibly be related to the effect of treatment and effects of patient’s habits and lifestyle. However it was showed that even in these circumstances they emerge one decade earlier than the age-matched subjects without bipolar disorder. When all these findings are taken together, it seems that MetS is one of the variables which is in a position as both an initiator and an outcome of bipolar disorder.
The mediator role of Childhood Trauma
Negative family history of BD was related to MetS for the first time in this study (Kesebir et al. 2017). It was suggested as one of the predictive variables of MetS in patients with first episode mania. This result is very important as it suggests possible alternative etiological links apart from MetS and genetic factors for BD whose monozygotic concordance is 70 percent. Molecular genetic studies showed that, BD shares similar conversions and deletions in same loci with some general medical conditions including coronary artery disease, hypertension, diabetes mellitus type I and II (So et al. 2013). However genetic association can only explain 10% of total variance of clinical co-existance (Lee et al. 2011). This outcome, which researchers call “missing heritability”, means that interactions with environmental influences have absolute role both in etiology and resilience in accordance with epigenetic principles (Kesebir et al. 2015). In our study childhood trauma is found as another predictive factor for MetS (Kesebir et al. 2017). This mentioned relationship was also suggested earlier by McIntry et al. (2012).
Acute stress prompts a response by an inflammatory reaction in the brain (Kesebir et al. 2014b). Autonomic nervous system is directly activated. Release of adrenaline and noradrenaline is end up with their binding to alpha and beta adrenergic receptors on cytokine cells. Subsequently, nuclear factor kappa-beta mediated proinflammatory cytokine release starts. On the other hand, chronical stress leads to HPA axis disorders and consequent hypercortisolism, so childhood traumas are frequently associated with obesity, diabetes, coronary artery disease, chronic obstructive pulmonary disease and autoimmune diseases. At this point abnormal stress response could play a role in the etiology of both a chronic psychiatric disorder and a comorbid medical condition. Hypertension and obesity are the medical conditions that are associated with childhood trauma in bipolar disorder (McIntyre et al. 2013). Additionally, early menarche and EEG abnormalities are found as the projections of childhood trauma on bipolar disorder (Kesebir et al. 2013a, 2013b).
Mediator role of Environmental Factors as climate, geographic factors, migration and changeable life styles
Although its genetic aspects are set forth more clearly in recent years, seasonality is a variable which can also be evaluated in the context of epigenetic principles, and according to our results it is a predictor clinical factor for MetS in first episode manic patients (Kesebir et al. 2017). Environmental factors as seasonality affect susceptibility to allostatic load. It is amply documented that bipolar symptoms or episodes are affected by seasonality in susceptible subsets. It could be conceptualized that MetS is a phenotypic manifestation of an abnormal stress response with somatic manifestations (McIntyre 2013). It would be interesting to know whether individuals with MetS syndrome seasonality are more or less likely to also experience breakthrough symptomatology. The principal circadian clock generates seasonal variations in behavior as well. Seasonality elevates the risk for metabolic syndrome, and evidence suggests that disruption of the clockwork can lead to alterations in metabolism. Englund et al.’s findings support that relationship between circadian clocks and the MetS (2009). Circadian gene variants associate to the risk factors of MetS, that they were associated with hypertension and high fasting blood glucose.
Summer type SAD is more frequent in our sample(56.8 %), (Kesebir et al. 2016b), nonetheless MetS was found to be more frequent (94.1% vs 64.3%) in winter type of SAD. Noteworthy but not a surprise, prevalence of obesity as defined by the World Health Organization (WHO) is relatively low in Asia compared to western countries (Pan, et al., 2008). In fact, Han et al. (2000) as different from western countries, in Chine summer type SAD more frequent than winter (Han et al. 2000). On the other hand, summer type SAD without regard to latitude (Levitan 2007, Elbi et al. 2002). In another comparative study, winter type SAD more frequent in Italy and summer type SAD in India (Tonetti et al. 2012). The first one regarded with photoperiodicity while the second one regarded climate and range of temperature. Between African and Afroamerican patient in Washington, winter type SAD similar in tehe two group, summer type SAD more frequent in the African patient (Guzman et al. 2007). In coclusion, SAD is dependent to climate, geography, genetic factors and interaction of ethnic and cultural variables.
There is not summer type SAD in England and Iceland (Magnusson and Stefansson 1999). MDD is not more frequent in Iceland than England but Iceland in the north. It is regarded to isolation from the other nacionality and tolerans to photoperiodisity. In fact, SAD more less in Iceland immigrant from the others. Living on city or urban is important. Living in the urban is independently sunlight, refer to be exposed to sunlight. In our sample all of patient with summer type SAD living in the city, all of patient with MetS, too. Grimaldi et al.’s (2009) tested which environmental, social, lifestyle, and health related factors of the individual contribute to the seasonal variations in mood and behavior and whether these influence the risks of the MetS and MDD, both conditions having a high prevalence in industrialized populations. 5480 individuals, representative of the general population aged 30 and over in Finland, were assessed for MetS using the ATP-III criteria, gave a self-report of seasonal variations in mood and behavior, and were interviewed for mood, anxiety, and alcohol use disorders using the DSM-IV criteria. The seasonal variations in mood and behavior have a metabolic factor composed of weight and appetite, and greater loadings on this factor increased the risk of metabolic syndrome. Self-reports of lighting experienced as poor at home contributed to scores on the metabolic factor.
Comorbidity, especially anxiety and alcohol-substance use disorders more frequent in the winter type SAD and MetS (+) patients (Kesebir et al. 2016b). When the anxiety disorder more frequent MetS (+) winter type SAD, alcohol-substance use disorder more frequent in MetS (+) summer type SAD. In Oslo, between five separate immigrant group, winter type SAD lowest in immigrant from Sri Lanka and hıghest from İran (Saheer ve ark. 2013). Our findings herein extend the seasonal pattern to the seasonal variations in mood and behavior that are part not only of depressive but also anxiety and alcohol use disorders.
There is a tendency for seasonal changes in mood and behavior to run in families, especially seasonality of the winter type, and this is largely due to a biological predisposition (Madden, et al., 1996, Kesebir et al. 2016b). In individuals having seasonal variations in their mood and behavior, physical activities are usually reduced, whereby the effect of exercise on and the feedback from a peripheral circadian clock of the skeletal muscle to the master circadian clock are altered (Zambon et al. 2003). This may predispose to delays in the circadian clockwork. In addition, carbohydrate craving in the evening is a usual sign, which may lead to delays in the circadian clockwork (Kräuchi et al. 2002). In patients with seasonal affective disorder, there are also increases in the resting metabolic rate during a depressive episode in winter (Gaist et al. 1990). Concerning a plausible network or a potential pathway that might link the light-exposure and food-intake responsive oscillators to a range of affective and behavioral outputs, the mechanisms of action remain to be elucidated at molecular level (Rosenthal et al. 1989). Lighting conditions and their dynamics may serve as a measure for intervention in order to influence the seasonal metabolic signals and in the end to prevent the MetS.
Subtype of depressive episode (melancholic subtype), number of manic episode and seasonality were differantiated in lithium induced hyperparathyroidism before lithium use (Kesebir et al. 2016c). 25(OH) vitamin D levels were lower and calcium and PTH levels were higher in ADHD comorbid bipolar patients (Bijlenga et al. 2013, Kesebir et al. 2016d). 25(OH) vitamin D status related to behavioral and affective disorders but pathophysiological mechanisms may be different in two disorder. It would be better if not only 25(OH) vitamin D levels, but also serum PTH levels were examed in ADHD comorbid bipolar patient except of lithium use.
Duration of delayed phase is more frequent in the MetS (+) patients both of winter and summer type SAD (Kesebir et al. 2016). Both delayed sleep phase syndrome (DSPS) and SAD may manifest similar delayed circadian phase problems (Lee, et al., 2011). Indication for DSPS was 26% in SAD and 2% in controls. Patients reported shorter sleep and longer sleep-onset latency. Bizim bulgumuzla uyumlu olarak çalışmalarında longer sleep showed lower odds for indication of metabolic syndrome. DSPS, in other words dysfunctional circadian system is may be compensatuar mechanisms for product of energy in the cell (Kesebir et al. 2016e) In fact, mitochondrial calcium stimulated oxidative phosphorylation. Elevated levels of calcium seen in some mania could initiative for the higher levels of mitochondrial respiration is also seen in depression At this point to be remember calcium levels influence the activity of the circadian clock and levels of circadian clock gen outputs. Circadian activity is governed a tightly selfregulated oscillatory rhythm in the expression of circadian controlled gene. But circadian regulation of interconnected translation transcriptional feedback loops has proven to be deceptive. Since this is the way it is fidelity and plasticity of the circadian clock is maintained byposttranslational modification of clocks proteins, the action of certain microRNAs and cyclically coordinated epigenetic regulation of clock protein transcription (Masri et al., 2012).
Mediator role of Affective Temperament between Childhood Trauma and Environmental Factors in MetS and/or BD
Temperament originates in the brain structure, and individual differences are attributable to neural and physiological function differences (Kesebir et al. 2005a). Affective temperament is a suggested endophenotype for BD as well. It has been suggested that temperament is associated with metabolic syndrome (MetS) markers, which may be partly mediated by lifestyle and socioeconomic status. Altınbaş et al. suggest that depressive temperament profiles may predispose an individual to the development of MetS in the winter (2013). In their study the proportions of MetS were 19.2, 23.1, 34.6, and 38.5% in the summer, fall, spring, and winter, respectively. Only depressive temperament scores were higher during the winter in patients with MetS.
Neuroticism and openness were confirmed as factors linked to seasonal mood variability (Oginska and Oginska-Bruchal, 2014). Additionally, the study revealed an association between susceptibility to mild winter depression and an avoidance-oriented coping style. The avoidance coping style was correlated positively with all the aspects of seasonality described by SPAQ (correlation coefficients from 0.21 to 0.34). Both sub-types of avoidance-oriented style, i.e. distraction and social diversion, were associated with marked subjective seasonal changes in sleep length, mood and the energy level. While the subjective amplitude of circadian rhythm proved to be connected with seasonality, the subjective acrophase of the rhythm (morningness-eveningness preference) did not.
Temperamental factors were related cross-sectionally to, as well as predicted for, the MetS precursors over the 3-year period (Ravaja et al. 1995). Mental vitality and positive emotionality were likely to be related and positive emotionality were likely to be related to a low MetS risk level, whereas hyperactivity, negative emotionality, responsivity to others, and cooperativeness were related to a high level of MetS risk. Same group’s results showed that a temperament profile characterized by a high level of persistence and reward dependence, an average level of novelty seeking, and a low level of harm avoidance was related to a high level of MetS risk factors (Keltikangas-Järvinen 1999). In a systematic review with thirteen cross-sectional analyses, and ten longitudinal analyses, hostility, anger, type A behavior and neuroticism and type D personality were associated with an increased prevalence of metabolic syndrome and its development over time (Mommersteeg and Pouwer 2012). In our study, two types of affective temperament were differantiated between MetS (+) and (-) subjects: Anxious and irritable temperaments (Kesebir et al. 2017). Hyperactivity, high level of persistence and reward dependence, average level of novelty seeking, and low level of harm avoidance which were reported in earlier studies are similar to the features defined for irritable temperament. Additionally, negative emotionality, responsivity to others and cooperativeness are features consistent with the properties defined for the anxious temperament.
Irritable temperament was associated with mixed episodes in patients with BD (Kesebir et al. 2005b). According to McIntyre, obesity may affect the symptomatic presentation of BD, by increasing the likelihood that these patients will present with mixed episodes (McIntyre 2013). I think this is applicable not only to obesity but also to MetS. Inappropriate psycopharmacological antidepressant use may contribute to this situation directly by increasing the risk of mixed episode and indirectly by increasing the risk of MetS.
On the other hand, there was no clear association between temperament measures and the occurrence and development of the metS. In our last study, triglyceride levels were found to be correlated with hyperthymic, irritable and anxious temperament scores (Kesebir et al. 2016f). There was a inverse correlation between HDL levels and irritable and anxious temperament scores. Blood pressure was found to be correlated with irritabl and anxious temperament scores. There was a strong correlation between waist circumference and cyclothymic and anxious temperament scores. There was not found to be any relation between blood fasting glucose levels and affective temperament scores. There is, however, a cluster of risk factors that include the presence of the metabolic syndrome, as well as a more negative prone temperament profile, that both predispose to the development of coronary heart disease and diabetes.
In conclusion, there is multidimensional explanation for bipolar disorders that is coherent, comprehensive, and explanatory. The presence of MetS seems to be correlated with the onset and progression of BD. Previous depressive episode, seasonality, negative family history and childhood trauma are determined as the predictors of MetS. Anxious and irritable temperament scores were higher in MetS (+) patients. This link could provide an interesting new paradigm for the study of the "systemic" nature of mood disorders. This may also contribute to the discovery of biological markers, increase in our diagnostic tools, development of protective and individual-spesific treatment options. At this point, some endocrinological drugs may be effective in the treatment of mood disorders. Use of Allopurinol and Tamoxifen was determined as antimanic treatment in guidelines for the treatment of mood disorder (Kesebir et al. 2014, Yıldız et al. 2008).