Melanoma and microbiota: Current understanding and future directions.

Over the last decade, the composition of the gut microbiota has been found to correlate with the outcomes of cancer patients treated with immunotherapy. Accumulating evidence points to the various mechanisms by which intestinal bacteria act on distal tumors and how to harness this complex ecosystem to circumvent primary resistance to immune checkpoint inhibitors. Here, we review the state of the microbiota field in the context of melanoma, the recent breakthroughs in defining microbial modes of action, and how to modulate the microbiota to enhance response to cancer immunotherapy. The host-microbe interaction may be deciphered by the use of "omics" technologies, and will guide patient stratification and the development of microbiota-centered interventions. Efforts needed to advance the field and current gaps of knowledge are also discussed.

Effect of short-term, high-dose probiotic supplementation on cognition, related brain functions and BDNF in patients with depression: a secondary analysis of a randomized controlled trial.

BACKGROUND: In major depressive disorder (MDD), cognitive dysfunctions strongly contribute to functional impairments but are barely addressed in current therapies. Novel treatment strategies addressing cognitive symptoms in depression are needed. As the gut microbiota-brain axis is linked to depression and cognition, we investigated the effect of a 4-week high-dose probiotic supplementation on cognitive symptoms in depression. METHODS: This randomized controlled trial included 60 patients with MDD, of whom 43 entered modified intention-to-treat analysis. A probiotic supplement or indistinguishable placebo containing maltose was administered over 31 days in addition to treatment as usual for depression. Participant scores on the Verbal Learning Memory Test (VLMT), Corsi Block Tapping Test, and both Trail Making Test versions as well as brain-derived neurotrophic factor levels were assessed at 3 different time points: before, immediately after and 4 weeks after intervention. Additionally, brain activation changes during working memory processing were investigated before and immediately after intervention. RESULTS: We found a significantly improved immediate recall in the VLMT in the probiotic group immediately after intervention, and a trend for a time × group interaction considering all time points. Furthermore, we found a time × group interaction in hippocampus activation during working memory processing, revealing a remediated hippocampus function in the probiotic group. Other measures did not reveal significant changes. LIMITATIONS: The modest sample size resulting from our exclusion of low-compliant cases should be considered. CONCLUSION: Additional probiotic supplementation enhances verbal episodic memory and affects neural mechanisms underlying impaired cognition in MDD. The present findings support the importance of the gut microbiota-brain axis in MDD and emphasize the potential of microbiota-related regimens to treat cognitive symptoms in depression. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier NCT02957591.

Effects of a probiotic add-on treatment on fronto-limbic brain structure, function, and perfusion in depression: Secondary neuroimaging findings of a randomized controlled trial.

BACKGROUND: Probiotics are suggested to improve depressive symptoms via the microbiota-gut-brain axis. We have recently shown a beneficial clinical effect of probiotic supplementation in patients with depression. Their underlying neural mechanisms remain unknown. METHODS: A multimodal neuroimaging approach including diffusion tensor imaging, resting-state functional MRI, and arterial spin labeling was used to investigate the effects of a four-weeks probiotic supplementation on fronto-limbic brain structure, function, and perfusion and whether these effects were related to symptom changes. RESULTS: Thirty-two patients completed both imaging assessments (18 placebo and 14 probiotics group). Probiotics maintained mean diffusivity in the left uncinate fasciculus, stabilized it in the right uncinate fasciculus, and altered resting-state functional connectivity (rsFC) between limbic structures and the temporal pole to a cluster in the precuneus. Moreover, a cluster in the left superior parietal lobule showed altered rsFC to the subcallosal cortex, the left orbitofrontal cortex, and limbic structures after probiotics. In the probiotics group, structural and functional changes were partly related to decreases in depressive symptoms. LIMITATIONS: This study has a rather small sample size. An additional follow-up MRI session would be interesting for seeing clearer changes in the relevant brain regions as clinical effects were strongest in the follow-up. CONCLUSION: Probiotic supplementation is suggested to prevent neuronal degeneration along the uncinate fasciculus and alter fronto-limbic rsFC, effects that are partly related to the improvement of depressive symptoms. Elucidating the neural mechanisms underlying probiotics' clinical effects on depression provide potential targets for the development of more precise probiotic treatments.

Clinical, gut microbial and neural effects of a probiotic add-on therapy in depressed patients: a randomized controlled trial.

A promising new treatment approach for major depressive disorder (MDD) targets the microbiota-gut-brain (MGB) axis, which is linked to physiological and behavioral functions affected in MDD. This is the first randomized controlled trial to determine whether short-term, high-dose probiotic supplementation reduces depressive symptoms along with gut microbial and neural changes in depressed patients. Patients with current depressive episodes took either a multi-strain probiotic supplement or placebo over 31 days additionally to treatment-as-usual. Assessments took place before, immediately after and again four weeks after the intervention. The Hamilton Depression Rating Sale (HAM-D) was assessed as primary outcome. Quantitative microbiome profiling and neuroimaging was used to detect changes along the MGB axis. In the sample that completed the intervention (probiotics N = 21, placebo N = 26), HAM-D scores decreased over time and interactions between time and group indicated a stronger decrease in the probiotics relative to the placebo group. Probiotics maintained microbial diversity and increased the abundance of the genus Lactobacillus, indicating the effectivity of the probiotics to increase specific taxa. The increase of the Lactobacillus was associated with decreased depressive symptoms in the probiotics group. Finally, putamen activation in response to neutral faces was significantly decreased after the probiotic intervention. Our data imply that an add-on probiotic treatment ameliorates depressive symptoms (HAM-D) along with changes in the gut microbiota and brain, which highlights the role of the MGB axis in MDD and emphasizes the potential of microbiota-related treatment approaches as accessible, pragmatic, and non-stigmatizing therapies in MDD. Trial Registration: www.clinicaltrials.gov , identifier: NCT02957591.

Fecal Microbiota Transplantation (FMT) as an Adjunctive Therapy for Depression-Case Report.

Depression is a debilitating disorder, and at least one third of patients do not respond to therapy. Associations between gut microbiota and depression have been observed in recent years, opening novel treatment avenues. Here, we present the first two patients with major depressive disorder ever treated with fecal microbiota transplantation as add-on therapy. Both improved their depressive symptoms 4 weeks after the transplantation. Effects lasted up to 8 weeks in one patient. Gastrointestinal symptoms, constipation in particular, were reflected in microbiome changes and improved in one patient. This report suggests further FMT studies in depression could be worth pursuing and adds to awareness as well as safety assurance, both crucial in determining the potential of FMT in depression treatment.

Neural mapping of anhedonia across psychiatric diagnoses: A transdiagnostic neuroimaging analysis.

Anhedonia has been associated with abnormal reward-related striatal dopamine functioning in patients with different psychiatric disorders. Here, we tested whether anhedonia expression mapped onto striatal volume across several psychiatric diagnoses. T1-weighted images from 313 participants including 89 healthy controls (HC), 22 patients with opioid use disorder (OUD), 50 patients with major depressive disorder (MDD), 45 patients with borderline personality disorder (BPD), 49 patients with first-episode psychosis (FEP), 43 patients with cocaine use disorder (CUD) and 15 patients with schizophrenia (SZ) were included. Anhedonia was assessed with subscores of the Beck Depression Inventory (BDI) and/or the Scale for the Assessment of Negative Symptoms (SANS). Voxel-based morphometry (VBM) was conducted for identifying dimensional symptom-structure associations using region of interest (ROI, dorsal and ventral striatum) and whole-brain analyses, as well as for group comparisons of striatal volume. ROI analyses revealed significant negative relationships between putamen volume and BDI and SANS anhedonia scores across OUD, MDD, BPD, CUD and SZ patients (n = 175) and MDD, FEP and SZ patients (n = 114), respectively. Whole-brain VBM analyses confirmed these associations and further showed negative relationships between anhedonia severity and volume of the bilateral cerebellum. There were group differences in right accumbens volume, which however were not related to anhedonia expression across the different diagnoses. Our findings indicate volumetric abnormalities in the putamen and cerebellum as a common neural substrate of anhedonia severity that cut across psychiatric entities.

Favorable impact of long-term exercise on disease symptoms in pediatric patients with inflammatory bowel disease.

BACKGROUND: Evidence is growing that both short- and long-term physical exercise have the potential to positively impact on the physiological system related to inflammatory indices, though, such patterns are unknown for pediatric patients with Inflammatory Bowel Disease (IBD). The aim of the present intervention study was to investigate the influence of a single bout and chronic moderate-intensity exercise on IBD-related inflammatory indices and exercise capacity among pediatric individuals with IBD and healthy controls. METHOD: Twenty-one pediatric patients with IBD, split into a "remission-group" (IBD-RE; n = 14) and an "active disease group" (IBD-AD; n = 7), were compared to 23 age matched healthy controls (HC). All participants completed a single bout of exercise at baseline and an 8-week exercise intervention. Before and after the single bout of exercise IBD-related inflammatory indices (erythrocyte sedimentation rate (ESR), albumin, C-reactive protein (CRP), cortisol, hemoglobin, hematocrit, thrombocytes and leukocytes) were assessed. RESULTS: At baseline, after a single bout of exercise, inflammation (albumin, hemoglobin, erythrocytes, hematocrit and leukocytes) increased in all three groups IBD-AD, IBD-RE and HC. CRP and thrombocytes were only elevated in IBD-AD and IBD-RE, compared to HC. After a longer-term exercise intervention, ESR, CRP and thrombocytes significantly decreased in all groups. The longer-term exercise intervention did not decrease acute immunopathologic responses after a single bout of exercise, compared to baseline. CONCLUSION: Whereas a single bout of exercise increases albumin, erythrocytes and leukocytes, longer-term moderate-intensity exercise reduced inflammatory markers in pediatric patients with IBD. Children and teenagers with IBD should be encouraged to engage in regular moderate-intensity exercise activities, as such activities may contribute to inflammation suppression and improved disease management.

Personalized Medicine: What's in it for Rare Diseases?

Personalised Medicine has become a reality over the last years. The emergence of 'omics' and big data has started revolutionizing healthcare. New 'omics' technologies lead to a better molecular characterization of diseases and a new understanding of the complexity of diseases. The approach of PM is already successfully applied in different healthcare areas such as oncology, cardiology, nutrition and for rare diseases. However, health systems across the EU are often still promoting the 'one-size fits all' approach, even if it is known that patients do greatly vary in their molecular characteristics and response to drugs and other interventions. To make use of the full potentials of PM in the next years ahead several challenges need to be addressed such as the integration of big data, patient empowerment, translation of basic to clinical research, bringing the innovation to the market and shaping sustainable healthcare systems.

Psychological wellbeing and physical activity in children and adolescents with inflammatory bowel disease compared to healthy controls.

BACKGROUND: Children and adolescents with inflammatory bowel disease (IBD) report impairments in daily activities, social interactions and coping. Findings regarding psychological functioning are inconsistent, while limited information is available on objectively assessed physical activity (PA). The aims of the present study were therefore to compare anthropometric dimensions, blood values, psychological functioning and PA of children and adolescents with IBD with healthy controls. METHODS: Forty-seven children and adolescents took part in the study. Of these, 23 were diagnosed with IBD (mean age: 13.88 years, 44% females). The IBD group was divided into a medically well adjusted "remission-group" (n = 14; IBD-RE) and a group with an "active state" of disease (n = 8; IBD-AD). Healthy controls (n = 24; HC) were age- and gender-matched. Participants' anthropometric data, blood values and objective PA were assessed. Further, participants completed questionnaires covering socio-demographic data and psychological functioning. RESULTS: Participants with IBD-AD showed higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) values, haemoglobin, and leukocyte values. IBD-AD had poorer psychological functioning and lower PA (average steps per day) compared to IBD-RE and HC. No mean differences were found between IBD-RE and HC. CONCLUSIONS: The pattern of results suggests that effective medical treatment of IBD in children and adolescents is associated with favorable physiological parameters, psychological dimensions and PA. Psychological counselling of children and adolescents in an active state of IBD seem to be advised in addition to standard treatment schedules. TRIAL REGISTRATION: NCT NCT02264275 ; Registered 8 October 2014.

Impaired objective and subjective sleep in children and adolescents with inflammatory bowel disease compared to healthy controls.

OBJECTIVE: Poor sleep and higher inflammation markers are associated, and impaired sleep quality is common among patients with inflammatory bowel disease (IBD). However, information on sleep among children and adolescents with IBD is currently lacking. The aims of the present study were to compare subjective and objective sleep of children and adolescents with IBD with healthy controls and to shed more light on the relationship between sleep and inflammation. We expected that poor sleep, as assessed via sleep electroencephalography recordings, would be observed among participants with IBD, but particularly among participants in an active state of disease. Furthermore, we expected that poor sleep and higher inflammatory markers would be associated. METHODS: A total of 47 children and adolescents participated in the study; 23 were diagnosed with IBD (mean age: 13.88 years, 44% female). The IBD group was divided into a medically well adjusted "remission-group" (IBD-RE; n = 14) and a group with an "active state of disease" (IBD-AD; n = 8). Healthy controls (HC; n = 24) were age and gender matched. Participants completed self-rating questionnaires for subjective sleep disturbances. Anthropometric data, acute and chronic inflammatory markers (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and objective sleep were considered. RESULTS: Compared to HC and IBD-RE, IBD-AD patients showed impaired objective sleep patterns (eg, more awakenings, longer sleep latency, and reduced stage 3 sleep). Linear relationships described the correlation between higher ESR and more stage 4 (minutes, percentage) sleep. Nonlinear relationships described the relation between ESR and subjective sleep quality (inverse U-shaped) and between CRP and sleep latency (U-shaped). CONCLUSION: In children and adolescents with an active IBD, objective sleep was impaired and overall sleep quality and inflammation indices were associated in a complex manner. It seems advisable to include assessment of subjective sleep quality in the care of pediatric IBD patients as an additional indicator for objective sleep disturbances and inflammation. TRIAL REGISTRATION NUMBER: NCT02264275.

The impact of gut hormones on the neural circuit of appetite and satiety: A systematic review.

The brain-gut-axis is an interdependent system affecting neural functions and controlling our eating behaviour. In recent decades, neuroimaging techniques have facilitated its investigation. We systematically looked into functional and neurochemical brain imaging studies investigating how key molecules such as ghrelin, glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY), cholecystokinin (CCK), leptin, glucose and insulin influence the function of brain regions regulating appetite and satiety. Of the 349 studies published before July 2016 identified in the database search, 40 were included (27 on healthy and 13 on obese subjects). Our systematic review suggests that the plasma level of ghrelin, the gut hormone promoting appetite, is positively correlated with activation in the pre-frontal cortex (PFC), amygdala and insula and negatively correlated with activation in subcortical areas such as the hypothalamus. In contrast, the plasma levels of glucose, insulin, leptin, PYY, GLP-1 affect the same brain regions conversely. Our study integrates previous investigations of the gut-brain matrix during food-intake and homeostatic regulation and may be of use for future meta-analyses of brain-gut interactions.

Big Data for Public Health Policy-Making: Policy Empowerment.

Digitization is considered to radically transform healthcare. As such, with seemingly unlimited opportunities to collect data, it will play an important role in the public health policy-making process. In this context, health data cooperatives (HDC) are a key component and core element for public health policy-making and for exploiting the potential of all the existing and rapidly emerging data sources. Being able to leverage all the data requires overcoming the computational, algorithmic, and technological challenges that characterize today's highly heterogeneous data landscape, as well as a host of diverse regulatory, normative, governance, and policy constraints. The full potential of big data can only be realized if data are being made accessible and shared. Treating research data as a public good, creating HDC to empower citizens through citizen-owned health data, and allowing data access for research and the development of new diagnostics, therapies, and public health policies will yield the transformative impact of digital health. The HDC model for data governance is an arrangement, based on moral codes, that encourages citizens to participate in the improvement of their own health. This then enables public health institutions and policymakers to monitor policy changes and evaluate their impact and risk on a population level.

Attitudes towards Personal Genomics and Sharing of Genetic Data among Older Swiss Adults: A Qualitative Study.

OBJECTIVE: To assess the willingness of older Swiss adults to share genetic data for research purposes and to investigate factors that might impact their willingness to share data. METHODS: Semi-structured interviews were conducted among 40 participants (19 male and 21 female) aged between 67 and 92 years, between December 2013 and April 2014 attending the Seniorenuniversität Zürich, Switzerland. All interviews were audio-recorded, transcribed verbatim, and anonymized. For the analysis of the interviews, an initial coding scheme was developed, refined over time, and applied afterwards to all interviews. RESULTS: The majority of participants were in favor of placing genetic data to research's disposal. Participant's motivations to share data were mainly driven by altruistic reasons and by contributing to the greater good. Furthermore, several factors which might impact the willingness to share data such as sharing data with private companies, generational differences, differences between sharing genetic data or health data, and sharing due to financial incentives were highlighted. Last, some participants indicated concerns regarding data sharing such as misuse of data, the fear of becoming a transparent citizen, and data safety. However, 20% of the participants express confidence in data protection. Even participants who were skeptical in the beginning of the interviews admitted the benefits of data sharing. DISCUSSION: Overall, this study suggests older citizens are willing to share their data for research purposes. However, most of them will only contribute if their data is appropriately protected and if they trust the research institution to use the shared data responsibly. More transparency and detailed information regarding the data usage are urgently needed. There is a great need to increase the engagement of older adults in research since they present a large segment of our society - one which is often underexamined in research. CONCLUSION: Increased focus on general public engagement, especially of older adults, in scientific research activities known as "citizen science" is needed to further strengthen the uptake of personalized medicine.

Attitudes towards personal genomics among older Swiss adults: An exploratory study.

OBJECTIVES: To explore attitudes of Swiss older adults towards personal genomics (PG). METHODS: Using an anonymized voluntary paper-and-pencil survey, data were collected from 151 men and women aged 60-89 years attending the Seniorenuniversität Zurich, Switzerland (Seniors' University). Analyses were conducted using descriptive and inferential statistics. RESULTS: One third of the respondents were aware of PG, and more than half indicated interest in undergoing PG testing. The primary motivation provided was respondents' interest in finding out about their own disease risk, followed by willingness to contribute to scientific research. Forty-four percent were not interested in undergoing testing because results might be worrisome, or due to concerns about the validity of the results. Only a minority of respondents mentioned privacy-related concerns. Further, 66% were interested in undergoing clinic-based PG motivated by the opportunity to contribute to scientific research (78%) and 75% of all study participants indicated strong preferences to donate genomic data to public research institutions. CONCLUSION: This study indicates a relatively positive overall attitude towards personal genomic testing among older Swiss adults, a group not typically represented in surveys about personal genomics. Genomic data of older adults can be highly relevant to late life health and maintenance of quality of life. In addition they can be an invaluable source for better understanding of longevity, health and disease. Understanding the attitudes of this population towards genomic analyses, although important, remains under-examined.