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Marith Van Schrojenstein Lantman,1 Marlou Mackus,1 Leila S Otten,1 Deborah de Kruijff,1 Aurora JAE van de Loo,1,2 Aletta D Kraneveld,1,2 Johan Garssen,1,3 Joris C Verster1,2,4 1Division of Pharmacology, Utrecht University, Utrecht, the Netherlands; 2Institute for Risk Assessment Sciences, Utrecht University, Utrecht,the Netherlands; 3Nutricia Research, Utrecht, the Netherlands; 4Centre for Human Psychopharmacology, Swinburne University, Melbourne, Australia Background: Mental resilience can be seen as a trait that enables an individual to recover from stress and to face the next stressor with optimism. People with resilient traits are considered to have a better mental and physical health. However, there are limited data available assessing the relationship between resilient individuals and their perspective of their health and immune status. Therefore, this study was conducted to examine the relationship between mental resilience, perceived health, and perceived immune status. Methods: A total of 779 participants recruited at Utrecht University completed a questionnaire consisting of demographic characteristics, the brief resilience scale for the assessment of mental resilience, the immune function questionnaire (IFQ), and questions regarding their perceived health and immune status. Results: When correcting for gender, age, height, weight, smoker status, amount of cigarettes smoked per week, alcohol consumption status, amount of drinks consumed per week, drug use, and frequency of past year drug use, mental resilience was significantly correlated with perceived health (r=0.233, p=0.0001), perceived immune functioning (r=0.124, p=0.002), and IFQ score (r=−0.185, p=0.0001). Conclusion: A significant, albeit modest, relationship was found between mental resilience and perceived immune functioning and health. Keywords: mental resilience, immune functioning, health, vitality, quality of life

Several dietary components have been shown to influence alcohol metabolism and thereby potentially affect the development of a hangover. From the literature, it is evident that dietary nicotinic acid and zinc play a pivotal role in the oxidation of ethanol into acetaldehyde. The aim of the current study was to associate dietary intake of nicotinic acid and zinc with hangover severity. To this end, data from n = 23 healthy social drinkers who participated in a naturalistic hangover study were analyzed. n = 10 of them reported to be hangover-resistant (the control group), whereas n = 13 reported to have regular hangovers (the hangover-sensitive group). Two 24 h dietary recall records were completed, one for the day of alcohol consumption and another one for an alcohol-free control day. Dietary nutrient intake was averaged and did not significantly differ between hangover-sensitive and hangover-resistant drinkers. For the hangover-sensitive drinkers, partial correlations with overall hangover severity were computed, controlling for estimated blood alcohol concentration. A bootstrapping technique was applied to account for the relatively small sample size. The results showed that dietary intake of nicotinic acid (rPB = &minus, 0.521) and zinc (rPB = &minus, 0.341) were significantly and negatively associated (p &lt, 0.002) with overall hangover severity. Dietary zinc intake was also significantly and negatively associated with severity of vomiting (rPB = &minus, 0.577, p &lt, 0.002). No significant associations with hangover severity were found for other nutrients, such as fat and fibers. In conclusion, this study suggests that social drinkers who have a higher dietary intake of nicotinic acid and zinc report significantly less severe hangovers. As hangover-resistant and hangover-sensitive drinkers had a similar dietary nutrient intake, the claim of being hangover-resistant must be based on other unknown biopsychosocial factors. These findings should be replicated in a larger sample and include more elaborate food frequency questionnaires or nutrient-specific dietary intake records for zinc and nicotinic acid, and preferably accompanied by nutrient assessments in urine and/or blood.

With the advancement of high-throughput DNA/RNA sequencing and computational analysis techniques, commensal bacteria are now considered almost as important as pathological ones. Understanding the interaction between these bacterial microbiota, host and asthma is crucial to reveal their role in asthma pathophysiology. Several airway and/or gut microbiome studies have shown associations between certain bacterial taxa and asthma. However, challenges remain before gained knowledge from these studies can be implemented into clinical practice, such as inconsistency between studies in choosing sampling compartments and/or sequencing approaches, variability of results in asthma studies, and not taking into account medication intake and diet composition especially when investigating gut microbiome. Overcoming those challenges, will help to better understand the complex asthma disease process. The therapeutic potential of using pro- and pre-biotics to prevent or reduce risk of asthma exacerbations requires further investigation. This review will focus on methodological issues regarding setting up a microbiome study, recent developments in asthma bacterial microbiome studies, challenges and future therapeutic potential. This article is protected by copyright. All rights reserved.

Formerly considered as a passive process, the resolution of acute inflammation is now recognized as an active host response, with a cascade of coordinated cellular and molecular events that promotes termination of the inflammatory response and initiates tissue repair and healing. In a state of immune fitness, the resolution of inflammation is contained in time and space enabling the restoration of tissue homeostasis. There is increasing evidence that poor and/or inappropriate resolution of inflammation participates in the pathogenesis of chronic inflammatory diseases, extending in time the actions of pro-inflammatory mechanisms, and responsible in the long run for excessive tissue damage and pathology. In this review, we will focus on how resolution can be the target for therapy in “Th1/Th17 cell-driven” immune diseases and “Th2 cell-driven” immune diseases, with inflammatory bowel diseases (IBD) and asthma, as relevant examples. We describe the main cells and mediators stimulating the resolution of inflammation and discuss how pharmacological and dietary interventions but also life style factors, physical and psychological conditions, might influence the resolution phase. A better understanding of the impact of endogenous and exogenous factors on the resolution of inflammation might open a whole area in the development of personalized therapies in non-resolving chronic inflammatory diseases.

OBJECTIVE: Recent evidence suggesting an important role of gut-derived inflammation in brain disorders has opened up new directions to explore the possible role of the gut-brain axis in neurodegenerative diseases. Given the prominence of dysbiosis and colonic dysfunction in patients with Parkinson's disease (PD), we propose that toll-like receptor 4 (TLR4)-mediated intestinal dysfunction could contribute to intestinal and central inflammation in PD-related neurodegeneration. DESIGN: To test this hypothesis we performed studies in both human tissue and a murine model of PD. Inflammation, immune activation and microbiota composition were measured in colonic samples from subjects with PD and healthy controls subjects and rotenone or vehicle-treated mice. To further assess the role of the TLR4 signalling in PD-induced neuroinflammation, we used TLR4-knockout (KO) mice in conjunction with oral rotenone administration to model PD. RESULTS: Patients with PD have intestinal barrier disruption, enhanced markers of microbial translocation and higher pro-inflammatory gene profiles in the colonic biopsy samples compared with controls. In this regard, we found increased expression of the bacterial endotoxin-specific ligand TLR4, CD3+ T cells, cytokine expression in colonic biopsies, dysbiosis characterised by a decrease abundance of SCFA-producing colonic bacteria in subjects with PD. Rotenone treatment in TLR4-KO mice revealed less intestinal inflammation, intestinal and motor dysfunction, neuroinflammation and neurodegeneration, relative to rotenone-treated wild-type animals despite the presence of dysbiotic microbiota in TLR4-KO mice. CONCLUSION: Taken together, these studies suggest that TLR4-mediated inflammation plays an important role in intestinal and/or brain inflammation, which may be one of the key factors leading to neurodegeneration in PD.

COPD is a chronic lung disease characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities. Furthermore, COPD is often characterized by extrapulmonary manifestations and comorbidities worsening COPD progression and quality of life. A neglected comorbidity in COPD management is mental health impairment defined by anxiety, depression and cognitive problems. This paper summarizes the evidence for impaired mental health in COPD and focuses on current pharmacological intervention strategies. In addition, possible mechanisms in impaired mental health in COPD are discussed with a central role for inflammation. Many comorbidities are associated with multi-organ-associated systemic inflammation in COPD. Considering the accumulative evidence for a major role of systemic inflammation in the development of neurological disorders, it can be hypothesized that COPD-associated systemic inflammation also affects the function of the brain and is an interesting therapeutic target for nutra- and pharmaceuticals.

Background: Dietary non-digestible galacto-oligosaccharides (GOS) suppress allergic responses in mice sensitized and challenged with house dust mite (HDM). Budesonide is the standard therapy for allergic asthma in humans but is not always completely effective. Aim: To compare the efficacy of budesonide or different doses of GOS alone or with a combination therapy of budesonide and GOS on HDM-allergic responses in mice. Methods:BALB/c mice were sensitized and challenged with HDM, while fed a control diet or a diet supplemented with 1 or 2.5 w/w% GOS, and either or not oropharyngeally instilled with budesonide. Systemic and local inflammatory markers, such as mucosal mast cell protease-1 (mMCP-1) in serum, pulmonary CCL17, CCL22, and IL-33 concentrations and inflammatory cell influx in the bronchoalveolar lavage fluid (BALF) were determined. Results: Budesonide or GOS alone suppressed the number of eosinophils in the BALF of HDM allergic mice whereas budesonide either or not combined with GOS lowered both eosinophil and lymphocyte numbers in the BALF of HDM-allergic mice. Both 1 w/w% and 2.5 w/w% GOS and/or budesonide suppressed serum mMCP-1 concentrations. However, budesonide nor GOS alone was capable of reducing Th2 driving chemokines CCL17, CCL22 and IL-33 protein levels in supernatants of lung homogenates of HDM allergic mice, whereas the combination therapy did. Moreover, IL-13 concentrations were only significantly suppressed in mice treated with budesonide while fed GOS. A similar tendency was observed for the frequency of GATA3+CD4+ Th2 and CD4+RORγt+ Th17 cells in the lungs of the allergic mice. Conclusion: Dietary intervention using GOS may be a novel way to further improve the efficacy of anti-inflammatory drug therapy in allergic asthma by lowering Th2 driving mediators and mast cell degranulation.

Background: Irritable bowel syndrome (IBS) can have a significant negative impact on quality of life, mood and wellbeing. The aim of this study was to investigate the association between experiencing IBS symptoms and insomnia, and perceived health status. Method: An online survey was conducted among n = 1950 Dutch university students (83.6% women). IBS was assessed with the Birmingham IBS Symptom Questionnaire, quality of life with the WHO-5 wellbeing index, and sleep outcomes with the SLEEP-50 questionnaire. Perceived immune functioning and general health were assessed using 1-item scales. Results: IBS symptom severity was significantly associated with insomnia complaints (r = 0.32, p = 0.0001), sleep quality (r = &minus, 0.21, p = 0.0001), sleep onset latency (r = 0.11, p = 0.0001) and the number of nightly awakenings (r = 0.24, p = 0.0001). Total sleep time was not significantly associated with IBS symptom severity. Significant correlations were also found between IBS symptom severity and perceived general health (r = &minus, 0.30, p = 0.0001), perceived immune functioning (r= &minus, 0.25, p = 0.0001), and quality of life (r = &minus, 0.24, p = 0.0001). Conclusions: Experiencing IBS complaints is associated with reduced perceived immune functioning, a poorer perception of general health, and sleep disturbances. These effects are reflected in a significantly lower reported quality of life in subjects with more IBS and/or sleep complaints.

Though Parkinson's disease (PD) clinical picture is generally dominated by motor impairment, non-motor symptoms, such as cognitive decline and gastrointestinal dysfunctions, may develop before motor symptoms and have major effects on quality of life. L-3,4-di-hydroxy-phenylalanine (Levodopa) is the most commonly used treatment of motor symptoms but has serious side-effects with prolonged use and does not stop the degenerative process. Moreover, gastrointestinal dysfunctions interfere with the absorption of levodopa and modify its effectiveness. Since most patients are on levodopa treatment, there is a need for combinational therapies that allow for an effective reduction of both motor and non-motor symptoms. We have recently shown that a diet containing precursors and cofactors required for membrane phospholipid synthesis, as well as prebiotic fibers, had therapeutic effects in a PD mouse model. We now investigate the effects of combined administration of the same diet together with levodopa in the rotenone model of PD. Mice were injected with rotenone or vehicle in the striatum. The dietary intervention started after full induction of motor symptoms. The effects of dietary intervention and oral treatment with different doses of levodopa were assessed weekly. Motor and cognitive functions were tested, intestinal transit was analyzed and histological examination of the brain and the colon was assessed. Our results confirm our previous findings that rotenone-induced motor and non-motor problems were alleviated by the Active diet (AD). Levodopa showed an additive beneficial effect on rotarod performance in rotenone-treated animals fed with the AD. No negative interaction effects were found between the AD and levodopa. Our findings suggest that the dietary intervention might confer additional clinical benefits on patients receiving levodopa treatment.

Pattern recognition receptors (PRRs) may contribute to inflammatory bowel diseases (IBD) development due to their microbial-sensing ability and the unique microenvironment in the inflamed gut. In this study, the PRR mRNA expression profile together with T cell-associated factors in the colon was examined using a chronic colitis mice model. 8–12 week old C57BL/6 mice were exposed to multiple dextran sodium sulfate (DSS) treatments interspersed with a rest period to mimic the course of chronic colitis. The clinical features and histological data were collected. The mRNA expressions of colonic PRRs, T cell-associated components were measured. Finally, the colons were scored for Foxp3+ cells. During chronic colitis, the histological data, but not the clinical manifestations demonstrated characteristic inflammatory symptoms in the distal colon. In contrast to acute colitis, the expression of all Toll-like receptors (Tlrs), except Tlr5 and Tlr9, was unaffected after repeated DSS treatments. The expression of Nod1 was decreased, while Nod2 increased. After third DSS treatment, only the expressions of Tlr3 and Tlr4 were significantly enhanced. Unlike other PRRs, decreased Tlr5 and increased Tlr9 mRNA expression persisted during the chronic colitis period. As the colitis progress, only the mRNA expression of Ifnγ and Il17 staid increased during chronic colitis, while the acute colitis-associated increase of Il23, and Il10 and Il12 was abolished. Finally, increased histological score of Foxp3+ cell in colon was found during the chronic colitis period. This study provides an expression pattern of PRRs during chronic colitis that is accompanied by a Th1- and Th17 cell-mediated immune response., Highlights • This study provides an extensive survey of PRRs in the colon during chronic DSS-induced colitis. • Chronic DSS colitis upregulates the mRNA expression of Tlr3, Tlr4, Tlr9 and Nod2. • As the DSS colitis progresses to a chronic status the expression of Tlr5 decreases. • The chronic DSS colitis results in a (progressive) increase of Th1 and Th17 cells.

Increasing evidence points at a role for the immune system in the genesis of the alcohol hangover. This study investigated the association between self-reported immune function and experiencing hangovers. Dutch students aged 18 to 30 years old were invited to complete an online survey. Eighteen items on immune-related complaints were completed to assess self-reported immune function. Alcohol consumption in the past month (with respect to usual consumption and the occasion of heaviest drinking) was also recorded. Subjects with an estimated blood alcohol concentration (eBAC) of 0.18% or higher on their heaviest drinking occasion in the prior month were included in the analyses. Self-reported immune function was compared between drinkers with a hangover and those who claimed to be hangover resistant. In total, of 481 subjects (79.2% women) with a mean (SD) age of 21.1 (1.9) years old were included in the analysis. Of these, 83.3% (n = 400) reported having hangovers and 16.8% (n = 81) claimed to be hangover resistant. Drinkers with hangovers had significantly higher self-reported overall immune function scores when compared to hangover-resistant drinkers (mean &plusmn, SD = 10.5 &plusmn, 3.6 versus 13.1 &plusmn, 4.9, p = 0.0001), indicating a poorer immune status. In conclusion, experiencing alcohol hangovers is associated with significantly poorer self-reported immune function.

Introduction Although most drinkers have experienced a hangover the day following heavy alcohol consumption, a minority claims to be hangover resistant despite consuming the same large quantities of alcohol as those reporting alcohol hangover. The aim of the current study was to examine if susceptibility to experiencing hangovers is related to a drinker's interpretation of wellbeing and psychological assets to bounce back. Methods A survey was conducted among 2295 Dutch students assessing their past month alcohol consumption patterns, and measuring mental resilience and wellbeing. Estimated peak blood alcohol concentration (e-pBAC) for their heaviest drinking occasion in the past month was computed for each participant. Data from participants who reported a past month hangover, i.e. hangover sensitive drinkers, were compared with hangover resistant drinkers. The analyses were conducted for (a) all participants reaching an e-pBAC ≥ 0.11% (N = 986, of which 24.6% claimed to be hangover resistant) and (b) participants reaching an e-pBAC ≥ 0.18% (N = 480, of which 16.7% claimed to be hangover resistant). Results For both e-pBAC cut-off values, no significant differences between hangover sensitive and hangover resistant drinkers were found for mental resilience and wellbeing. Conclusion The current findings suggest that having a hangover is not simply an expression of poor psychological coping with the next-day consequences of heavy alcohol consumption.

Recent investigations have focused on the potential role of gastrointestinal (GI) abnormalities in the pathogenesis of Parkinson's disease (PD). The 'dual-hit' hypothesis of PD speculates that a putative pathogen enters the brain via two routes: the olfactory system and the GI system. Here, we investigated (1) whether local exposures of the neurotoxin rotenone in the gut or the brain of mice could induce PD-like neurological and GI phenotypes as well as a characteristic neuropathology in accordance with this 'dual-hit hypothesis' and (2) the effects of a diet containing uridine and fish oil providing docosahexaenoic acid (DHA), in both models. Mice were given rotenone either orally or by an injection in the striatum. Dietary interventions were started 1 week before rotenone exposures. We found that (1) both oral and intrastriatal administration of rotenone induced similar PD-like motor deficits, dopaminergic cell loss, delayed intestinal transit, inflammation, and alpha-synuclein accumulation in the colon; (2) the uridine and DHA containing diet prevented rotenone-induced motor and GI dysfunctions in both models. The models suggest possible bidirectional communication between the gut and the brain for the genesis of PD-like phenotype and pathology. The dietary intervention may provide benefits in the prevention of motor and non-motor symptoms in PD.

Pattern recognition receptors (PRRs) may contribute to inflammatory bowel diseases (IBD) development due to their microbial-sensing ability and the unique microenvironment in the inflamed gut. In this study, the PRR mRNA expression profile together with T cell-associated factors in the colon was examined using a chronic colitis mice model. 8-12 week old C57BL/6 mice were exposed to multiple dextran sodium sulfate (DSS) treatments interspersed with a rest period to mimic the course of chronic colitis. The clinical features and histological data were collected. The mRNA expressions of colonic PRRs, T cell-associated components were measured. Finally, the colons were scored for Foxp3+ cells. During chronic colitis, the histological data, but not the clinical manifestations demonstrated characteristic inflammatory symptoms in the distal colon. In contrast to acute colitis, the expression of all Toll-like receptors (Tlrs), except Tlr5 and Tlr9, was unaffected after repeated DSS treatments. The expression of Nod1 was decreased, while Nod2 increased. After third DSS treatment, only the expressions of Tlr3 and Tlr4 were significantly enhanced. Unlike other PRRs, decreased Tlr5 and increased Tlr9 mRNA expression persisted during the chronic colitis period. As the colitis progress, only the mRNA expression of Ifnγ and Il17 staid increased during chronic colitis, while the acute colitis-associated increase of Il23, and Il10 and Il12 was abolished. Finally, increased histological score of Foxp3+ cell in colon was found during the chronic colitis period. This study provides an expression pattern of PRRs during chronic colitis that is accompanied by a Th1- and Th17 cell-mediated immune response.

Intestinal epithelial cells (IEC) drive regulatory T cell (Treg) responses by promoting the differentiation of aldehyde dehydrogenase (ALDH)-expressing CD103+ dendritic cells (DC). Apical stimulation of TLR9 by CpG DNA on IEC supports galectin-9 expression by IEC, which is promoted by short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (GF). While galectin-9 can induce the maturation of monocyte-derived DC (moDC), the contribution of galectin-9 on the induction of ALDH activity in DC is not known. To this end, DC were stimulated with galectin-9, and ALDH activity and the expression of CD103 were assessed. ALDH activity was increased by moDC exposed to galectin-9, while the expression of CD103 remained unaltered. Galectin-9 secreted by IEC apically exposed to CpG DNA and GF enhanced ALDH activity, but not CD103 expression by moDC, which was abrogated upon galectin-9 neutralization. Similar observations were found in murine GM-CSF-cultured bone marrow-derived DC (BMDC). Using Flt3L-cultured BMDC and ex vivo murine splenic DC, it was observed that galectin-9 only enhanced ALDH activity in the presence of GM-CSF in CD103- cells. The induction of ALDH activity in BMDC was dependent on p38 and PI3K signaling. These data indicate a novel role for galectin-9 in modulating innate immunity by inducing ALDH activity in DC.

Introduction The aim of this study was to investigate the usefulness of ethyl glucuronide (EtG) and ethyl sulfate (EtS) as biomarkers of the hangover state.Methods Thirty-sixhealthy social drinkers participated in this study, being of naturalistic design. Eighteen participants experience regular hangovers (the hangover group), whereas the other 18 claim to not experience a hangover (the hangover-immune group). On a control day (alcohol-free) day and a post-alcohol day, urine EtG and EtS concentrations were determined and hangover severity assessed.Results Urinary EtG and EtS concentrations were significantly increased on post-alcohol day compared to the control day (p = .0001). Both EtG and EtS concentrations did not significantly correlate with the overall hangover score, nor with the estimated peak blood alcohol concentrations and number of alcoholic drinks. EtG correlated significantly only with the individual hangover symptom "headache" (p = .033; r = .403). No significant correlations were found with the EtG to EtS ratio. EtG and EtS concentrations significantly correlated with urine ethanol concentrations.Conclusions Although urine EtG and EtS concentration did not significantly correlate to estimated peak blood alcohol concentrations or the number of alcoholic drinks consumed, a significant correlation was found with urine ethanol concentration. However, urine EtG and EtS concentrations did not significantly correlate with overall hangover severity.

Dietary intervention with short-chain galacto-oligosaccharides (scGOS), long-chain fructo-oligosaccharides (lcFOS) and Bifidobacterium breve M-16V (Bb) (GF/Bb) suppresses food allergic symptoms in mice, potentially via intestinal epithelial cell (IEC)-derived galectin-9. Furthermore, in vitro studies showed galacto- and fructo-oligosaccharides (GF) to enhance the immunomodulatory capacity of a TLR9 ligand representing bacterial CpG DNA when exposed to IEC. In this study, we investigated whether GF/Bb modulates dendritic cells (DCs) and subsequent Th2 and regulatory T cell (Treg) frequency in the small intestinal lamina propria (SI-LP). BALB/c mice were fed GF/Bb during oral OVA sensitization. DC and T cell phenotype were determined in SI-LP mononuclear cells using flow cytometry. Murine bone marrow-derived DCs (BMDCs) were exposed to recombinant galectin-9 or human monocyte-derived DCs (moDCs) and were cultured in IEC-conditioned medium from GF and TLR9 ligand-exposed HT-29 cells. GF/Bb reduced allergic symptoms and enhanced serum galectin-9 levels, while suppressing activation, restoring phagocytic capacity, and normalizing CD103 expression of SI-LP DCs of OVA-allergic mice. In vitro, galectin-9 suppressed LPS-induced activation markers and cytokine secretion by BMDCs, and IEC-conditioned medium suppressed moDC activation in a galectin-9-dependent manner. Besides suppression of SI-LP DC activation, dietary GF/Bb also lowered the frequency of activated Th2 cells, while enhancing Treg in the SI-LP of OVA-allergic mice compared to the control diet. Dietary intervention with GF/Bb enhances galectin-9 and suppresses allergic symptoms of OVA-allergic mice in association with reduced intestinal DC and Th2 activation and increased Treg frequency in these mice.

Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic nigrostriatal neurons, with reductions in the function and amount of dopaminergic synapses. Therefore, synapse loss and membrane-related pathology provide relevant targets for interventions in PD. We previously showed the beneficial preventive effects of a dietary intervention containing uridine and DHA, two precursors for membrane synthesis, in the intrastriatal rotenone model for PD. Here, we examined the therapeutic potential of the same dietary intervention on motor, cognitive, and gastrointestinal symptoms. In addition, we tested the effects of an extended nutritional formula based on the same precursors plus other nutrients that increase membrane phospholipid synthesis as well as prebiotic fibers. C57BL/6J mice received a unilateral rotenone injection in the striatum. Dietary interventions started 28 days after surgery, when motor-symptoms had developed. Readout parameters included behavioral tasks measuring motor function and spatial memory as well as intestinal function and histological examination of brain and gut to assess PD-like pathology. Our results show that rotenone-induced motor and non-motor problems were partially alleviated by the therapeutic dietary interventions providing uridine and DHA. The extended nutritional intervention containing both precursors and other nutrients that increase phospholipid synthesis as well as prebiotic fibers was more effective in normalizing rotenone-induced motor and non-motor abnormalities. The latter diet also restored striatal DAT levels, indicating its neurorestorative properties. This is the first study demonstrating beneficial effects of specific dietary interventions, given after full development of symptoms, on a broad spectrum of motor and non-motor symptoms in a mouse model for PD.

Parkinson's disease (PD) is a neurodegenerative disorder for which there is no cure. Most patients suffer from sporadic PD, which is likely caused by a combination of genetic and environmental factors. Braak's hypothesis states that sporadic PD is caused by a pathogen that enters the body via the nasal cavity, and subsequently is swallowed and reaches the gut, initiating Lewy pathology (LP) in the nose and the digestive tract. A staging system describing the spread of LP from the peripheral to the central nervous system was also postulated by the same research group. There has been criticism to Braak's hypothesis, in part because not all patients follow the proposed staging system. Here, we review literature that either supports or criticizes Braak's hypothesis, focused on the enteric route, digestive problems in patients, the spread of LP on a tissue and a cellular level, and the toxicity of the protein αSynuclein (αSyn), which is the major constituent of LP. We conclude that Braak's hypothesis is supported by in vitro, in vivo, and clinical evidence. However, we also conclude that the staging system of Braak only describes a specific subset of patients with young onset and long duration of the disease.

Purpose of Review: Patients suffering from Parkinson's disease (PD) are known to experience gastrointestinal dysfunction that might precede the onset of motor symptoms by several years. Evidence suggests an important role of the gut-brain axis in PD pathogenesis. These interactions might be essentially influenced by the gut microbiota. Here, we review recent findings supporting that changes in the gut microbiota composition might be a trigger for inflammation contributing to neurodegeneration in PD. Recent Findings: Recent research revealed that PD patients exhibit a pro-inflammatory microbiota profile in their intestinal tract that might increase gut permeability, allowing leakage of bacterial products and inflammatory mediators from the intestines. Evidence in literature indicates that alpha-synuclein deposition might start in the enteric nervous system by pro-inflammatory immune activity and then propagates to the CNS. Alternatively, the peripheral inflammatory response could impact the brain through systemic mechanisms. Summary: A better understanding of the gut-brain interactions and the role of the intestinal microbiota in the regulation of immune responses might bring new insights in PD pathological progression and might lead to novel diagnostics and therapeutic approaches.

Background The small intestine is a specialized compartment were close interactions take place between host, microbes, food antigens and dietary fatty acids. Dietary fats get absorbed by epithelial cells and processed into a range of lipoprotein particles after which they are basolaterally secreted and collected in the lymphatics. In contrast to the colon, the small intestine is covered only by a thin mucus coat that allows for intimate interactions between host-cells and microbes. Lipoproteins have long been recognized as protective factors in infectious diseases via the neutralization of bacterial toxins like lipopolysaccharides. Much less attention has been given to the potential role of lipoproteins as factors contributing to the maintenance of small intestinal immune homeostasis via modulating bacteria-induced immune responses. Results Lipoproteins VLDL, LDL and HDL were found to neutralize TLR responses towards specific TLR-ligands or a selection of gram-negative and gram-positive bacteria. Attenuation of TLR2 activity was acute and only slightly improved by longer pre-incubation times of ligands and lipoproteins with no differences between bacterial-lipopeptides or bacteria. In contrast, attenuation of TLR4 responses was only observed after extensive preincubation of lipoproteins and LPS. Preincubation of bacteria and lipoproteins led only to a modest attenuation of TLR4 activity. Moreover, compared to TLR2, TLR4 activity could only be attenuated by lipoproteins over a small ligand dose range. Conclusions These results demonstrate the ability of lipoproteins VLDL, LDL and HDL to inhibit TLR responses towards bacterial-ligands and bacteria. Presence of lipoproteins was found to modulate the MAMP-induced cytokine release by primary human monocytes measured as changes in the release of IL-6, TNFα, GM-CSF and IFNγ. Using TLR2 and TLR4-reporter cells, lipoproteins were found to inhibit TLR responses with differences in affinity and kinetics. These data establish a role for lipoproteins as immunoregulatory molecules, attenuating TLR-responses and thereby positively contributing to mucosal homeostasis. Electronic supplementary material The online version of this article (doi:10.1186/s12865-016-0180-x) contains supplementary material, which is available to authorized users.