Multi-omics analysis of the gut microbiome and metabolites associated with the psychoneurological symptom cluster in children with cancer receiving chemotherapy.

BACKGROUND: Children with cancer receiving chemotherapy commonly report a cluster of psychoneurological symptoms (PNS), including pain, fatigue, anxiety, depression, and cognitive dysfunction. The role of the gut microbiome and its functional metabolites in PNS is rarely studied among children with cancer. This study investigated the associations between the gut microbiome-metabolome pathways and PNS in children with cancer across chemotherapy as compared to healthy children. METHODS: A case-control study was conducted. Cancer cases were recruited from Children's Healthcare of Atlanta and healthy controls were recruited via flyers. Participants reported PNS using the Pediatric Patient-Reported Outcomes Measurement Information System. Data for cases were collected pre-cycle two chemotherapy (T0) and post-chemotherapy (T1), whereas data for healthy controls were collected once. Gut microbiome and its metabolites were measured using fecal specimens. Gut microbiome profiling was performed using 16S rRNA V4 sequencing, and metabolome was performed using an untargeted liquid chromatography-mass spectrometry approach. A multi-omics network integration program analyzed microbiome-metabolome pathways of PNS. RESULTS: Cases (n = 21) and controls (n = 14) had mean ages of 13.2 and 13.1 years. For cases at T0, PNS were significantly associated with microbial genera (e.g., Ruminococcus, Megasphaera, and Prevotella), which were linked with carnitine shuttle (p = 0.0003), fatty acid metabolism (p = 0.001) and activation (p = 0.001), and tryptophan metabolism (p = 0.008). Megasphaera, clustered with aspartate and asparagine metabolism (p = 0.034), carnitine shuttle (p = 0.002), and tryptophan (p = 0.019), was associated with PNS for cases at T1. Gut bacteria with potential probiotic functions, along with fatty acid metabolism, tryptophan, and carnitine shuttle, were more clustered in cancer cases than the control network and this linkage with PNS needs further studies. CONCLUSIONS: Using multi-omics approaches, this study indicated specific microbiome-metabolome pathways linked with PNS in children with cancer across chemotherapy. Due to limitations such as antibiotic use in cancer cases, these findings need to be further confirmed in a larger cohort.

Associations between TCA cycle plasma metabolites and fatigue in black females with systemic lupus erythematosus: An untargeted metabolomics pilot study.

OBJECTIVE: In this pilot study, we used untargeted metabolomics to identify biochemical mechanisms or biomarkers potentially underlying SLE-related fatigue. METHODS: Metabolon conducted untargeted metabolomic plasma profiling using ultrahigh performance liquid chromatography/tandem mass spectrometry on plasma samples of 23 Black females with systemic lupus erythematosus (SLE) and 21 no SLE controls. Fatigue phenotypes of general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation were measured with the reliable and valid Multidimensional Fatigue Inventory (MFI). RESULTS: A total of 290 metabolites were significantly different between the SLE and no SLE groups, encompassing metabolites related to glycolysis, TCA cycle activity, heme catabolism, branched chain amino acids, fatty acid metabolism, and steroids. Within the SLE group, controlling for age and co-morbidities, TCA cycle metabolites of alpha-ketoglutarate (AKG) and succinate were statistically significantly associated (p < .05) with physical and general fatigue. CONCLUSION: While pervasive perturbations in the entire TCA cycle have been implicated as a potential mechanism for fatigue, our results suggest individual metabolites of AKG and succinate may be potential biomarkers or targets of intervention for fatigue symptom management in SLE. Additionally, perturbations in heme metabolism in the SLE group provide additional insights into mechanisms that promote systemic inflammation.

Bacterial Butyrate in Parkinson's Disease Is Linked to Epigenetic Changes and Depressive Symptoms.

BACKGROUND: The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. OBJECTIVES: Here, we investigate whether the changes in the gut microbiome and associated metabolites are related to PD symptoms and epigenetic markers in leucocytes and neurons. METHODS: Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified genome-wide DNA methylation by targeted bisulfite sequencing. RESULTS: We show that lower fecal butyrate and reduced counts of genera Roseburia, Romboutsia, and Prevotella are related to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA regions in PD overlap with those altered in gastrointestinal (GI), autoimmune, and psychiatric diseases. CONCLUSIONS: Decreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain GI and psychiatric disorders, which could be relevant for their epidemiological relation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Transgenic Mice Expressing Human α-Synuclein in Noradrenergic Neurons Develop Locus Ceruleus Pathology and Nonmotor Features of Parkinson's Disease.

Degeneration of locus ceruleus (LC) neurons and dysregulation of noradrenergic signaling are ubiquitous features of Parkinson's disease (PD). The LC is among the first brain regions affected by α-synuclein (asyn) pathology, yet how asyn affects these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells, while dysregulation of NE neurotransmission may exacerbate disease progression, particularly nonmotor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed, transgene expression is usually driven by pan-neuronal promoters and thus has not been selectively targeted to LC neurons. Here we report a novel transgenic mouse expressing human wild-type asyn under control of the noradrenergic-specific dopamine ß-hydroxylase promoter (DBH-hSNCA). These mice developed oligomeric and conformation-specific asyn in LC neurons, alterations in hippocampal and LC microglial abundance, upregulated GFAP expression, degeneration of LC fibers, decreased striatal DA metabolism, and age-dependent behaviors reminiscent of nonmotor symptoms of PD that were rescued by adrenergic receptor antagonists. These mice provide novel insights into how asyn pathology affects LC neurons and how central noradrenergic dysfunction may contribute to early PD pathophysiology.SIGNIFICANCE STATEMENT ɑ-Synuclein (asyn) pathology and loss of neurons in the locus ceruleus (LC) are two of the most ubiquitous neuropathologic features of Parkinson's disease (PD). Dysregulated norepinephrine (NE) neurotransmission is associated with the nonmotor symptoms of PD, including sleep disturbances, emotional changes such as anxiety and depression, and cognitive decline. Importantly, the loss of central NE may contribute to the chronic inflammation in, and progression of, PD. We have generated a novel transgenic mouse expressing human asyn in LC neurons to investigate how increased asyn expression affects the function of the central noradrenergic transmission and associated behaviors. We report cytotoxic effects of oligomeric and conformation-specific asyn, astrogliosis, LC fiber degeneration, disruptions in striatal dopamine metabolism, and age-dependent alterations in nonmotor behaviors without inclusions.

Genetic and Environmental Factors in Parkinson's Disease Converge on Immune Function and Inflammation.

Idiopathic Parkinson's disease (iPD) is a movement disorder characterized by the degeneration of dopaminergic neurons and aggregation of the protein α-synuclein. Patients with iPD vary in age of symptom onset, rate of progression, severity of motor and non-motor symptoms, and extent of central and peripheral inflammation. Genetic and environmental factors are believed to act synergistically in iPD pathogenesis. We propose that environmental factors (pesticides and infections) increase the risk for iPD via the immune system and that the role of PD risk genes in immune cells is worthy of investigation. This review highlights the major PD-relevant genes expressed in immune cells and key environmental factors that activate immune cells and, alone or in combination with other factors, may contribute to iPD pathogenesis. By reviewing these interactions, we seek to enable the future development of immunomodulatory approaches to prevent or delay onset of iPD. © 2020 International Parkinson and Movement Disorder Society.

Interactions Between Commensal Bacteria and Enteric Neurons, via FPR1 Induction of ROS, Increase Gastrointestinal Motility in Mice.

BACKGROUND & AIMS: Reduced gastrointestinal (GI) motility is a feature of disorders associated with intestinal dysbiosis and loss of beneficial microbes. It is not clear how consumption of beneficial commensal microbes, marketed as probiotics, affects the enteric nervous system (ENS). We studied the effects of the widely used probiotic and the commensal Lactobacillus rhamnosus GG (LGG) on ENS and GI motility in mice. METHODS: Conventional and germ free C57B6 mice were gavaged with LGG and intestinal tissues were collected; changes in the enteric neuronal subtypes were assessed by real-time polymerase chain reaction, immunoblots, and immunostaining. Production of reactive oxygen species (ROS) in the jejunal myenteric plexi and phosphorylation (p) of mitogen-activated protein kinase 1 (MAPK1) in the enteric ganglia were assessed by immunoblots and immunostaining. Fluorescence in situ hybridization was performed on jejunal cryosections with probes to detect formyl peptide receptor 1 (FPR1). GI motility in conventional mice was assessed after daily gavage of LGG for 1 week. RESULTS: Feeding of LGG to mice stimulated myenteric production of ROS, increased levels of phosphorylated MAPK1, and increased expression of choline acetyl transferase by neurons (P < .001). These effects were not observed in mice given N-acetyl cysteine (a ROS inhibitor) or LGGΩSpaC (an adhesion-mutant strain of LGG) or FPR1-knockout mice. Gavage of mice with LGG for 1 week significantly increased stool frequency, reduced total GI transit time, and increased contractions of ileal circular muscle strips in ex vivo experiments (P < .05). CONCLUSIONS: Using mouse models, we found that LGG-mediated signaling in the ENS requires bacterial adhesion, redox mechanisms, and FPR1. This pathway might be activated to increase GI motility in patients.

Stool Immune Profiles Evince Gastrointestinal Inflammation in Parkinson's Disease.

BACKGROUND: Gastrointestinal symptoms are common in Parkinson's disease and frequently precede the development of motor impairments. Intestinal inflammation has been proposed as a driver of disease pathology, and evaluation of inflammatory mediators in stool could possibly identify valuable early-stage biomarkers. We measured immune- and angiogenesis-related proteins in human stool to examine inflammatory profiles associated with Parkinson's disease. METHODS: Stool samples and subjects' self-reported metadata were obtained from 156 individuals with Parkinson's disease and 110 without, including spouse and nonhousehold controls. Metadata were probed for disease-associated differences, and levels of 37 immune and angiogenesis factors in stool homogenates were measured by multiplexed immunoassay and compared across experimental groups. RESULTS: Parkinson's disease patients reported greater incidence of intestinal disease and digestive problems than controls. Direct comparison of levels of stool analytes in patients and controls revealed elevated vascular endothelial growth factor receptor 1, interleukin-1α, and CXCL8 in patients' stool. Paired comparison of patients and spouses suggested higher levels of multiple factors in patients, but this was complicated by sex differences. Sex, body mass index, a history of smoking, and use of probiotics were found to strongly influence levels of stool analytes. Multivariate analysis accounting for these and other potential confounders confirmed elevated levels of interleukin-1α and CXCL8 and also revealed increased interleukin-1ß and C-reactive protein in stool in Parkinson's disease. These differences were not dependent on subject age or disease duration. CONCLUSIONS: Levels of stool immune factors indicate that intestinal inflammation is present in patients with Parkinson's disease. © 2018 International Parkinson and Movement Disorder Society.

Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration.

Neutrophil [polymorphonuclear leukocyte (PMN)] transepithelial migration (TEM) is a hallmark of inflammatory mucosal disorders. PMN TEM is associated with epithelial injury; however, mechanisms involved in this process are not well defined. The current work describes a new mechanism whereby deposition of PMN membrane-derived microparticles (PMN-MPs) onto intestinal epithelial cells (IECs) during TEM leads to loss of epithelial cadherins, thus promoting epithelial injury and increased PMN recruitment. PMN-MPs secreted by activated PMNs during TEM displayed a high level of enzymatically active matrix metalloproteinase 9 (MMP-9), and were capable of mediating potent effects on IEC integrity. Isolated PMN-MPs efficiently bound to IEC monolayers and induced cleavage of desmoglein-2 (DSG-2) but not E-cadherin, leading to disruption of IEC intercellular adhesions. Furthermore, PMN-MP binding to intestinal epithelium in vitro in transwell assays and in vivo in ligated intestinal loop preparations facilitated increases in PMN TEM. These effects were MMP-9 dependent and were reversed in the presence of specific pharmacological inhibitors. Finally, we demonstrated that IEC Dsg-2 serves as a barrier for migrating PMNs, and its removal by PMN-MP-associated MMP-9 facilitates PMN trafficking across epithelial layers. Our findings thus implicate PMN-MPs in PMN-mediated inflammation and epithelial damage, as observed in inflammatory disorders of mucosal surfaces.-Butin-Israeli, V., Houser, M. C., Feng, M., Thorp, E. B., Nusrat, A., Parkos, C. A, Sumagin, R. Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration.

Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice.

The mechanisms underlying the association between chronic psychological stress, development of metabolic syndrome (MetS), and behavioral impairment in obesity are poorly understood. The aim of the present study was to assess the effects of mild chronic psychological stress on metabolic, inflammatory, and behavioral profiles in a mouse model of diet-induced obesity. We hypothesized that (1) high-fat high-fructose diet (HFHF) and psychological stress would synergize to mediate the impact of inflammation on the central nervous system in the presence of behavioral dysfunction, and that (2) HFHF and stress interactions would impact insulin and lipid metabolism. C57Bl/6 male mice underwent a combination of HFHF and two weeks of chronic psychological stress. MetS-related conditions were assessed using untargeted plasma metabolomics, and structural and immune changes in the gut and liver were evaluated. Inflammation was measured in plasma, liver, gut, and brain. Our results show a complex interplay of diet and stress on gut alterations, energetic homeostasis, lipid metabolism, and plasma insulin levels. Psychological stress and HFHF diet promoted changes in intestinal tight junctions proteins and increases in insulin resistance and plasma cholesterol, and impacted the RNA expression of inflammatory factors in the hippocampus. Stress promoted an adaptive anti-inflammatory profile in the hippocampus that was abolished by diet treatment. HFHF increased hippocampal and hepatic Lcn2 mRNA expression as well as LCN2 plasma levels. Behavioral changes were associated with HFHF and stress. Collectively, these results suggest that diet and stress as pervasive factors exacerbate MetS-related conditions through an inflammatory mechanism that ultimately can impact behavior. This rodent model may prove useful for identification of possible biomarkers and therapeutic targets to treat metabolic syndrome and mood disorders.

Longitudinal Renal Function Degradation Among Florida Agricultural Workers.

OBJECTIVE: This longitudinal study evaluated renal function and acute kidney injury (AKI) over time in U.S. agricultural workers. METHODS: We followed Florida agricultural workers from January 2020 to August 2022, collecting blood and urine pre- and post-workday during 5 visits. RESULTS: Pre-workday eGFR function in all participants was lower in summers but relatively consistent over time. In participants who worked almost exclusively in fernery operations (piece-rate compensation), we observed a high incidence of post-workday AKI in 2020 (21%) that increased to 43% by the end of the study. In comparison, 11% of nursery workers (hourly compensation) had AKI, and this rate was fairly stable. CONCLUSION: AKI risk over time differs according to the type of agricultural work. Piece rate workers who are incentivized to forgo rest breaks and hydration to earn higher wages demonstrate steadily increasing rates of AKI.

A Pilot Study Examining the Use of Ultrasound to Measure Intravascular Volume Status in Agricultural Workers in a Field-Based Research Setting.

OBJECTIVE: The aim of this pilot study was to explore if internal jugular vein (IJV) ultrasound studies on agricultural workers in a field-based research setting could assess volume status during a hydration intervention. METHODS: We performed pre- and post-work shift IJV ultrasound images on 30 agricultural workers. The IJV collapsibility index values were <39% (euvolemic) or ≥39% (hypovolemic). RESULTS: Of the water group, 13% (2/15) had an IJV collapsibility index ≥39%, and this increased to 19% (3/16) by the end of the work shifts. The electrolyte group did not have any workers start the work shift with an IJV collapsibility index ≥39%; however, at the postshift assessment, 15% (2/13) were hypovolemic. CONCLUSION: Internal jugular vein ultrasounds may have the potential to be a useful tool to determine volume status in field-based research settings. Further investigation is needed to confirm these findings.

Inflammatory profiles, gut microbiome, and kidney function are impacted after high-fidelity firefighter training.

BACKGROUND: Firefighters are frequently exposed to high temperatures, environmental toxicants, and strenuous physical demands. The health impacts of these occupational exposures on processes including inflammation and kidney function as well as on the gut microbiota are poorly understood. A firefighter training course may provide a controlled environment to assess these health risks. METHODS: Basic health measures, stool, and blood samples were obtained from 24 firefighters participating in a one-week, heat-intensive training course. Indicators of inflammation, gut permeability, kidney health, and stool microbiota composition were measured before and after the training course in 18 participants. Urine specific gravity was measured before and after a heat-intensive training day to evaluate dehydration. RESULTS: The majority of firefighters in this cohort were categorized as hypertensive and experienced multiple heat-related illness symptoms during the training week and dehydration after the heat-intensive training day. While plasma IL-1ß, CXCL8, and NGAL decreased over the training week, other indicators of inflammation and acute kidney injury increased, and estimated kidney function declined. Microbiota composition shifted over the course of the training week, with changes in Peptostreptococcus anaerobius and Streptococcus. CONCLUSIONS: This pilot study conducted in a controlled field setting suggests that the occupational environment of firefighters may increase their risk for systemic inflammation and kidney disease.

Unsupervised Hierarchical Clustering of Head and Neck Cancer Patients by Pre-Treatment Plasma Metabolomics Creates Prognostic Metabolic Subtypes.

There is growing evidence that the metabolism is deeply intertwined with head and neck squamous cell carcinoma (HNSCC) progression and survival but little is known about circulating metabolite patterns and their clinical potential. We performed unsupervised hierarchical clustering of 209 HNSCC patients via pre-treatment plasma metabolomics to identify metabolic subtypes. We annotated the subtypes via pathway enrichment analysis and investigated their association with overall and progression-free survival. We stratified the survival analyses by smoking history. High-resolution metabolomics extracted 186 laboratory-confirmed metabolites. The optimal model created two patient clusters, of subtypes A and B, corresponding to 41% and 59% of the study population, respectively. Fatty acid biosynthesis, acetyl-CoA transport, arginine and proline, as well as the galactose metabolism pathways differentiated the subtypes. Relative to subtype B, subtype A patients experienced significantly worse overall and progression-free survival but only among ever-smokers. The estimated three-year overall survival was 61% for subtype A and 86% for subtype B; log-rank p = 0.001. The association with survival was independent of HPV status and other HNSCC risk factors (adjusted hazard ratio = 3.58, 95% CI: 1.46, 8.78). Our findings suggest that a non-invasive metabolomic biomarker would add crucial information to clinical risk stratification and raise translational research questions about testing such a biomarker in clinical trials.

The impact of heat exposures on biomarkers of AKI and plasma metabolome among agricultural and non-agricultural workers.

BACKGROUND: Agricultural workers are consistently exposed to elevated heat exposures and vulnerable to acute kidney injury. The underlying pathophysiology and detailed molecular mechanisms of AKI among agricultural workers, and the disproportionate burden of HRI and heat stress exposure are not well understood, especially at the level of cellular metabolism. OBJECTIVE: The aim of this study was to examine the impact of heat exposures on renal biomarkers and on the human metabolome via untargeted high-resolution metabolomics among agricultural and non-agricultural workers. METHODS: Blood and urine samples were collected pre- and post-work shift from 63 agricultural workers and 27 non- agricultural workers. We evaluated pre- and post-work shift renal biomarkers and completed untargeted metabolomics using high-resolution mass spectrometry with liquid chromatography. Metabolome-wide association studies (MWAS) models identified the metabolic features differentially expressed between agricultural workers and non-agricultural workers. RESULTS: Median values of pre-shift creatinine and osteopontin (p < 0.05) were higher for agricultural workers than non-agricultural workers. Metabolic pathway enrichment analyses revealed 27 diverse pathways differed between agricultural workers and non-agricultural workers (p < 0.05) including TCA cycle and urea cycle, carbohydrate metabolism, histidine metabolism and evidence for altered microbiome shikimate pathway. CONCLUSION: This is the first investigation on the metabolic pathways that are affected among agricultural workers who are exposed to heat compared to non-heat exposed workers. This study shows extensive responses of central metabolic systems to heat exposures that impact human health.

Associations of differentially expressed genes with psychoneurological symptoms in patients with head and neck cancer: A longitudinal study.

OBJECTIVE: Patients with head and neck cancer (HNC) experience psychoneurological symptoms (PNS, i.e., depression, fatigue, sleep disturbance, pain, and cognitive dysfunction) during intensity-modulated radiotherapy (IMRT) that negatively impact their functional status, quality of life, and overall survival. The underlying mechanisms for PNS are still not fully understood. This study aimed to examine differentially expressed genes and pathways related to PNS for patients undergoing IMRT (i.e., before, end of, 6 months, and 12 months after IMRT). METHODS: Participants included 142 patients with HNC (mean age 58.9 ± 10.3 years, 72.5% male, 83.1% White). Total RNA extracted from blood leukocytes were used for genome-wide gene expression assays. Linear mixed effects model was used to examine the association between PNS and gene expression across time. Gene Ontology (GO) enrichment analysis was employed to identify pathways related to PNS. RESULTS: A total of 1352 genes (162 upregulated, 1190 downregulated) were significantly associated with PNS across time (false discovery rate (FDR) < 0.05). Among these genes, 112 GO terms were identified (FDR < 0.05). The top 20 GO terms among the significant upregulated genes were related to immune and inflammatory responses, while the top 20 GO terms among the significant downregulated genes were associated with telomere maintenance. CONCLUSION: This study is the first to identify genes and pathways linked to immune and inflammatory responses and telomere maintenance that are associated with PNS in patients with HNC receiving IMRT. Inflammation and aging markers may be candidate biomarkers for PNS. Understanding biological markers may produce targets for novel interventions.

Soluble TNF mediates amyloid-independent, diet-induced alterations to immune and neuronal functions in an Alzheimer's disease mouse model.

Introduction: Increasing evidence indicates that neurodegenerative diseases, including Alzheimer's disease (AD), are a product of gene-by-environment interplay. The immune system is a major contributor mediating these interactions. Signaling between peripheral immune cells and those within the microvasculature and meninges of the central nervous system (CNS), at the blood-brain barrier, and in the gut likely plays an important role in AD. The cytokine tumor necrosis factor (TNF) is elevated in AD patients, regulates brain and gut barrier permeability, and is produced by central and peripheral immune cells. Our group previously reported that soluble TNF (sTNF) modulates cytokine and chemokine cascades that regulate peripheral immune cell traffic to the brain in young 5xFAD female mice, and in separate studies that a diet high in fat and sugar (HFHS) dysregulates signaling pathways that trigger sTNF-dependent immune and metabolic responses that can result in metabolic syndrome, which is a risk factor for AD. We hypothesized that sTNF is a key mediator of peripheral immune cell contributions to gene-by-environment interactions to AD-like pathology, metabolic dysfunction, and diet-induced gut dysbiosis. Methods: Female 5xFAD mice were subjected to HFHS diet for 2 months and then given XPro1595 to inhibit sTNF for the last month or saline vehicle. We quantified immune cell profiles by multi-color flow cytometry on cells isolated from brain and blood; metabolic, immune, and inflammatory mRNA and protein marker biochemical and immunhistological analyses, gut microbiome, and electrophysiology in brain slices were also performed. Results: Here, we show that selective inhibition of sTNF signaling via the biologic XPro1595 modulates the effects of an HFHS diet in 5xFAD mice on peripheral and central immune profiles including CNS-associated CD8+ T cells, the composition of gut microbiota, and long-term potentiation deficits. Discussion: Obesogenic diet induces immune and neuronal dysfunction in 5xFAD mice and sTNF inhibition mitigates its effects. A clinical trial in subjects at risk for AD due to genetic predisposition and underlying inflammation associated with peripheral inflammatory co-morbidities will be needed to investigate the extent to which these findings translate to the clinic.

Inflammation and immune dysfunction in Parkinson disease.

Parkinson disease (PD) is a progressive neurodegenerative disease that affects peripheral organs as well as the central nervous system and involves a fundamental role of neuroinflammation in its pathophysiology. Neurohistological and neuroimaging studies support the presence of ongoing and end-stage neuroinflammatory processes in PD. Moreover, numerous studies of peripheral blood and cerebrospinal fluid from patients with PD suggest alterations in markers of inflammation and immune cell populations that could initiate or exacerbate neuroinflammation and perpetuate the neurodegenerative process. A number of disease genes and risk factors have been identified as modulators of immune function in PD and evidence is mounting for a role of viral or bacterial exposure, pesticides and alterations in gut microbiota in disease pathogenesis. This has led to the hypothesis that complex gene-by-environment interactions combine with an ageing immune system to create the 'perfect storm' that enables the development and progression of PD. We discuss the evidence for this hypothesis and opportunities to harness the emerging immunological knowledge from patients with PD to create better preclinical models with the long-term goal of enabling earlier identification of at-risk individuals to prevent, delay and more effectively treat the disease.

COVID-19 and Agricultural Workers: A Descriptive Study.

Agricultural workers, designated as "essential" at the start of the COVID-19 pandemic, work in harsh labor conditions, and now have the added challenge of continuing to work during the COVID-19 pandemic. The aim of this study was to assess agricultural workers' COVID-19 related history, employer-based safety measures, individual preventive practices, and COVID-19 vaccination uptake. A questionnaire study was conducted among agricultural workers in Central Florida about COVID-19 during the month of June 2020 and again in July 2021. Among 92 agricultural workers in June 2020, 47% were obese; 11% had had a COVID-19 nasal test; 87% were able to social distance at work and 34% reported employer provided face masks; 15% reported not willing to get the COVID-19 vaccine and 25% were unsure. 40% could self-isolate if they contracted COVID-19. In a follow-up visit in July 2021, 53% of participants reported receiving a COVID-19 vaccine. Agricultural workers are particularly vulnerable to COVID-19 due to existing health risk factors and lack of essential protective resources. Occupational health protections social safety net programs are urgently needed to prevent infections in vulnerable workers, and reduce community spread, and increase COVID-19 vaccination rates.

The Health Status of Hispanic Agricultural Workers in Georgia and Florida.

To examine the health status of Hispanic agricultural workers in Florida and Georgia. Health data from agricultural workers in the Farm Worker Family Health Program (June 2019) and research studies in Florida (May 2015 and May 2019) were examined. Data from 728 agricultural workers were collected through sociodemographic questionnaire and clinical data. In the Florida sample, 83% were overweight or obese, 70% elevated blood pressure, 60% met the definition of prediabetes. In Georgia, 64% were overweight or obese and 67% had elevated blood pressure. Weak correlations were observed between BMI and systolic blood pressure (unadjusted r = 0.20), diastolic blood pressure (unadjusted r = 0.19), and glucose (unadjusted r = 0.14). Adjusting for age and gender did not show statistically significant correlation between BMI and systolic and diastolic blood pressure or glucose. While BMI has been shown to be strongly associated with high blood pressure and impaired glucose, we found a weak correlation among agricultural workers. Given the common and high use of pesticides and elevated rates of hypertension, impaired glucose, and adiposity in agricultural workers, the public health impact of this relationship may require and lead to occupational reform that protects the health of agricultural workers. Future studies should assess occupational and environmental factors and lifestyle differences between agricultural workers and the general population to better understand these discrepancies in health status.