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Introduction: Posttraumatic stress disorder (PTSD) is a debilitating disorder characterized by intrusive memories, avoidance, negative thoughts and moods, and heightened arousal. Many patients also report gastrointestinal symptoms. Cognitive behavioral therapy (CBT) is an evidence-based treatment approach for PTSD that successfully reduces symptoms. However, many patients still meet criteria for PTSD after treatment or continue to have symptoms indicating the need for new treatment strategies for PTSD. Patients with PTSD have a disrupted intestinal microbiome (i.e., dysbiosis) which can promote neuroinflammation; thus, modulation of the microbiome could be an alternative or adjunct treatment approach for PTSD. Methods: The current study was a 12-week, double-blind, placebo-controlled trial seeking to understand if CBT combined with a microbiota-modifying, prebiotic fiber intervention would beneficially impact clinical outcomes in veterans with PTSD (n = 70). This proof-of-concept, pilot trial was designed to assess: (1) the relationship between severity of PTSD symptoms and microbiota composition and SCFA levels (i.e., acetate, propionate, butyrate), (2) if CBT treatment with a concomitant prebiotic fiber intervention would beneficially impact clinical outcomes in veterans with PTSD, (3) evaluate the feasibility and acceptability of a prebiotic intervention as an adjunct treatment to CBT, and (4) assess the impact of treatment on the intestinal microbiota and stool SCFA (i.e., mechanism). Results: This study found that PTSD severity may be associated with reduced abundance of taxa capable of producing the SCFA propionate, and that a subset of individuals with PTSD may benefit from a microbiota-modifying prebiotic intervention. Conclusion: This study suggests that targeting the intestinal microbiome through prebiotic supplementation could represent a promising avenue for enhancing treatment outcomes in some individuals with PTSD. Clinical trial registration: https://clinicaltrials.gov/ , identifier NCT05424146. [ABSTRACT FROM AUTHOR]

HIV-infection is associated with dramatic changes in the intestinal mucosa. The impact of other viral pathogens is unclear.Eighty biopsies from left and right colon (n=63) and terminal ileum (n = 17) were collected from 19 HIV-infected and 22 HIV-uninfected subjects. Levels of cytomegalovirus (CMV) and Epstein Barr Virus (EBV) DNA were measured by droplet-digital (dd)PCR. Mucosal gene expression was measured via multiplex-assay. Microbiome analysis was performed using bacterial 16S-rDNA-pyrosequencing. The effect of CMV and EBV replication on the microbiome composition and mRNA-expression of selected cytokines (IL-6,IFN-γ,IL-1β, CCL2,IL-8 IFN-β1) was evaluated.Overall, CMV and EBV were detected in at least one intestinal site in 60.5% and 78.9% of subjects, respectively. HIV-infected individuals demonstrated less detectable CMV (p = 0.04); CMV was more frequently detected in terminal ileum than colon (p = 0.04). Detectable EBV was more frequent among HIV-infected (p = 0.05) without differences by intestinal site. The number of operational taxonomic units did not differ by CMV or EBV detection status. Among HIV-infected subjects, higher CMV was only associated with lower relative abundance of Actinobacteria in the ileum (p = 0.03). Presence of CMV was associated with up-regulated expression of all selected cytokines in the ileum (p

HIV-infection is associated with dramatic changes in the intestinal mucosa. The impact of other viral pathogens is unclear.Eighty biopsies from left and right colon (n=63) and terminal ileum (n = 17) were collected from 19 HIV-infected and 22 HIV-uninfected subjects. Levels of cytomegalovirus (CMV) and Epstein Barr Virus (EBV) DNA were measured by droplet-digital (dd)PCR. Mucosal gene expression was measured via multiplex-assay. Microbiome analysis was performed using bacterial 16S-rDNA-pyrosequencing. The effect of CMV and EBV replication on the microbiome composition and mRNA-expression of selected cytokines (IL-6,IFN-γ,IL-1β, CCL2,IL-8 IFN-β1) was evaluated.Overall, CMV and EBV were detected in at least one intestinal site in 60.5% and 78.9% of subjects, respectively. HIV-infected individuals demonstrated less detectable CMV (p = 0.04); CMV was more frequently detected in terminal ileum than colon (p = 0.04). Detectable EBV was more frequent among HIV-infected (p = 0.05) without differences by intestinal site. The number of operational taxonomic units did not differ by CMV or EBV detection status. Among HIV-infected subjects, higher CMV was only associated with lower relative abundance of Actinobacteria in the ileum (p = 0.03). Presence of CMV was associated with up-regulated expression of all selected cytokines in the ileum (p

Introduction: Alzheimer's disease (AD) prevalence has increased in the last century which can be attributed to increased lifespan, but environment is also important. Exposure to artificial light at night is one environmental factor that may influence AD. Methods: This study evaluated the relationship between outdoor nighttime light exposure and AD prevalence in the United States using satellite acquired outdoor nighttime light intensity and Medicare data. Results: Higher outdoor nighttime light was associated with higher prevalence of AD. While atrial fibrillation, diabetes, hyperlipidemia, hypertension, and stroke were associated more strongly with AD prevalence than nighttime light intensity, nighttime light was more strongly associated with AD prevalence than alcohol abuse, chronic kidney disease, depression, heart failure, and obesity. Startlingly, nighttime light exposure more strongly associated with AD prevalence in those under the age of 65 than any other disease factor examined. Discussion: These data suggest light exposure at night may influence AD, but additional studies are needed. [ABSTRACT FROM AUTHOR]

Brain derived neurotrophic factor (BDNF) may play an important role in the success of treatment for posttraumatic stress disorder (PTSD). Pre- and post-treatment blood samples were analyzed for 40 veterans who completed a 3-week intensive outpatient treatment for PTSD. The treatment included Cognitive Processing Therapy, mindfulness, and yoga as core treatment components. PTSD symptoms were assessed at pre-treatment, post-treatment, and 3-month follow-up. Participants reported large decreases in PTSD symptoms from pre-to post-treatment (d = 1.46, p < 0.001) and pre-treatment to 3-month follow-up (d = 0.91, p < 0.001). Unexpectedly, participants demonstrated a decrease in BDNF from pre-to post-treatment (d = 0.64, p < 0.001). Changes in BDNF from pre-to post-treatment were not significantly associated with PTSD symptom improvement. However, higher levels of post-treatment BDNF were significantly associated with lower PTSD symptoms at 3-month follow-up (n = 27, r = −0.57, p = 0.002) and greater improvements in PTSD symptoms from pre-treatment to 3-month follow-up (n = 27, r = 0.50, p = 0.008). Higher levels of post-treatment BDNF may facilitate the long-term success of intensive PTSD treatment. Further research with larger samples is needed to evaluate the processes by which BDNF may affect consolidation of improvements after completion of PTSD treatment. • The sample included 40 veterans who completed a 3-week intensive treatment for PTSD. • Serum brain derived neurotrophic factor (BDNF) was assayed pre- and post-treatment. • On average, serum BDNF significantly decreased from pre-to post-treatment. • Higher post-treatment BDNF was associated with better outcomes at 3-month follow-up. [ABSTRACT FROM AUTHOR]

Introduction: Aging studies in humans and mice have played a key role in understanding the intestinal microbiome and an increased abundance of “inflammaging” Gram-negative (Gn) bacteria. The mechanisms underlying this inflammatory profile in the aging microbiome are unknown. We tested the hypothesis that an aging-related decrease in colonic crypt epithelial cell anti)microbial peptide (AMP) gene expression could promote colonic microbiome inflammatory Gn dysbiosis and inflammaging. Methods: As a model of aging, C57BL/6J mice fecal (colonic) microbiota (16S) and isolated colonic crypt epithelial cell gene expression (RNA-seq) were assessed at 2 months (mth) (human: 18 years old; yo), 15 mth (human: 50 yo), and 25 mth (human: 84 yo). Informatics examined aging-related microbial compositions, differential colonic crypt epithelial cell gene expressions, and correlations between colonic bacteria and colonic crypt epithelial cell gene expressions. Results: Fecal microbiota exhibited significantly increased relative abundances of pro-inflammatory Gn bacteria with aging. Colonic crypt epithelial cell gene expression analysis showed significant age-related downregulation of key AMP genes that repress the growth of Gn bacteria. The aging-related decrease in AMP gene expressions is significantly correlated with an increased abundance in Gn bacteria (dysbiosis), loss of colonic barrier gene expression, and senescence- and inflammation-related gene expression. Conclusion: This study supports the proposed model that aging-related loss of colonic crypt epithelial cell AMP gene expression promotes increased relative abundances of Gn inflammaging-associated bacteria and gene expression markers of colonic inflammaging. These data may support new targets for aging-related therapies based on intestinal genes and microbiomes. [ABSTRACT FROM AUTHOR]

In large amounts, alcohol and its metabolites can overwhelm the gastrointestinal tract (GI) and liver and lead to damage both within the GI and in other organs. Specifically, alcohol and [...]

The excessive use of alcohol is a global problem causing many adverse pathological health effects and a significant financial health care burden. This review addresses the effect of alcohol consumption [...]

In Dec. 2019‐January 2020, a pneumonia illness originating in Wuhan, China, designated as coronavirus disease 2019 (COVID‐19) was shown to be caused by a novel RNA coronavirus designated as severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). People with advanced age, male sex, and/or underlying health conditions (obesity, type 2 diabetes, cardiovascular disease, hypertension, chronic kidney disease, and chronic lung disease) are especially vulnerable to severe COVID‐19 symptoms and death. These risk factors impact the immune system and are also associated with poor health, chronic illness, and shortened longevity. However, a large percent of patients without these known risk factors also develops severe COVID‐19 disease that can result in death. Thus, there must exist risk factors that promote exaggerated inflammatory and immune response to the SARS‐CoV‐2 virus leading to death. One such risk factor may be alcohol misuse and alcohol use disorder because these can exacerbate viral lung infections like SARS, influenza, and pneumonia. Thus, it is highly plausible that alcohol misuse is a risk factor for either increased infection rate when individuals are exposed to SARS‐CoV‐2 virus and/or more severe COVID‐19 in infected patients. Alcohol use is a well‐known risk factor for lung diseases and ARDS in SARS patients. We propose that alcohol has three key pathogenic elements in common with other COVID‐19 severity risk factors: namely, inflammatory microbiota dysbiosis, leaky gut, and systemic activation of the NLRP3 inflammasome. We also propose that these three elements represent targets for therapy for severe COVID‐19. [ABSTRACT FROM AUTHOR]

Circadian Disruption and Society The circadian clock is a sophisticated mechanism that functions to synchronize (i.e., entrain) endogenous systems with the 24-hour day in a wide variety of organisms, from [...]

The coronavirus disease 2019 (COVID-19) pandemic began in January 2020 in Wuhan, China, with a new coronavirus designated SARS-CoV-2. The principal cause of death from COVID-19 disease quickly emerged as acute respiratory distress syndrome (ARDS). A key ARDS pathogenic mechanism is the "Cytokine Storm", which is a dramatic increase in inflammatory cytokines in the blood. In the last two years of the pandemic, a new pathology has emerged in some COVID-19 survivors, in which a variety of long-term symptoms occur, a condition called post-acute sequelae of COVID-19 (PASC) or "Long COVID". Therefore, there is an urgent need to better understand the mechanisms of the virus. The spike protein on the surface of the virus is composed of joined S1–S2 subunits. Upon S1 binding to the ACE2 receptor on human cells, the S1 subunit is cleaved and the S2 subunit mediates the entry of the virus. The S1 protein is then released into the blood, which might be one of the pivotal triggers for the initiation and/or perpetuation of the cytokine storm. In this study, we tested the hypothesis that the S1 spike protein is sufficient to activate inflammatory signaling and cytokine production, independent of the virus. Our data support a possible role for the S1 spike protein in the activation of inflammatory signaling and cytokine production in human lung and intestinal epithelial cells in culture. These data support a potential role for the SARS-CoV-2 S1 spike protein in COVID-19 pathogenesis and PASC. [ABSTRACT FROM AUTHOR]

Posttraumatic stress disorder (PTSD) is a psychiatric disorder, resulting from exposure to traumatic events. Current recommended first-line interventions for the treatment of PTSD include evidence-based psychotherapies, such as cognitive processing therapy (CPT). Psychotherapies are effective for reducing PTSD symptoms, but approximately two-thirds of veterans continue to meet diagnostic criteria for PTSD after treatment, suggesting there is an incomplete understanding of what factors sustain PTSD. The intestine can influence the brain and this study evaluated intestinal readouts in subjects with PTSD. Serum samples from controls without PTSD (n = 40) from the Duke INTRuST Program were compared with serum samples from veterans with PTSD (n = 40) recruited from the Road Home Program at Rush University Medical Center. Assessments included microbial metabolites, intestinal barrier, and intestinal epithelial cell function. In addition, intestinal readouts were assessed in subjects with PTSD before and after a 3-wk CPT-based intensive treatment program (ITP) to understand if treatment impacts the intestine. Compared with controls, veterans with PTSD had a proinflammatory intestinal environment including lower levels of microbiota- derived metabolites, such as acetic, lactic, and succinic acid, intestinal barrier dysfunction [lipopolysaccharide (LPS) and LPS-binding protein], an increase in HMGB1, and a concurrent increase in the number of intestinal epithelial cell-derived extracellular vesicles. The ITP improved PTSD symptoms but no changes in intestinal outcomes were noted. This study con- firms the intestine is abnormal in subjects with PTSD and suggests that effective treatment of PTSD does not alter intestinal readouts. Targeting beneficial changes in the intestine may be an approach to enhance existing PTSD treatments. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disease associated with aging. PD patients have systemic and neuroinflammation which is hypothesized to contribute to neurodegeneration. Recent studies highlight the importance of the gut-brain axis in PD pathogenesis and suggest that gut-derived inflammation can trigger and/or promote neuroinflammation and neurodegeneration in PD. However, it is not clear whether microbiota dysbiosis, intestinal barrier dysfunction, or intestinal inflammation (common features in PD patients) are primary drivers of disrupted gut-brain axis in PD that promote neuroinflammation and neurodegeneration. Objective: To determine the role of microbiota dysbiosis, intestinal barrier dysfunction, and colonic inflammation in neuroinflammation and neurodegeneration in a genetic rodent model of PD [α-synuclein overexpressing (ASO) mice]. Methods: To distinguish the role of intestinal barrier dysfunction separate from inflammation, low dose (1%) dextran sodium sulfate (DSS) was administered in cycles for 52 days to ASO and control mice. The outcomes assessed included intestinal barrier integrity, intestinal inflammation, stool microbiome community, systemic inflammation, motor function, microglial activation, and dopaminergic neurons. Results: Low dose DSS treatment caused intestinal barrier dysfunction (sugar test, histological analysis), intestinal microbiota dysbiosis, mild intestinal inflammation (colon shortening, elevated MPO), but it did not increase systemic inflammation (serum cytokines). However, DSS did not exacerbate motor dysfunction, neuroinflammation (microglial activation), or dopaminergic neuron loss in ASO mice. Conclusion: Disruption of the intestinal barrier without overt intestinal inflammation is not associated with worsening of PD-like behavior and pathology in ASO mice. [ABSTRACT FROM AUTHOR]

Many lifestyle factors affect bone. Sleep deprivation increases risk for fractures and alcohol consumption can lead to alterations in the skeleton. How combined exposure to these two risk factors affects bone is unclear. Thus, we sought to determine the effects of circadian rhythm disruption and chronic alcohol intake on bone structure and mechanical properties in mice. A total of 120 male C57BL/6J mice were used in two cohorts of 60 mice each because of limited availability of light‐tight housing cabinets. One cohort was born in winter and the other in summer. Mice were randomly assigned to circadian disruption (weekly shifting of the light/dark cycle) and control (no shifting) groups beginning at 8 to 12 weeks of age for 12 weeks at which time mice were administered an alcohol‐containing or control diet for an additional 10 weeks. Bone structure and mechanical properties of the femur were assessed by micro‐computed tomography and three‐point bending, respectively. The initial data analysis revealed a likely cohort effect. Thus, we used a three‐way analysis of variance to assess the effects of circadian rhythm disruption, alcohol intake, and cohort. Circadian rhythm disruption alone had minimal effects on bone structure and mechanical properties. Alcohol intake reduced body mass and had minimal effects on cortical bone regardless of circadian disruption. Alcohol intake resulted in higher trabecular bone volume, but these beneficial effects were blunted when circadian rhythm was disrupted. Cohort significantly affected body size, many cortical bone structure outcomes, some trabecular bone structure outcomes, and tissue‐level material properties. Thus, cohort had the predominant effect on bone structure and mechanical properties in this study, with chronic alcohol intake and environmental circadian disruption having less consistent effects. The data indicate that season of birth may affect skeletal phenotypes and that studies requiring multiple cohorts should determine if a cohort effect exists. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease that impacts 45 million people worldwide and is ranked as the 6th top cause of death among all adults by the Centers for Disease Control and Prevention. While genetics is an important risk factor for the development of AD, environment and lifestyle are also contributing risk factors. One such environmental factor is diet, which has emerged as a key influencer of AD development/progression as well as cognition. Diets containing large quantities of saturated/trans-fats, refined carbohydrates, limited intake of fiber, and alcohol are associated with cognitive dysfunction while conversely diets low in saturated/trans-fats (i.e., bad fats), high mono/polyunsaturated fats (i.e., good fats), high in fiber and polyphenols are associated with better cognitive function and memory in both humans and animal models. Mechanistically, this could be the direct consequence of dietary components (lipids, vitamins, polyphenols) on the brain, but other mechanisms are also likely to be important. Diet is considered to be the single greatest factor influencing the intestinal microbiome. Diet robustly influences the types and function of micro-organisms (called microbiota) that reside in the gastrointestinal tract. Availability of different types of nutrients (from the diet) will favor or disfavor the abundance and function of certain groups of microbiota. Microbiota are highly metabolically active and produce many metabolites and other factors that can affect the brain including cognition and the development and clinical progression of AD. This review summarizes data to support a model in which microbiota metabolites influence brain function and AD. [ABSTRACT FROM AUTHOR]

The incretin hormone glucagon-like peptide 1 (GLP-1) has neuroprotective effects in animal models of Parkinson's disease (PD), and GLP-1 receptor agonists are associated with clinical improvements in human PD patients. GLP-1 is produced and secreted by intestinal L-cells in response to consumption of a meal. Specifically, intestinal microbiota produce short chain fatty acids (SCFA) which, in turn, promote secretion of GLP-1 into the systemic circulation, from which it can enter the brain. Our group and others have reported that PD patients have an altered intestinal microbial community that produces less SCFA compared to age-matched controls. In this report, we demonstrate that PD patients have diminished GLP-1 secretion in response to a meal compared to their household controls. Peak postprandial GLP-1 levels did not correlate with PD disease severity, motor function, or disease duration. These data provide the scientific rationale for future studies designed to elucidate the role of GLP-1 in the pathogenesis of PD and test the potential utility of GLP-1-directed therapies. [ABSTRACT FROM AUTHOR]

Background: Physiological circadian rhythms (CRs) are complex processes with 24-hour oscillations that regulate diverse biological functions. Chronic weekly light/dark (LD) shifting (CR disruption; CRD) in mice results in colonic hyperpermeability. However, the mechanisms behind this phenomenon are incompletely understood. One potential innovative in vitro method to study colonic CRs are colon organoids. The goals of this study were to utilize circadian clock gene Per2 luciferase reporter (Per2::Luc) mice to measure the effects of chronic LD shifting on colonic tissue circadian rhythmicity ex vivo and to determine if organoids made from shifted mice colons recapitulate the in vivo phenotype. Methods: Non-shifted (NS) and shifted (S) BL6 Per2::Luc mice were compared after a 22-week experiment. NS mice had a standard 12h light/12h dark LD cycle throughout. S mice alternated 12h LD patterns weekly, with light from 6am-6pm one week followed by shifting light to 6pm-6am the next week for 22 weeks. Mice were tested for intestinal permeability while colon tissue and organoids were examined for CRs of bioluminescence and proteins of barrier function and cell fate. Results: There was no absolute difference in NS vs. S 24h circadian period or phase. However, chronic LD shifting caused Per2::Luc S mice colon tissue to exhibit significantly greater variability in both the period and phase of Per2::Luc rhythms than NS mice colon tissue and organoids. Chronic LD shifting also resulted in increased colonic permeability of the Per2::Luc mice as well as decreased protein markers of intestinal permeability in colonic tissue and organoids from shifted Per2:Luc mice. Conclusions: Our studies support a model in which chronic central circadian disruption by LD shifting alters the circadian phenotype of the colon tissue and results in colon leakiness and loss of colonic barrier function. These CRD-related changes are stably expressed in colon stem cell derived organoids from CRD mice. [ABSTRACT FROM AUTHOR]

The inflammatory hypothesis posits that sustained neuroinflammation is sufficient to induce neurodegeneration and the development of Alzheimer's disease (AD) and Alzheimer's dementia. One potential source of inflammation is the intestine which harbors pro-inflammatory microorganisms capable of promoting neuroinflammation. Systemic inflammation is robustly associated with neuroinflammation as well as low levels of brain derived neurotrophic factor (BDNF) in the systemic circulation and brain. Thus, in this pilot study, we tested the hypothesis that intestinal barrier dysfunction precedes risk of death, incident AD dementia and MCI, cognitive impairment and neuropathology. Serum BDNF was associated with changes in global cognition, working memory, and perceptual speed but not risk of death, incident AD dementia, incident MCI, or neuropathology. Neither of the markers of intestinal barrier integrity examined, including lipopolysaccharide binding protein (LBP) nor intestinal fatty acid binding protein (IFABP), were associated with risk of death, incident AD dementia, incident mild cognitive impairment (MCI), change in cognition (global or domains), or neuropathology. Taken together, the data in this pilot study suggest that intestinal barrier dysfunction does not precede diagnosis of AD or MCI, changes in cognition, or brain pathology. However, since MCI and AD are related to global cognition, the findings with BDNF and the contiguous cognitive measures suggest low power with the trichotomous cognitive status measures. Future studies with larger sample sizes are necessary to further investigate the results from this pilot study. [ABSTRACT FROM AUTHOR]