Respiratory exposure to agricultural dust extract promotes increased intestinal Tnfα expression, gut barrier dysfunction, and endotoxemia in mice.

Concentrated animal feeding operations (CAFOs) are responsible for the production of global greenhouse gases and harmful environmental pollutants including hydrogen sulfide, ammonia, and particulate matter. Swine farmers are frequently exposed to organic dust that is proinflammatory in the lung and are thus at greater risk of developing pneumonia, asthma, and other respiratory conditions. In addition to respiratory disease, air pollutants are directly associated with altered gastrointestinal (GI) physiology and the development of GI diseases, thereby highlighting the gut-lung axis in disease progression. Instillation of hog dust extract (HDE) for 3 wk has been reported to promote the development of chronic airway inflammation in mice, however, the impact of HDE exposure on intestinal homeostasis is poorly understood. We report that 3-wk intranasal exposure of HDE is associated with increased intestinal macromolecule permeability and elevated serum endotoxin concentrations in C57BL/6J mice. In vivo studies also indicated mislocalization of the epithelial cell adhesion protein, E-cadherin, in the colon as well as an increase in the proinflammatory cytokine, Tnfα, in the proximal colon. Moreover, mRNA expression of the Paneth cell-associated marker, Lyz1, was increased the proximal colon, whereas the expression of the goblet cell marker, Muc2, was unchanged in the epithelial cells of the ileum, cecum, and distal colon. These results demonstrate that airway exposure to CAFOs dusts promote airway inflammation and modify the gastrointestinal tract to increase intestinal permeability, induce systemic endotoxemia, and promote intestinal inflammation. Therefore, this study identifies complex physiological consequences of chronic exposure to organic dusts derived from CAFOs on the gut-lung axis.NEW & NOTEWORTHY Agricultural workers have a higher prevalence of occupational respiratory symptoms and are at greater risk of developing respiratory diseases. However, gastrointestinal complications have also been reported, yet the intestinal pathophysiology is understudied. This work is novel because it emphasizes the role of an inhaled environmental pollutant on the development of intestinal pathophysiological outcomes. This work will provide foundation for other studies evaluating how agricultural dusts disrupts host physiology and promotes debilitating gastrointestinal and systemic disorders.

Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment.

AIMS: To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI). METHODS: Adult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin. KEY FINDINGS: Compared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces. SIGNIFICANCE: Our findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI.

JAK-STAT Pathway Regulation of Intestinal Permeability: Pathogenic Roles and Therapeutic Opportunities in Inflammatory Bowel Disease.

The epithelial barrier forms the interface between luminal microbes and the host immune system and is the first site of exposure to many of the environmental factors that trigger disease activity in chronic inflammatory bowel disease (IBD). Disruption of the epithelial barrier, in the form of increased intestinal permeability, is a feature of IBD and other inflammatory diseases, including celiac disease and type 1 diabetes. Variants in genes that regulate or belong to the JAK-STAT signaling pathway are associated with IBD risk. Inhibitors of the JAK-STAT pathway are now effective therapeutic options in IBD. This review will discuss emerging evidence that JAK inhibitors can be used to improve defects in intestinal permeability and how this plays a key role in resolving intestinal inflammation.

Every breath you take: Impacts of environmental dust exposure on intestinal barrier function-from the gut-lung axis to COVID-19.

As countries continue to industrialize, major cities experience diminished air quality, whereas rural populations also experience poor air quality from sources such as agricultural operations. These exposures to environmental pollution from both rural and populated/industrialized sources have adverse effects on human health. Although respiratory diseases (e.g., asthma and chronic obstructive pulmonary disease) are the most commonly reported following long-term exposure to particulate matter and hazardous chemicals, gastrointestinal complications have also been associated with the increased risk of lung disease from inhalation of polluted air. The interconnectedness of these organ systems has offered valuable insights into the roles of the immune system and the micro/mycobiota as mediators of communication between the lung and the gut during disease states. A topical example of this relationship is provided by reports of multiple gastrointestinal symptoms in patients with coronavirus disease 2019 (COVID-19), whereas the rapid transmission and increased risk of COVID-19 has been linked to poor air quality and high levels of particulate matter. In this review, we focus on the mechanistic effects of environmental pollution on disease progression with special emphasis on the gut-lung axis.

Probiotic Supplementation Has a Limited Effect on Circulating Immune and Inflammatory Markers in Healthy Adults: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: A main mechanism of action proposed for oral probiotic supplementation is immunomodulation, which is expected to impart health benefits in the host by influencing circulating immune and inflammatory factors. To date, the effectiveness of probiotic supplementation for immunomodulation in healthy adults without disease has not been evaluated in a systematic review. OBJECTIVE: The objective of this systematic review was to evaluate the effect of probiotic supplementation on circulating immune and inflammatory markers of healthy adults compared to placebo. METHODS: PubMed, SCOPUS, ISI Web of Science, ProQuest, and Cochrane databases were searched for English articles up to May 15, 2019. Additional papers were identified by checking references of relevant papers. Only randomized controlled trials studying the administration of probiotic supplements compared to placebo on immune and inflammatory markers in healthy adults (aged 18 to 65 years), without acute or chronic disease, and in generally good health were examined. Independent extraction of articles was conducted by two authors using predefined search terms and restrictions/filters. The methodologic quality of each study was appraised using the Academy of Nutrition and Dietetics Evidence Analysis Library Quality Rating Worksheet and the body of evidence was assessed using the Academy of Nutrition and Dietetics Grade Definitions and Conclusion Grading Table. RESULTS: Eighteen articles, including 819 subjects, met eligibility criteria and were included in the present systematic review. Five articles were rated neutral in quality and 13 were rated high in quality. Eight articles reported a significant effect on immune and/or inflammatory parameters including increases in natural killer cells, lymphocytes, and monocytes, and decreases in proinflammatory cytokine concentrations. CONCLUSIONS: Based on the 18 articles extracted in this systemic review, probiotic supplementation was concluded to have a limited effect on immune and inflammatory markers in healthy adults. Overall, the evidence was heterogenous, precluding a meta-analysis, and difficult to aggregate and conclude on effect size. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO ref CRD42018110856.

A comparison of the nutritional physiology and gut microbiome of urban and rural house sparrows (Passer domesticus).

Urbanization influences food quality and availability for many wild species, but our knowledge of the consequences urbanization has on the nutritional physiology of these animals is currently limited. To fill this gap, we captured House Sparrows (Passer domesticus) from rural and urban environments and hypothesized that increased access to human refuse in urban areas may significantly alter the gut microbiome and nutritional physiology of Sparrows. While there were no significant differences in circulating triglycerides or free glycerol concentrations between populations, urban birds had significantly greater blood glucose concentrations, which suggests greater circulating glucagon concentrations, accessibility to carbohydrates, and/or higher rates of gluconeogenesis in an urban setting. Rural birds had significantly more plasma uric acid, suggesting that they may metabolize more proteins or experience lower inflammation than urban birds. Rural birds also had significantly higher liver free glycerol concentrations, indicating that they metabolize more fat than urban birds. There were no significant differences in the relative abundance of gut microbial taxa at the phyla level between the two populations, but linear discriminant analysis effect size (LEfSe) showed that urban House Sparrows were more enriched with class- and order-level microbes from the phylum Proteobacteria, which are implicated in several mammalian intestinal and extra-intestinal diseases. These findings demonstrate that urbanization significantly alters the nutritional physiology and the composition of the gut microbiome of House Sparrows.

A novel organic mineral complex prevented high fat diet-induced hyperglycemia, endotoxemia, liver injury and endothelial dysfunction in young male Sprague-Dawley rats.

The prevalence of metabolic syndrome (MetSyn) has risen 35% since 2012 and over two-thirds of Americans exhibit features characterizing this condition (obesity, dyslipidemia, hyperglycemia, insulin resistance and/or endothelial dysfunction). The aim of this study was to evaluate the effects of a novel dietary supplemental organic mineral complex (OMC) on these risk factors in a rodent model of MetSyn. Six-week old male Sprague-Dawley rats were fed either standard chow or a high-fat diet (HFD) composed of 60% kcal from fat for 10 weeks. Rats were also treated with OMC in their drinking water at either 0 mg/mL (control), 0.6 mg/mL, or 3.0 mg/mL. The HFD-treated rats exhibited significantly increased body mass (p<0.05), epididymal fat pad mass (p<0.001), waist circumference (p = 0.010), in addition to elevations in plasma endotoxins (p<0.001), ALT activity (p<0.001), fasting serum glucose (p = 0.025) and insulin concentrations (p = 0.009). OMC did not affect body weight or adiposity induced by the HFD. At the higher dose OMC significantly blunted HFD-induced hyperglycemia (p = 0.021), whereas both low and high doses of OMC prevented HFD-induced endotoxemia (p = 0.002 and <0.001, respectively) and hepatocyte injury (ALT activity, p<0.01). Despite evidence of oxidative stress (elevated urinary H2O2 p = 0.032) in HFD-fed rats, OMC exhibited no demonstrable antioxidative effect. Consistent with prior studies, mesenteric arteries from HFD rats had more uncoupled eNOS (p = 0.006) and iNOS protein expression (p = 0.027) in addition to impaired endothelium-dependent vasodilation that was abrogated by the high dose of OMC (p<0.05). This effect of OMC may be attributed to the high nitrate content of the supplement. These findings suggest that the OMC supplement, particularly at the higher dose, ameliorated several risk factors associated with MetSyn via a non-antioxidant-dependent mechanism.