R. Horner

Altered gut microbiome in a mouse model of Gulf War Illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activation

Many of the symptoms of Gulf War Illness (GWI) that include neurological abnormalities, neuroinflammation, chronic fatigue and gastrointestinal disturbances have been traced to Gulf War chemical exposure. Though the association and subsequent evidences are strong, the mechanisms that connect exposure to intestinal and neurological abnormalities remain unclear. Using an established rodent model of Gulf War Illness, we show that chemical exposure caused significant dysbiosis in the gut that included increased abundance of phylum Firmicutes and Tenericutes, and decreased abundance of Bacteroidetes. Several gram negative bacterial genera were enriched in the GWI-model that included Allobaculum sp. Altered microbiome caused significant decrease in tight junction protein Occludin with a concomitant increase in Claudin-2, a signature of a leaky gut. Resultant leaching of gut caused portal endotoxemia that led to upregulation of toll like receptor 4 (TLR4) activation in the small intestine and the brain. TLR4 knock out mice and mice that had gut decontamination showed significant decrease in tyrosine nitration and inflammatory mediators IL1β and MCP-1 in both the small intestine and frontal cortex. These events signified that gut dysbiosis with simultaneous leaky gut and systemic endotoxemia-induced TLR4 activation contributes to GW chemical-induced neuroinflammation and gastrointestinal disturbances.

Increased butyrate priming in the gut stalls microbiome associated-gastrointestinal inflammation and hepatic metabolic reprogramming in a mouse model of Gulf War Illness

ABSTRACT Most of the associated pathologies in Gulf War Illness (GWI) have been ascribed to chemical and pharmaceutical exposures during the war. Since an increased number of veterans complain of gastrointestinal (GI), neuroinflammatory and metabolic complications as they age and there are limited options for a cure, the present study was focused to assess the role of butyrate, a short chain fatty acid for attenuating GWI‐associated GI and metabolic complications. Results in a GWI‐mouse model of permethrin and pyridostigmine bromide (PB) exposure showed that oral butyrate restored gut homeostasis and increased GPR109A receptor copies in the small intestine (SI). Claudin‐2, a protein shown to be upregulated in conditions of leaky gut was significantly decreased following butyrate administration. Butyrate decreased TLR4 and TLR5 expressions in the liver concomitant to a decrease in TLR4 activation. GW‐chemical exposure showed no clinical signs of liver disease but a significant alteration of metabolic markers such as SREBP1c, PPAR‐&agr;, and PFK was evident. Liver markers for lipogenesis and carbohydrate metabolism that were significantly upregulated following GW chemical exposure were attenuated by butyrate priming in vivo and in human primary hepatocytes. Further, Glucose transporter Glut‐4 that was shown to be elevated following liver complications were significantly decreased in these mice after butyrate administration. Finally, use of TLR4 KO mice completely attenuated the liver metabolic changes suggesting the central role of these receptors in the GWI pathology. In conclusion, we report a butyrate specific mechanistic approach to identify and treat increased metabolic abnormalities in GWI veterans with systemic inflammation, chronic fatigue, GI disturbances, metabolic complications and weight gain.

Patient portal adoption and use by hospitalized cancer patients: a retrospective study of its impact on adverse events, utilization, and patient satisfaction

BackgroundPortal use has been studied among outpatients, but its utility and impact on inpatients is unclear. This study describes portal adoption and use among hospitalized cancer patients and investigates associations with selected safety, utilization, and satisfaction measures.MethodsA retrospective review of 4594 adult hospitalized cancer patients was conducted between 2012 and 2014 at Mayo Clinic in Jacksonville, Florida, comparing portal adopters, who registered for a portal account prior to hospitalization, with nonadopters. Adopters were classified by their portal activity during hospitalization as active or inactive inpatient users. Univariate and several logistic and linear regression models were used for analysis.ResultsOf total patients, 2352 (51.2%) were portal adopters, and of them, 632 (26.8%) were active inpatient users. Portal adoption was associated with patients who were young, female, married, with higher income, and had more frequent hospitalizations (P < .05). Active inpatient use was associated with patients who were young, married, nonlocals, with higher disease severity, and were hospitalized for medical treatment (P < .05). In univariate analyses, self-management knowledge scores were higher among adopters vs nonadopters (84.3 and 80.0, respectively; P = .01) and among active vs inactive inpatient users (87.0 and 83.3, respectively; P = .04). In regression models adjusted for age and disease severity, the association between portal behaviors and majority of measures were not significant (P > .05).ConclusionsOver half of our cancer inpatients adopted a portal prior to hospitalization, with increased adoption associated with predisposing and enabling determinants (eg: age, sex, marital status, income), and increased inpatient use associated with need (eg: nonlocal residence and disease severity). Additional research and greater effort to expand the portal functionality is needed to impact inpatient outcomes.