Exosomes and metabolic functionin mice exposed to alternating dark-light cycles mimicking night shift work schedules

Sleep is an important modulator of metabolic function. Disruptions of sleep in circadian rhythm are common in modern societies and are associated with increased risk of developing cardiometabolic disorders. Exosomes are ubiquitous extracellular vesicles that may play a mechanistic role in metabolic derangements. We hypothesized that alternating dark-light cycles mimicking shift work in mice would alter fecal microbiota and colonic epithelium permeability and alter plasma exosome cargo and metabolic function. C57BL/6 mice were randomly assigned to (i) control day light (CL), or (ii) inverted dark-light every 2 weeks for 8 weeks (IN). Body weight, fat mass and HOMA-IR were measured, along with Tregs, metabolic, and resident macrophages in visceral white adipose tissue (vWAT). Fecal water samples were incubated with confluent colonic epithelium cell cultures in electric cell-substrate impedance sensing (ECIS) arrays, and plasma exosomes were added to differentiated adipocytes and insulin-induced pAKT/AKT expression changes were assessed by western blots. Mice exposed to IN showed elevated HOMA-IR, and their fecal samples showed altered microbiota which promote increased permeability of the colonic epithelial cell barrier. Plasma exosomes decreased pAKT/AKT responses to exogenous insulin compared to CL, and altered expression of circadian clock genes. Inflammatory macrophages (Ly-6chigh) were increased in IN-exposed vWAT, while Tregs were decreased. Thus, gut microbiota and the cargo of plasma exosomes are altered by periodic shifts in environmental lighting, and effectively alter metabolic function, possibly via induction of systemic inflammation and altered clock expression in target tissues. Further exploration of exosomal miRNA signatures in shift workers and their putative metabolic organ cell targets appears warranted

Aorta macrophage inflammatory and epigenetic changes in a murine model of obstructive sleep apnea: Potential role of CD36

Obstructive sleep apnea (OSA) affects 8-10% of the population, is characterized by chronic intermittent hypoxia (CIH), and causally associates with cardiovascular morbidities. In CIH-exposed mice, closely mimicking the chronicity of human OSA, increased accumulation and proliferation of pro-inflammatory metabolic M1-like macrophages highly expressing CD36, emerged in aorta. Transcriptomic and MeDIP-seq approaches identified activation of pro-atherogenic pathways involving a complex interplay of histone modifications in functionally-relevant biological pathways, such as inflammation and oxidative stress in aorta macrophages. Discontinuation of CIH did not elicit significant improvements in aorta wall macrophage phenotype. However, CIH-induced aorta changes were absent in CD36 knockout mice, Our results provide mechanistic insights showing that CIH exposures during sleep in absence of concurrent pro-atherogenic settings (i.e., genetic propensity or dietary manipulation) lead to the recruitment of CD36(+)high macrophages to the aortic wall and trigger atherogenesis. Furthermore, long-term CIH-induced changes may not be reversible with usual OSA treatment

Chronic sleep disruption alters gut microbiota, induces systemic and adipose tissue inflammation and insulin resistance in mice.

Chronic sleep fragmentation (SF) commonly occurs in human populations, and although it does not involve circadian shifts or sleep deprivation, it markedly alters feeding behaviors ultimately promoting obesity and insulin resistance. These symptoms are known to be related to the host gut microbiota. Mice were exposed to SF for 4 weeks and then allowed to recover for 2 weeks. Taxonomic profiles of fecal microbiota were obtained prospectively, and conventionalization experiments were performed in germ-free mice. Adipose tissue insulin sensitivity and inflammation, as well as circulating measures of inflammation, were assayed. Effect of fecal water on colonic epithelial permeability was also examined. Chronic SF-induced increased food intake and reversible gut microbiota changes characterized by the preferential growth of highly fermentative members of Lachnospiraceae and Ruminococcaceae and a decrease of Lactobacillaceae families. These lead to systemic and visceral white adipose tissue inflammation in addition to altered insulin sensitivity in mice, most likely via enhanced colonic epithelium barrier disruption. Conventionalization of germ-free mice with SF-derived microbiota confirmed these findings. Thus, SF-induced metabolic alterations may be mediated, in part, by concurrent changes in gut microbiota, thereby opening the way for gut microbiome-targeted therapeutics aimed at reducing the major end-organ morbidities of chronic SF

A Pilot Randomized-Controlled Trial on the Effect of CPAP Treatment on Glycemic Control in Gestational Diabetes: Study Design and Methods

Background: Gestational diabetes (GDM) is associated with adverse short- and long-term maternal and fetal outcomes. Observational data support a link between sleep-disordered breathing (SDB) during pregnancy and GDM. However, it is unknown whether treatment of SDB with continuous positive airway pressure (CPAP) improves glucose control in this patient population. In addition, CPAP adherence and feasibility as a treatment option in pregnancy is unknown. This pilot randomized, controlled trial aims to primarily determine the feasibility of CPAP treatment in pregnant women with SDB and GDM. This study is also investigating the effect of SDB treatment on 24-h glucose profiles as an exploratory outcome.Objectives: To describe the study methodology in this ongoing study of pregnant women with GDM and SDB.Patients and Methods: Pregnant women with GDM and SDB defined by apnea-hypopnea index (AHI) ≥10 (Chicago Scoring Criteria) on level 2 polysomnography are randomized to either auto titrating CPAP (experimental group) or a nasal dilator strip (control group) until delivery. The primary outcome, objectively-assessed adherence to CPAP, is measured over the course of the treatment period using device-specific software. Recruitment and retention rates will be calculated to assess the feasibility for planning future trials. Twenty-four hour glucose profiles are measured over a 72-h period using the continuous glucose monitoring (CGM) system, before and after the intervention.Conclusion: The results of this study will be highly informative to determine whether CPAP is a feasible treatment for pregnant women with GDM and SDB, a specialized population at risk for substantial comorbidity. The trial results will ultimately be useful in planning future SDB treatment trials in pregnancy and GDM.The study is registered on clinicaltrials.gov (NCT02245659)

Hepatocellular Carcinoma: Understanding the Inflammatory Implications of the Microbiome

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. It is well known that repeated inflammatory insults in the liver can cause hepatic cellular injury that lead to cirrhosis and, ultimately, hepatocellular carcinoma. Furthermore, the microbiome has been implicated in multiple inflammatory conditions which predispose patients to malignancy. With this in mind, we explore the inflammatory implications of the microbiome on pathways that lead to HCC. We also focus on how an understanding of these underlying inflammatory principles lead to a more wholistic understanding of this deadly disease, as well as potential therapeutic implications

Exploring the Inflammatory Pathogenesis of Colorectal Cancer

Colorectal cancer is one of the most commonly diagnosed cancers worldwide. Traditionally, mechanisms of colorectal cancer formation have focused on genetic alterations including chromosomal damage and microsatellite instability. In recent years, there has been a growing body of evidence supporting the role of inflammation in colorectal cancer formation. Multiple cytokines, immune cells such T cells and macrophages, and other immune mediators have been identified in pathways leading to the initiation, growth, and metastasis of colorectal cancer. Outside the previously explored mechanisms and pathways leading to colorectal cancer, initiatives have been shifted to further study the role of inflammation in pathogenesis. Inflammatory pathways have also been linked to some traditional risk factors of colorectal cancer such as obesity, smoking and diabetes, as well as more novel associations such as the gut microbiome, the gut mycobiome and exosomes. In this review, we will explore the roles of obesity and diet, smoking, diabetes, the microbiome, the mycobiome and exosomes in colorectal cancer, with a specific focus on the underlying inflammatory and metabolic pathways involved. We will also investigate how the study of colon cancer from an inflammatory background not only creates a more holistic and inclusive understanding of this disease, but also creates unique opportunities for prevention, early diagnosis and therapy

Exploring the Inflammatory Pathogenesis of Colorectal Cancer

Colorectal cancer is one of the most commonly diagnosed cancers worldwide. Traditionally, mechanisms of colorectal cancer formation have focused on genetic alterations including chromosomal damage and microsatellite instability. In recent years, there has been a growing body of evidence supporting the role of inflammation in colorectal cancer formation. Multiple cytokines, immune cells such T cells and macrophages, and other immune mediators have been identified in pathways leading to the initiation, growth, and metastasis of colorectal cancer. Outside the previously explored mechanisms and pathways leading to colorectal cancer, initiatives have been shifted to further study the role of inflammation in pathogenesis. Inflammatory pathways have also been linked to some traditional risk factors of colorectal cancer such as obesity, smoking and diabetes, as well as more novel associations such as the gut microbiome, the gut mycobiome and exosomes. In this review, we will explore the roles of obesity and diet, smoking, diabetes, the microbiome, the mycobiome and exosomes in colorectal cancer, with a specific focus on the underlying inflammatory and metabolic pathways involved. We will also investigate how the study of colon cancer from an inflammatory background not only creates a more holistic and inclusive understanding of this disease, but also creates unique opportunities for prevention, early diagnosis and therapy