Alzheimer’s disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.
Both obesity and sarcopenia are frequently associated in ageing, and together may promote the progression of related conditions such as diabetes and frailty. However, little is known about the pathophysiological mechanisms underpinning this association. Here we show that systemic alanine metabolism is linked to glycaemic control. We find that expression of alanine aminotransferases is increased in the liver in mice with obesity and diabetes, as well as in humans with type 2 diabetes. Hepatocyte-selective silencing of both alanine aminotransferase enzymes in mice with obesity and diabetes retards hyperglycaemia and reverses skeletal muscle atrophy through restoration of skeletal muscle protein synthesis. Mechanistically, liver alanine catabolism driven by chronic glucocorticoid and glucagon signalling promotes hyperglycaemia and skeletal muscle wasting. We further provide evidence for amino acid–induced metabolic cross-talk between the liver and skeletal muscle in ex vivo experiments. Taken together, we reveal a metabolic inter-tissue cross-talk that links skeletal muscle atrophy and hyperglycaemia in type 2 diabetes.
γδ T cells link immunity to nutrition Gamma delta (γδ) T cells are immune cells best known for host barrier defenses in epithelial tissues. Sullivan et al. discovered a previously unrecognized role for γδ T cells in sensing nutrient uptake in the small intestine (see the Perspective by Talbot and Littman). The researchers analyzed mice fed a high-carbohydrate versus a high-protein diet and observed remodeling of the small intestinal epithelium in response to dietary carbohydrates. Nutrient availability triggered an epithelial–immune cell circuit that was required for digestion and absorption of carbohydrates. Intestinal γδ T cells regulated the expression of a carbohydrate transcriptional program by limiting interleukin-22 production from type 3 innate lymphoid cells. These findings may also provide insights into how γδ T cells modulate metabolic disease. Structured Abstract INTRODUCTION The gastrointestinal (GI) tract is a multikingdom cellular ecosystem that facilitates the procurement of nutrients from the environment. In constant contact with the external world, the small intestine is at once a gateway for life-threatening pathogens and toxins and the site of absorption for life-sustaining nutrients. Consequently, this tissue is tasked with the challenge of balancing its primary functions of nutrient uptake and host defense in response to a complex and constantly changing environment.This challenge is particularly daunting for omnivores, whose diets change on daily, seasonal, and developmental time scales. The diverse diets of such generalists stand in contrast to those of specialists—animals that consume restricted diets—such as carnivores and herbivores. Whereas these specialists have evolved fixed morphologic adaptations in the organization of the GI tract that facilitate efficient nutrient uptake from their restricted diets, generalists must constantly adapt to the shifting availability of food sources of diverse nutrient composition encountered throughout life. These ongoing changes in diet exist alongside encounters with ingested toxins, enteric pathogens, and commensal microbes. Omnivorous lifestyles therefore require that the GI tracts of such animals dynamically adapt to the changes in availability of different nutrients. We examined the molecular and cellular mechanisms that regulate intestinal adaptation to diverse foods. RATIONALE We investigated how the enzymes and transporters involved in the digestion and absorption of macronutrients are regulated in response to diet. We designed special animal diets that differed only in the ratio of protein to carbohydrates and evaluated gene expression changes in the GI tract, as well as systemic metabolism, after feeding these diets to mice. Recent discoveries pertaining to intestinal defenses against parasitic and microbial pathogens have demonstrated that interactions between intestinal epithelial cells and lymphocytes—the largest population of lymphocytes in the body—coordinate tissue responses to enteric infection. Guided by these findings, we hypothesized that the regulation of nutrient-handling machinery may involve coordination between tissue-resident lymphocytes and intestinal epithelial cells. Furthermore, recent work investigating mechanisms of host defense in this tissue led us to hypothesize that cellular remodeling of the intestinal epithelium, which occurs in response to certain infections, may also underlie its adaptation to different nutrients. RESULTS A carbohydrate transcriptional program comprising enzymes and transporters that mediate the digestion and absorption of carbohydrates was induced on demand in small-intestine epithelial cells in response to carbohydrate availability. The induction of this transcriptional program was specifically due to the availability of carbohydrates and reflected functional changes in nutrient handling at the tissue and systemic levels. Mice fed a high-carbohydrate diet exhibited changes in the frequency of specialized enterocyte subsets. This indicated that functional specialization exists within the enterocyte compartment, which constitutes approximately 80% of the intestinal epithelium. This also suggested that the induction of the carbohydrate transcriptional program involved cellular remodeling of the intestinal epithelium. The induction of this program and corresponding epithelial remodeling occurred rapidly, after only 5 days of high-carbohydrate feeding. Unexpectedly, the on-demand induction of this program required γδ T cells, a population of lymphocytes enriched at barrier surfaces whose biology remains poorly understood. Intestinal γδ T cells were altered by diet, with changes observed in their transcriptome, tissue localization, and behavior. The diet-dependent regulation of this program by γδ T cells involved suppression of a negative regulator, interleukin-22 (IL-22). Thus, we defined an epithelial-lymphocyte circuit that regulates the intestinal response to nutrient sensing and facilitates the adaptation to diverse diets. CONCLUSION Our work demonstrates a role for intestinal lymphocytes in regulating the tissue response to dietary nutrients. Together with other studies in the realm of host-pathogen interactions, our results indicate that lymphocyte-epithelial circuits and epithelial remodeling represent general features of how the intestine adapts to environmental change. By linking nutrition and barrier function at both the cellular and molecular levels, these adaptations allow this complex tissue to adjust the balance between nutrient uptake and host defense in response to environmental change.
Authors: Merel C. Postema, Amaia Carrion-Castillo, Simon E. Fisher, Guy Vingerhoets, Clyde Francks
Date Added: Apr 21, 2021
Authors: Merel C. Postema, Amaia Carrion-Castillo, Simon E. Fisher, Guy Vingerhoets, Clyde Francks
Situs inversus (SI), a left-right mirror reversal of the visceral organs, can occur with recessive Primary Ciliary Dyskinesia (PCD). However, most people with SI do not have PCD, and the etiology of their condition remains poorly studied. We sequenced the genomes of 15 people with SI, of which six had PCD, as well as 15 controls. Subjects with non-PCD SI in this sample had an elevated rate of left-handedness (five out of nine), which suggested possible developmental mechanisms linking brain and body laterality. The six SI subjects with PCD all had likely recessive mutations in genes already known to cause PCD. Two non-PCD SI cases also had recessive mutations in known PCD genes, suggesting reduced penetrance for PCD in some SI cases. One non-PCD SI case had recessive mutations in PKD1L1, and another in CFAP52 (also known as WDR16). Both of these genes have previously been linked to SI without PCD. However, five of the nine non-PCD SI cases, including three of the left-handers in this dataset, had no obvious monogenic basis for their condition. Environmental influences, or possible random effects in early development, must be considered.
The Diversion Alert Program (DAP) was developed to combat illicit drug use and prescription drug diversion by facilitating communication between law enforcement and healthcare providers with the goal of limiting drug-related harms and criminal behaviors. Our objectives in this report were to analyze 2014-2017 DAP for: 1) trends in drug arrests and, 2) differences in arrests by offense, demographics (sex and age) and by region.
Background & study aimsCorona virus disease-19 (COVID-19) pandemic has markedly impacted routine medical services including gastrointestinal (GI) endoscopy. We aim to report the real-life performance in high volume GI endoscopy units during the pandemic.Patients and methodsA web-based survey covering all aspects of daily performance in GI endoscopy units was sent to endoscopy units worldwide. Responses were collected and data were analyzed to reveal the effect of COVID-19 pandemic on endoscopy practice.ResultsParticipants from 48 countries (n = 163) responded to the survey with response rate of 67.35%. The majority (85%) decreased procedure volume by over 50%, and four endoscopy units (2.45%) completely stopped. The top three indications for procedures included upper GI bleeding (89.6%), lower GI bleeding (65.6%) and cholangitis (62.6%). The majority (93.9%) triaged patients for COVID-19 prior to procedure. N95 masks were used in (57.1%), isolation gowns in (74.2%) and head covers in (78.5%). Most centers (65%) did not extend use of N95 masks, however 50.9% of centers reused N95 masks. Almost all (91.4%) centers used standard endoscopic decontamination and most (69%) had no negative pressure rooms. Forty-two centers (25.8%) reported positive cases of SARS-CoV-2 infection among patients and 50 (30.7%) centers reported positive cases of SARS-CoV-2 infection among their healthcare workers.ConclusionsMost GI endoscopy centers had a significant reduction in their volume and most procedures performed were urgent. Most centers used the recommended personal protective equipment (PPE) by GI societies however there is still a possibility of transmission of SARS-CoV-2 infection in GI endoscopy units.