Enteroendocrine Cell Regulation of the Gut-Brain Axis

Enteroendocrine cells (EECs) are an essential interface between the gut and brain that communicate signals about nutrients, pain, and even information from our microbiome. EECs are hormone-producing cells expressed throughout the gastrointestinal epithelium and have been leveraged by pharmaceuticals like semaglutide (Ozempic, Wegovy), terzepatide (Mounjaro), and retatrutide (Phase 2) for diabetes and weight control, and linaclotide (Linzess) to treat irritable bowel syndrome (IBS) and visceral pain. This review focuses on role of intestinal EECs to communicate signals from the gut lumen to the brain. Canonically, EECs communicate information about the intestinal environment through a variety of hormones, dividing EECs into separate classes based on the hormone each cell type secretes. Recent studies have revealed more diverse hormone profiles and communication modalities for EECs including direct synaptic communication with peripheral neurons. EECs known as neuropod cells rapidly relay signals from gut to brain via a direct communication with vagal and primary sensory neurons. Further, this review discusses the complex information processing machinery within EECs, including receptors that transduce intraluminal signals and the ion channel complement that govern initiation and propagation of these signals. Deeper understanding of EEC physiology is necessary to safely treat devastating and pervasive conditions like irritable bowel syndrome and obesity

Intestinal Neuropod Cell GUCY2C Regulates Visceral Pain

Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting number of evoked action potentials. Conversely, the GUCY2C agonist linaclotide eliminated neuronal hyperexcitability produced by GUCY2C-sufficient - but not GUCY2C-deficient - neuropod cells, an effect independent of bulk epithelial cells or extracellular cGMP. Genetic elimination of intestinal GUCY2C amplified nociceptive signaling in VP that was comparable with chemically induced VP but refractory to linaclotide. Importantly, eliminating GUCY2C selectively in neuropod cells also increased nociceptive signaling and VP that was refractory to linaclotide. In the context of loss of GUCY2C hormones in patients with VP, these observations suggest a specific role for neuropod GUCY2C signaling in the pathophysiology and treatment of these pain syndromes

Fluctuating temperature modifies heat-mortality association around the globe

Studies have investigated the effects of heat and temperature variability (TV) on mortality. However, few assessed whether TV modifies the heat-mortality association. Data on daily temperature and mortality in the warm season were collected from 717 locations across 36 countries. TV was calculated as the standard deviation of the average of the same and previous days’ minimum and maximum temperatures. We used location-specific quasi-Poisson regression models with an interaction term between the cross-basis term for mean temperature and quartiles of TV to obtain heat-mortality associations under each quartile of TV, and then pooled estimates at the country, regional, and global levels. Results show the increased risk in heat-related mortality with increments in TV, accounting for 0.70% (95% confidence interval [CI]: −0.33 to 1.69), 1.34% (95% CI: −0.14 to 2.73), 1.99% (95% CI: 0.29–3.57), and 2.73% (95% CI: 0.76–4.50) of total deaths for Q1–Q4 (first quartile–fourth quartile) of TV. The modification effects of TV varied geographically. Central Europe had the highest attributable fractions (AFs), corresponding to 7.68% (95% CI: 5.25–9.89) of total deaths for Q4 of TV, while the lowest AFs were observed in North America, with the values for Q4 of 1.74% (95% CI: −0.09 to 3.39). TV had a significant modification effect on the heat-mortality association, causing a higher heat-related mortality burden with increments of TV. Implementing targeted strategies against heat exposure and fluctuant temperatures simultaneously would benefit public health

a three-stage modelling study

Funding Information: This study was supported by the Australian Research Council (DP210102076) and the Australian National Health and Medical Research Council (APP2000581). YW was supported by the China Scholarship Council (number 202006010044). SL was supported by an Emerging Leader Fellowship of the Australian National Health and Medical Research Council (number APP2009866). QZ was supported by the Program of Qilu Young Scholars of Shandong University, Jinan, China. BW was supported by the China Scholarship Council (number 202006010043). JK and AU were supported by the Czech Science Foundation (project number 20–28560S). NS was supported by the National Institute of Environmental Health Sciences-funded HERCULES Center (P30ES019776). S-CP and YLG were supported by the Ministry of Science and Technology (Taiwan; MOST 109–2621-M-002–021). YH was supported by the Environment Research and Technology Development Fund (JPMEERF15S11412) of the Environmental Restoration and Conservation Agency. MdSZSC and PHNS were supported by the São Paulo Research Foundation (FAPESP). ST was supported by the Science and Technology Commission of Shanghai Municipality (grant number 18411951600). HO and EI were supported by the Estonian Ministry of Education and Research (IUT34–17). JM was supported by a fellowship of Fundação para a Ciência e a Tecnlogia (SFRH/BPD/115112/2016). AG and FS were supported by the Medical Research Council UK (grant ID MR/R013349/1), the Natural Environment Research Council UK (grant ID NE/R009384/1), and the EU's Horizon 2020 project, Exhaustion (grant ID 820655). AS, SR, and FdD were supported by the EU's Horizon 2020 project, Exhaustion (grant ID 820655). VH was supported by the Spanish Ministry of Economy, Industry and Competitiveness (grant ID PCIN-2017–046). AT was supported by MCIN/AEI/10.13039/501100011033 (grant CEX2018-000794-S). YG was supported by the Career Development Fellowship (number APP1163693) and Leader Fellowship (number APP2008813) of the Australian National Health and Medical Research Council. Statistics South Africa kindly provided the mortality data, but had no other role in the study. This Article is published in memory of Simona Fratianni, who helped to contribute the data for Romania. Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Increased mortality risk is associated with short-term temperature variability. However, to our knowledge, there has been no comprehensive assessment of the temperature variability-related mortality burden worldwide. In this study, using data from the MCC Collaborative Research Network, we first explored the association between temperature variability and mortality across 43 countries or regions. Then, to provide a more comprehensive picture of the global burden of mortality associated with temperature variability, global gridded temperature data with a resolution of 0·5° × 0·5° were used to assess the temperature variability-related mortality burden at the global, regional, and national levels. Furthermore, temporal trends in temperature variability-related mortality burden were also explored from 2000–19. Methods: In this modelling study, we applied a three-stage meta-analytical approach to assess the global temperature variability-related mortality burden at a spatial resolution of 0·5° × 0·5° from 2000–19. Temperature variability was calculated as the SD of the average of the same and previous days’ minimum and maximum temperatures. We first obtained location-specific temperature variability related-mortality associations based on a daily time series of 750 locations from the Multi-country Multi-city Collaborative Research Network. We subsequently constructed a multivariable meta-regression model with five predictors to estimate grid-specific temperature variability related-mortality associations across the globe. Finally, percentage excess in mortality and excess mortality rate were calculated to quantify the temperature variability-related mortality burden and to further explore its temporal trend over two decades. Findings: An increasing trend in temperature variability was identified at the global level from 2000 to 2019. Globally, 1 753 392 deaths (95% CI 1 159 901–2 357 718) were associated with temperature variability per year, accounting for 3·4% (2·2–4·6) of all deaths. Most of Asia, Australia, and New Zealand were observed to have a higher percentage excess in mortality than the global mean. Globally, the percentage excess in mortality increased by about 4·6% (3·7–5·3) per decade. The largest increase occurred in Australia and New Zealand (7·3%, 95% CI 4·3–10·4), followed by Europe (4·4%, 2·2–5·6) and Africa (3·3, 1·9–4·6). Interpretation: Globally, a substantial mortality burden was associated with temperature variability, showing geographical heterogeneity and a slightly increasing temporal trend. Our findings could assist in raising public awareness and improving the understanding of the health impacts of temperature variability. Funding: Australian Research Council, Australian National Health & Medical Research Council.publishersversionpublishe

Seasonality of mortality under climate change: a multicountry projection study

A warming climate can substantially change the seasonality of mortality in the future. Our projections suggest that health-care systems should consider preparing for a potentially increased demand during warm seasons and sustained high demand during cold seasons, particularly in regions characterised by arid, temperate, and continental climates

Global, regional, and national burden of mortality associated with non-optimal ambient temperatures from 2000 to 2019: a three-stage modelling study.

BACKGROUND: Exposure to cold or hot temperatures is associated with premature deaths. We aimed to evaluate the global, regional, and national mortality burden associated with non-optimal ambient temperatures. METHODS: In this modelling study, we collected time-series data on mortality and ambient temperatures from 750 locations in 43 countries and five meta-predictors at a grid size of 0·5° × 0·5° across the globe. A three-stage analysis strategy was used. First, the temperature-mortality association was fitted for each location by use of a time-series regression. Second, a multivariate meta-regression model was built between location-specific estimates and meta-predictors. Finally, the grid-specific temperature-mortality association between 2000 and 2019 was predicted by use of the fitted meta-regression and the grid-specific meta-predictors. Excess deaths due to non-optimal temperatures, the ratio between annual excess deaths and all deaths of a year (the excess death ratio), and the death rate per 100 000 residents were then calculated for each grid across the world. Grids were divided according to regional groupings of the UN Statistics Division. FINDINGS: Globally, 5 083 173 deaths (95% empirical CI [eCI] 4 087 967-5 965 520) were associated with non-optimal temperatures per year, accounting for 9·43% (95% eCI 7·58-11·07) of all deaths (8·52% [6·19-10·47] were cold-related and 0·91% [0·56-1·36] were heat-related). There were 74 temperature-related excess deaths per 100 000 residents (95% eCI 60-87). The mortality burden varied geographically. Of all excess deaths, 2 617 322 (51·49%) occurred in Asia. Eastern Europe had the highest heat-related excess death rate and Sub-Saharan Africa had the highest cold-related excess death rate. From 2000-03 to 2016-19, the global cold-related excess death ratio changed by -0·51 percentage points (95% eCI -0·61 to -0·42) and the global heat-related excess death ratio increased by 0·21 percentage points (0·13-0·31), leading to a net reduction in the overall ratio. The largest decline in overall excess death ratio occurred in South-eastern Asia, whereas excess death ratio fluctuated in Southern Asia and Europe. INTERPRETATION: Non-optimal temperatures are associated with a substantial mortality burden, which varies spatiotemporally. Our findings will benefit international, national, and local communities in developing preparedness and prevention strategies to reduce weather-related impacts immediately and under climate change scenarios. FUNDING: Australian Research Council and the Australian National Health and Medical Research Council

Global, regional, and national burden of mortality associated with short-term temperature variability from 2000-19: a three-stage modelling study.

BACKGROUND: Increased mortality risk is associated with short-term temperature variability. However, to our knowledge, there has been no comprehensive assessment of the temperature variability-related mortality burden worldwide. In this study, using data from the MCC Collaborative Research Network, we first explored the association between temperature variability and mortality across 43 countries or regions. Then, to provide a more comprehensive picture of the global burden of mortality associated with temperature variability, global gridded temperature data with a resolution of 0·5° × 0·5° were used to assess the temperature variability-related mortality burden at the global, regional, and national levels. Furthermore, temporal trends in temperature variability-related mortality burden were also explored from 2000-19. METHODS: In this modelling study, we applied a three-stage meta-analytical approach to assess the global temperature variability-related mortality burden at a spatial resolution of 0·5° × 0·5° from 2000-19. Temperature variability was calculated as the SD of the average of the same and previous days' minimum and maximum temperatures. We first obtained location-specific temperature variability related-mortality associations based on a daily time series of 750 locations from the Multi-country Multi-city Collaborative Research Network. We subsequently constructed a multivariable meta-regression model with five predictors to estimate grid-specific temperature variability related-mortality associations across the globe. Finally, percentage excess in mortality and excess mortality rate were calculated to quantify the temperature variability-related mortality burden and to further explore its temporal trend over two decades. FINDINGS: An increasing trend in temperature variability was identified at the global level from 2000 to 2019. Globally, 1 753 392 deaths (95% CI 1 159 901-2 357 718) were associated with temperature variability per year, accounting for 3·4% (2·2-4·6) of all deaths. Most of Asia, Australia, and New Zealand were observed to have a higher percentage excess in mortality than the global mean. Globally, the percentage excess in mortality increased by about 4·6% (3·7-5·3) per decade. The largest increase occurred in Australia and New Zealand (7·3%, 95% CI 4·3-10·4), followed by Europe (4·4%, 2·2-5·6) and Africa (3·3, 1·9-4·6). INTERPRETATION: Globally, a substantial mortality burden was associated with temperature variability, showing geographical heterogeneity and a slightly increasing temporal trend. Our findings could assist in raising public awareness and improving the understanding of the health impacts of temperature variability. FUNDING: Australian Research Council, Australian National Health & Medical Research Council

Geographical Variations of the Minimum Mortality Temperature at a Global Scale

Background: Minimum mortality temperature (MMT) is an important indicator to assess the temperature-mortality association, indicating long-term adaptation to local climate. Limited evidence about the geographical variability of the MMT is available at a global scale.Methods: We collected data from 658 communities in 43 countries under different climates. We estimated temperature-mortality associations to derive the MMT for each community using Poisson regression with distributed lag nonlinear models. We investigated the variation in MMT by climatic zone using a mixed-effects meta-analysis and explored the association with climatic and socioeconomic indicators.Results: The geographical distribution of MMTs varied considerably by country between 14.2 and 31.1 °C decreasing by latitude. For climatic zones, the MMTs increased from alpine (13.0 °C) to continental (19.3 °C), temperate (21.7 °C), arid (24.5 °C), and tropical (26.5 °C). The MMT percentiles (MMTPs) corresponding to the MMTs decreased from temperate (79.5th) to continental (75.4th), arid (68.0th), tropical (58.5th), and alpine (41.4th). The MMTs indreased by 0.8 °C for a 1 °C rise in a community’s annual mean temperature, and by 1 °C for a 1 °C rise in its SD. While the MMTP decreased by 0.3 centile points for a 1 °C rise in a community’s annual mean temperature and by 1.3 for a 1 °C rise in its SD.Conclusions: The geographical distribution of the MMTs and MMTPs is driven mainly by the mean annual temperature, which seems to be a valuable indicator of overall adaptation across populations. Our results suggest that populations have adapted to the average temperature, although there is still more room for adaptation

Mortality risk attributable to wildfire-related PM2·5 pollution : a global time series study in 749 locations

BACKGROUND : Many regions of the world are now facing more frequent and unprecedentedly large wildfires. However, the association between wildfire-related PM2·5 and mortality has not been well characterised. We aimed to comprehensively assess the association between short-term exposure to wildfire-related PM2·5 and mortality across various regions of the world. METHODS : For this time series study, data on daily counts of deaths for all causes, cardiovascular causes, and respiratory causes were collected from 749 cities in 43 countries and regions during 2000–16. Daily concentrations of wildfire-related PM2·5 were estimated using the three-dimensional chemical transport model GEOS-Chem at a 0·25° × 0·25° resolution. The association between wildfire-related PM2·5 exposure and mortality was examined using a quasi-Poisson time series model in each city considering both the current-day and lag effects, and the effect estimates were then pooled using a random-effects meta-analysis. Based on these pooled effect estimates, the population attributable fraction and relative risk (RR) of annual mortality due to acute wildfire-related PM2·5 exposure was calculated. FINDINGS : 65·6 million all-cause deaths, 15·1 million cardiovascular deaths, and 6·8 million respiratory deaths were included in our analyses. The pooled RRs of mortality associated with each 10 μg/m³ increase in the 3-day moving average (lag 0–2 days) of wildfire-related PM2·5 exposure were 1·019 (95% CI 1·016–1·022) for all-cause mortality, 1·017 (1·012–1·021) for cardiovascular mortality, and 1·019 (1·013–1·025) for respiratory mortality. Overall, 0·62% (95% CI 0·48–0·75) of all-cause deaths, 0·55% (0·43–0·67) of cardiovascular deaths, and 0·64% (0·50–0·78) of respiratory deaths were annually attributable to the acute impacts of wildfire-related PM2·5 exposure during the study period. INTERPRETATION : Short-term exposure to wildfire-related PM2·5 was associated with increased risk of mortality. Urgent action is needed to reduce health risks from the increasing wildfires.The Australian Research Council, the Australian National Health and Medical Research Council, a Career Development Fellowship of the Australian National Health and Medical Research Council, an Early Career Fellowship of the Australian National Health and Medical Research Council, the National Natural Science Foundation of China, the Czech Science Foundation, the Spanish Ministry of Economy, Industry and Competitiveness, the National Key Research and Development Program of China, EU’s Horizon 2020 Project Exhaustion, the Ministry of Science and Technology of Taiwan, the Medical Research Council UK, the Natural Environment Research Council UK, a fellowship of the Fundação para a Ciência e a Tecnologia, the Science and Technology Commission of Shanghai Municipality and the National Institute of Environmental Health Sciences-funded HERCULES Center.http://www.thelancet.com/planetary-healtham2022Geography, Geoinformatics and Meteorolog

Guanylyl cyclase C as a Diagnostic and Therapeutic Target in Colorectal Cancer

Colorectal cancer remains a major cause of mortality in the USA, despite advances in prevention and screening. Existing therapies focus primarily on generic treatment such as surgical intervention and chemotherapy, depending on disease severity. As personalized medicine and targeted molecular oncology continue to develop as promising treatment avenues, there has emerged a need for effective targets and biomarkers of colorectal cancer. The transmembrane receptor guanylyl cyclase C (GUCY2C) regulates intestinal homeostasis and has emerged as a tumor suppressor. Further, it is universally expressed in advanced metastatic colorectal tumors, as well as other cancer types that arise through intestinal metaplasia. In this context, GUCY2C satisfies many characteristics of a compelling target and biomarker for gastrointestinal malignancies