Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease

Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1(-/-) and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a proinflammatory phenotype and the release of cytokines such as TNF-alpha Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.Peer reviewe

Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk

Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI 2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining https://researchonline.ljmu.ac.uk/images/research_banner_face_lab_290.jpgunderweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesity

Interactions between diet, gut microbiota and metabolic diseases : focus on protein consumption

La physiopathologie du diabète de type 2 (DT2) est complexe et multifactorielle. La consommation de protéines d’origine animale associée à la survenue du DT2. Ce lien pourrait s’expliquer par la production par le microbiote intestinal de métabolites délétères issus de la dégradation des protéines dont l’Imidazole Propionate (ImP). Des études récentes ont montré que les personnes avec un DT2 ont un microbiote intestinal altéré, avec notamment une diminution de la diversité microbienne. Notre hypothèse est que chez les personnes avec une microbiote intestinal altéré, une consommation de protéines peut avoir un effet délétère sur le métabolisme via la fabrication de ces métabolites. Grâce à une collaboration, à partir d’une étude transversale multicentrique et multi-ethnique, et des données d’une étude d’intervention diététique chez des patients avec un syndrome métabolique nous avons confirmé l’absence d’effet majeur de la consommation de protéine sur l’alfa et la beta diversité du microbiote intestinal. Nous avons observé toutefois une modification de l’abondance de certaines espèces et un enrichissement des fonctions de synthèse et dégradation des acides aminés. Nous avons, grâce à l’analyse de la cohorte Metacardis, confirmé l’association entre l’ImP, le statut diabétique et la dysbiose du microbiote intestinal. Enfin, nous avons mené l’étude Microdiet, essai randomisé, auprès de patients avec un DT2 avec un régime enrichi vs. appauvri en protéines. Il n’y avait pas d’effet sur la concentration d’ImP. Nous n’avons pas observé d’effet différent sur le métabolisme glucidique de l’enrichissement en protéines en fonction de la richesse initiale du microbiote.The pathophysiology of type 2 diabetes (T2D) is complex and multifactorial. Animal protein consumption is associated with the onset of T2D. This link could be explained by the production by the gut microbiota of deleterious metabolites resulting from the degradation of proteins, including Imidazole Propionate (ImP). Recent studies have shown that people with T2D have an altered gut microbiota, including a decrease in microbial diversity. Our hypothesis is that in people with an altered gut microbiota, protein consumption can have a deleterious effect on the metabolism through the production of these metabolites. Thanks to a collaboration, from a multicentric and multi-ethnic cross-sectional study, and data from a dietary intervention study in patients with metabolic syndrome we confirmed the absence of major effect of protein consumption on alfa and beta diversity of the gut microbiota. However, we have observed a change in the abundance of certain species and an enrichment in the functions of amino acid synthesis and degradation. We have, through analysis of the Metacardis cohort, confirmed the association between ImP, diabetic status and dysbiosis of the gut microbiota. Finally, we conducted the Microdiet study, a randomized trial, in patients with T2D on an enriched diet vs. depleted in protein. There was no effect on the concentration of ImP. We did not observe a different effect on glucose metabolism from protein enrichment depending on the initial richness of the microbiota

Interactions entre alimentation, microbiote intestinal et les maladies métaboliques : focus sur la consommation de protéines

The pathophysiology of type 2 diabetes (T2D) is complex and multifactorial. Animal protein consumption is associated with the onset of T2D. This link could be explained by the production by the gut microbiota of deleterious metabolites resulting from the degradation of proteins, including Imidazole Propionate (ImP). Recent studies have shown that people with T2D have an altered gut microbiota, including a decrease in microbial diversity. Our hypothesis is that in people with an altered gut microbiota, protein consumption can have a deleterious effect on the metabolism through the production of these metabolites. Thanks to a collaboration, from a multicentric and multi-ethnic cross-sectional study, and data from a dietary intervention study in patients with metabolic syndrome we confirmed the absence of major effect of protein consumption on alfa and beta diversity of the gut microbiota. However, we have observed a change in the abundance of certain species and an enrichment in the functions of amino acid synthesis and degradation. We have, through analysis of the Metacardis cohort, confirmed the association between ImP, diabetic status and dysbiosis of the gut microbiota. Finally, we conducted the Microdiet study, a randomized trial, in patients with T2D on an enriched diet vs. depleted in protein. There was no effect on the concentration of ImP. We did not observe a different effect on glucose metabolism from protein enrichment depending on the initial richness of the microbiota.La physiopathologie du diabète de type 2 (DT2) est complexe et multifactorielle. La consommation de protéines d’origine animale associée à la survenue du DT2. Ce lien pourrait s’expliquer par la production par le microbiote intestinal de métabolites délétères issus de la dégradation des protéines dont l’Imidazole Propionate (ImP). Des études récentes ont montré que les personnes avec un DT2 ont un microbiote intestinal altéré, avec notamment une diminution de la diversité microbienne. Notre hypothèse est que chez les personnes avec une microbiote intestinal altéré, une consommation de protéines peut avoir un effet délétère sur le métabolisme via la fabrication de ces métabolites. Grâce à une collaboration, à partir d’une étude transversale multicentrique et multi-ethnique, et des données d’une étude d’intervention diététique chez des patients avec un syndrome métabolique nous avons confirmé l’absence d’effet majeur de la consommation de protéine sur l’alfa et la beta diversité du microbiote intestinal. Nous avons observé toutefois une modification de l’abondance de certaines espèces et un enrichissement des fonctions de synthèse et dégradation des acides aminés. Nous avons, grâce à l’analyse de la cohorte Metacardis, confirmé l’association entre l’ImP, le statut diabétique et la dysbiose du microbiote intestinal. Enfin, nous avons mené l’étude Microdiet, essai randomisé, auprès de patients avec un DT2 avec un régime enrichi vs. appauvri en protéines. Il n’y avait pas d’effet sur la concentration d’ImP. Nous n’avons pas observé d’effet différent sur le métabolisme glucidique de l’enrichissement en protéines en fonction de la richesse initiale du microbiote

Maladie de Basedow, goitres multinodulaires et hyperthyroïdie infra-clinique

Subclinical hyperthyroidism is a common clinical entity, defined by serum TSH below the reference range, with normal FT4 and FT3 levels in an asymptomatic patient. Whether or not subclinical hyperthyroidism should be treated remains a matter of debate. Cross-sectional and longitudinal population-based studies demonstrate association of subclinical hyperthyroidism with risk of atrial fibrillation and osteoporosis, and with cardiovascular and all-cause mortality. However, there are no randomized clinical trials addressing whether long-term health outcomes are improved by treating subclinical hyperthyroidism; in the absence of evidence one way or the other, it seems appropriate to use decision trees taking account of TSH concentration and presence of risk factors (age > 65 years or post-menopause, osteoporosis and cardiac disease).SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Treatment options of subclinical hyperthyroidism and cardiovascular risk

Subclinical hyperthyroidism (SCH) is common and is characterized by laboratory findings of a persistently low TSH level and normal FT4 and FT3 values. The interpretation of studies on the clinical significance of SCH have been complicated by the fact that the degree and etiology of SCH varies, but research has suggested that it is associated with osteoporosis, weight changes, adverse cardiovascular effects including an increased risk of atrial fibrillation, and an increased all-cause mortality rate. We discuss SCH and review the literature on its suspected cardiovascular effects, which are more likely to be seen in the elderly and in patients with more significant degrees of TSH suppression. We then discuss SCH treatment options in detail and suggest an algorithm for the management of SCH that takes into consideration the TSH level and the presence of clinical risk factors.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Re: Body weight change is unpredictable after total thyroidectomy

SCOPUS: le.jinfo:eu-repo/semantics/publishe

Pancreatic enzyme replacement therapy in subjects with exocrine pancreatic insufficiency and diabetes mellitus: a real-life, case–control study

International audienceAbstract Background Exocrine pancreatic insufficiency (EPI) can be associated with all types of diabetes. Pancreatic enzyme replacement therapy (PERT) has short and long-term benefits in subjects with EPI, but its effects on diabetes control are uncertain. We aimed to study the effects of PERT initiation on glycemic control in subjects with diabetes and EPI from any cause. Methods In this retrospective study, we compared subjects with EPI and diabetes who were prescribed PERT with subjects with diabetes who had a fecal elastase-1 concentration dosage, but did not receive PERT. The primary outcome was the effect of PERT on hypoglycemia frequency and severity. The secondary outcomes were the effects of PERT on gastro-intestinal disorders, HbA 1c and body mass index (BMI). Results 48 subjects were included in each group. Overall, PERT did not have any significant effect on hypoglycemia frequency or severity, but hypoglycemia frequency tended to decrease in subjects with chronic pancreatitis. While 19% of subjects experienced mild hyperglycemia after PERT initiation, we did not report any keto-acidosis or any other severe adverse event. Gastro-intestinal disorders improved in 80% of subjects treated with PERT, versus in 20% of control subjects ( p = 0.02). Gastro-intestinal disorders improved in 87% of subjects with recommended dosage of PERT, versus in 50% of subjects with underdosage (NS). HbA 1c and BMI evolution did not differ between the groups. Conclusions PERT initiation is safe in subjects with diabetes and EPI. It does not globally decrease hypoglycemia severity of frequency, but is associated with a decrease in gastro-intestinal disorders. Trial registration Retrospectively registered. The database was registered with the Commission Nationale Informatique et Libertés (CNIL), registration number: 2203351v0. The study was approved by the local ethics committee CLEP, registration number: AAA-2023-0904