Genital Dysbiosis and Different Systemic Immune Responses Based on the Trimester of Pregnancy in SARS-CoV-2 Infection

Respiratory infections are common in pregnancy with conflicting evidence supporting their association with neonatal congenital anomalies, especially during the first trimester. We profiled cytokine and chemokine systemic responses in 242 pregnant women and their newborns after SARS-CoV-2 infection, acquired in different trimesters. Also, we tested transplacental IgG passage and maternal vaginal–rectal microbiomes. IgG transplacental passage was evident, especially with infection acquired in the first trimester. G-CSF concentration—involved in immune cell recruitment—decreased in infected women compared to uninfected ones: a beneficial event for the reduction of inflammation but detrimental to ability to fight infections at birth. The later the infection was acquired, the higher the systemic concentration of IL-8, IP-10, and MCP-1, associated with COVID-19 disease severity. All infected women showed dysbiosis of vaginal and rectal microbiomes, compared to uninfected ones. Two newborns tested positive for SARS-CoV-2 within the first 48 h of life. Notably, their mothers had acute infection at delivery. Although respiratory infections in pregnancy are reported to affect babies’ health, with SARS-CoV-2 acquired early during gestation this risk seems low because of the maternal immune response. The observed vaginal and rectal dysbiosis could be relevant for neonatal microbiome establishment, although in our series immediate neonatal outcomes were reassuring

Italian Children Exposure to Bisphenol A: Biomonitoring Data from the LIFE PERSUADED Project

A human biomonitoring (HBM) study on bisphenol A (BPA) in Italian children and adolescents was performed within the LIFE PERSUADED project, considering the residing areas, sex and age. The median urinary BPA level was 7.02 mu g/L, with children living in the South of Italy or in urban areas having higher levels than those residing in the North or in rural areas. Children aged 4-6 years had higher BPA levels than those aged 7-10 and 11-14 years, but no differences were detected between sexes. The exposure in Italian children was higher compared to children from other countries, but lower than the HBM guidance value (135 mu g/L). The estimated daily intake was 0.17 mu g/kg body weight (bw) per day, about 24-fold below the temporary Tolerable Daily Intake of 4 mu g/kg bw per day established by the European Food Safety Authority. However, this threshold was exceeded in 1.44% of the enrolled children, raising concern about the overall exposure of Italian young population

Metabolic dysfunction-associated steatotic liver disease (MASLD): insights on pathophysiological mechanisms through metabolomics and fluxomics

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is now estimated that be from 38% of the general population to 70% in subjects with obesity or diabetes. MASLD pathophysiology is associated to diet rich in saturated lipids, sucrose that stimulates de novo lipogenesis (DNL) and accumulation of lipotoxic compounds that can impair cellular metabolism and induces mitochondrial dysfunction. However, if DNL is a major driver of MASLD and a possible target for pharmacological intervention has not yet been clarified. Moreover, whether Western diet impacts mitochondrial function through accumulation of lipotoxic species has been poorly investigated. The goal of my thesis was to study the changes in hepatic lipid metabolism (DNL and lipid profile) induced by MASLD focusing on the de novo synthesis of triglycerides and ceramides measured in vivo using a novel fluxomic method based on deuterium incorporation in newly synthesized lipids after administration water labelled with deuterium. Two animal model of MASLD were studied: mice fed high fat high sucrose (HFHS) diet and methionine choline-deficient (MCD) diet. Both HFHS and MCD diets were associated with hepatic accumulation of lipotoxic species like ceramides, which were more pronounced in MCD. Plasma lipid concentrations were instead increased in mice fed HFHS and decreased in MCD. Both HFHS and MCD induced a change in mitochondrial lipidomic profile with increased phospholipid content, but hepatic mitochondrial function was unaltered, even in presence of hepatic inflammation, indicating that it is not the cause of hepatic fat accumulation and neither of progression of liver disease Among lipids, ceramides are among the ones mostly associated with MASLD as mediators of insulin resistance, thus potentially linked to hepatic steatosis and MASLD progression. Ceramide synthesis and its relationship with DNL and triglyceride (TG) synthesis were studied. Incorporation of fatty acids synthesized by DNL, as palmitate, into hepatic ceramides was increased in HFHS compared to control diets. On the other hand, incorporation of DNL fatty acids in TGs was reduced in HFHS compared to control diets. The effect of weight loss by switching from HFHS diet to a control diet, CC and/or intermittent fasting (IF) was investigated. For this purpose, mice fed with HFHS diet ad libitum were compared with mice that underwent IF without changes diet, switched to CC diet with or without IF, 4 groups. Changes in weight and metabolites/lipids synthesis and concentrations were achieved more in CC+IF group, followed by CC and HFHS+IF group, indicating the importance of diet composition to restore liver metabolism, where caloric restriction is associated with low-fat intake. In conclusion, the results of my thesis have shown that hepatic steatosis, driven by HFHS or MCD diet, does not impair mitochondrial function, although it is associated with lipid remodeling, and is not excluded that in the long run this lipotoxic compounds can cause mitochondrial dysfunction. Although HFHS diet is associated with lower incorporation of newly synthesized (DNL) fatty acids into hepatic triglycerides, I have shown that DNL drives ceramide synthesis, inducing lipotoxicity. Finally, I have shown that not only caloric restriction (by IF), but also diet composition and low-fat intake are important to restore liver metabolism

Valutazione del metabolismo glucidico e lipidico postprandiale in soggetti con steatosi epatica non alcolica (NAFLD)

Lo studio del metabolismo ha assunto negli ultimi anni un'importanza sempre maggiore, in quanto le sue alterazioni sono un fattore di rischio per lo sviluppo di malattie cardiometaboliche sempre più in aumento nella popolazione industrializzata. Uno dei fattori di rischio per lo sviluppo di queste malattie è la steatosi epatica non alcolica (NAFLD) che include un ampio spettro di condizioni che vanno dalla semplice steatosi epatica alla steatoepatite non alcolica (NASH) con presenza o meno di cirrosi. Lo scopo della tesi è quello di valutare il metabolismo del glucosio e del glicerolo in soggetti con NAFLD, dalla misura dell’arricchimento di traccianti marcati con isotopi stabili, infusi per via endovenosa in campioni plasmatici. Per fare questo tipo di analisi è stata utilizzata la gascromatografia spettrometria di massa (GC-MS), che permette di quantificare e discriminare composti marcati e non marcati isotopicamente, in quanto possiedono un diverso peso molecolare. Il protocollo sperimentale consiste nell’infusione per via endovenosa di 6,6-2H-glucosio e D5-glicerolo durante una fase di digiuno (circa 2 ore in cui il tracciante si equilibra nel pool plasmatico) seguito da un pasto lipidico durante il quale vengono prelevati dei campioni di sangue ogni 30 minuti per 4 ore. Sono stati studiati 15 soggetti con NAFLD e 5 soggetti di controllo. Il tracciante di glucosio permette di valutare la produzione epatica di glucosio mentre il tracciante di glicerolo consente la valutazione della lipolisi

Assessment of Exposure to Di-(2-ethylhexyl) Phthalate (DEHP) Metabolites and Bisphenol A (BPA) and Its Importance for the Prevention of Cardiometabolic Diseases

Exposomics analyses have highlighted the importance of biomonitoring of human exposure to pollutants, even non-persistent, for the prevention of non-communicable diseases such as obesity, diabetes, non-alcoholic fatty liver disease, atherosclerosis, and cardiovascular diseases. Phthalates and bisphenol A (BPA) are endocrine disrupting chemicals (EDCs) widely used in industry and in a large range of daily life products that increase the risk of endocrine and cardiometabolic diseases especially if the exposure starts during childhood. Thus, biomonitoring of exposure to these compounds is important not only in adulthood but also in childhood. This was the goal of the LIFE-PERSUADED project that measured the exposure to phthalates (DEHP metabolites, MEHP, MEHHP, MEOHP) and BPA in Italian mother–children couples of different ages. In this paper we describe the method that was set up for the LIFE PERSUADED project and validated during the proficiency test (ICI/EQUAS) showing that accurate determination of urinary phthalates and BPA can be achieved starting from small sample size (0.5 mL) using two MS techniques applied in cascade on the same deconjugated matrix

The color of fat and its central role in the development and progression of metabolic diseases

Excess caloric intake does not always translate to an expansion of the subcutaneous adipose tissue (SAT) and increase in fat mass. It is now recognized that adipocyte type (white, WAT, or brown, BAT), size (large vs. small) and metabolism are important factors for the development of cardiometabolic diseases. When the subcutaneous adipose tissue is not able to expand in response to increased energy intake the excess substrate is stored as visceral adipose tissue or as ectopic fat in tissues as muscle, liver and pancreas. Moreover, adipocytes become dysfunctional (adiposopathy, or sick fat), adipokines secretion is increased, fat accumulates in ectopic sites like muscle and liver and alters insulin signaling, increasing the demand for insulin secretion. Thus, there are some subjects that despite having normal weight have the metabolic characteristics of the obese (NWMO), while some obese expand their SAT and remain metabolically healthy (MHO). In this paper we have reviewed the recent findings that relate the metabolism of adipose tissue and its composition to metabolic diseases. In particular, we have discussed the possible role of dysfunctional adipocytes and adipose tissue resistance to the antilipolytic effect of insulin on the development of impaired glucose metabolism. Finally we have reviewed the possible role of BAT vs. WAT in the alteration of lipid and glucose metabolism and the recent studies that have tried to stimulate browning in human adipose tissue

The Subtle Balance between Lipolysis and Lipogenesis: A Critical Point in Metabolic Homeostasis

Excessive accumulation of lipids can lead to lipotoxicity, cell dysfunction and alteration in metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas and muscle. This is now a recognized risk factor for the development of metabolic disorders, such as obesity, diabetes, fatty liver disease (NAFLD), cardiovascular diseases (CVD) and hepatocellular carcinoma (HCC). The causes for lipotoxicity are not only a high fat diet but also excessive lipolysis, adipogenesis and adipose tissue insulin resistance. The aims of this review are to investigate the subtle balances that underlie lipolytic, lipogenic and oxidative pathways, to evaluate critical points and the complexities of these processes and to better understand which are the metabolic derangements resulting from their imbalance, such as type 2 diabetes and non alcoholic fatty liver disease