Environmental factors, such as chemical exposures, are likely to play a crucial role in the development of several human chronic diseases. However, how the specific exposures contribute to the onset ...and progress of various diseases is still poorly understood. In part, this is because comprehensive characterization of the chemical exposome is a highly challenging task, both due to its complex dynamic nature as well as due to the analytical challenges. Herein, the analytical challenges in the field of exposome research are reviewed, with specific emphasis on the sampling, sample preparation, and analysis, as well as challenges in the compound identification. The primary focus is on the human chemical exposome, that is, exposures to mixtures of environmental chemicals and its impact on human metabolome. In order to highlight the recent progress in the exposome research in relation to human health and disease, selected examples of human exposome studies are presented.
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and is often associated with aspects of metabolic syndrome. Despite its prevalence and the importance of ...early diagnosis, there is a lack of robustly validated biomarkers for diagnosis, prognosis and monitoring of disease progression in response to a given treatment. In this Review, we provide an overview of the contribution of metabolomics and lipidomics in clinical studies to identify biomarkers associated with NAFLD and nonalcoholic steatohepatitis (NASH). In addition, we highlight the key metabolic pathways in NAFLD and NASH that have been identified by metabolomics and lipidomics approaches and could potentially be used as biomarkers for non-invasive diagnostic tests. Overall, the studies demonstrated alterations in amino acid metabolism and several aspects of lipid metabolism including circulating fatty acids, triglycerides, phospholipids and bile acids. Although we report several studies that identified potential biomarkers, few have been validated.
Sample preparation before chromatographic separation is the most time-consuming and error-prone part of the analytical procedure. Therefore, selecting and optimizing an appropriate sample preparation ...scheme is a key factor in the final success of the analysis, and the judicious choice of an appropriate procedure greatly influences the reliability and accuracy of a given analysis. The main objective of this review is to critically evaluate the applicability, disadvantages, and advantages of various sample preparation techniques. Particular emphasis is placed on extraction techniques suitable for both liquid and solid samples. graphic removed
Lipidomics is increasingly being used in clinical research, offering new opportunities for disease prediction and detection. One of the key challenges of clinical applications of lipidomics is the ...high sensitivity of measured lipid levels to many analytical, physiological, and environmental factors, which therefore must be taken into account when designing the studies. Here we critically discuss the complete clinical lipidomics workflow, including selection of the subjects, the sample type, the sample preprocessing conditions, and the analytical method and methods for data processing. We also review the lipidomics applications which investigate the confounding factors such as age, gender, fasting time, and handling procedures for measuring blood lipid metabolites.
There is evidence of a positive association between per- and polyfluoroalkyl substances (PFASs) and cholesterol levels in human plasma, which may be due to common reabsorption of PFASs and bile acids ...(BAs) in the gut. Here we report development and validation of a method that allows simultaneous, quantitative determination of PFASs and BAs in plasma, using 150 μL or 20 μL of sample. The method involves protein precipitation using 96-well plates. The instrumental analysis was performed with ultra-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS), using reverse-phase chromatography, with the ion source operated in negative electrospray mode. The mass spectrometry analysis was carried out using multiple reaction monitoring mode. The method proved to be sensitive, robust, and with sufficient linear range to allow reliable determination of both PFASs and BAs. The method detection limits were between 0.01 and 0.06 ng mL
−1
for PFASs and between 0.002 and 0.152 ng mL
−1
for BAs, with the exception of glycochenodeoxycholic acid (0.56 ng mL
−1
). The PFAS measured showed excellent agreement with certified plasma PFAS concentrations in NIST SRM 1957 reference serum. The method was tested on serum samples from 20 healthy individuals. In this proof-of-concept study, we identified significant associations between plasma PFAS and BA levels, which suggests that PFAS may alter the synthesis and/or uptake of BAs.
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Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through ...activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum.
► The gut microbiota reduces bile acid pool size and composition ► The gut microbiota activates FXR by alleviating receptor antagonism ► Tauro-conjugated muricholic acids are naturally occurring FXR antagonists
Colonization of the fetal and infant gut microbiome results in dynamic changes in diversity, which can impact disease susceptibility. To examine the relationship between human gut microbiome dynamics ...throughout infancy and type 1 diabetes (T1D), we examined a cohort of 33 infants genetically predisposed to T1D. Modeling trajectories of microbial abundances through infancy revealed a subset of microbial relationships shared across most subjects. Although strain composition of a given species was highly variable between individuals, it was stable within individuals throughout infancy. Metabolic composition and metabolic pathway abundance remained constant across time. A marked drop in alpha-diversity was observed in T1D progressors in the time window between seroconversion and T1D diagnosis, accompanied by spikes in inflammation-favoring organisms, gene functions, and serum and stool metabolites. This work identifies trends in the development of the human infant gut microbiome along with specific alterations that precede T1D onset and distinguish T1D progressors from nonprogressors.
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•Gut microbial metabolic pathways but not taxonomies are stable throughout infancy•Strain composition of high-abundance species remains constant throughout infancy•Decreased community diversity occurs after seroconversion but before onset of T1D•T1D onset is preceded by increased inflammation-associated organisms and pathways
Kostic et al. perform a microbiome analysis of type 1 diabetes (T1D), examining the infant gut microbiome as T1D develops. Microbial metabolic pathways remain remarkably stable throughout infancy. T1D onset is preceded by a drop in community diversity and a spike in inflammation-associated species and metabolic pathways.
The composition of human breast milk (HBM) exhibits significant variability both between individuals and within the same individual. While environmental factors are believed to play a role in this ...variation, their influence on breast milk composition remains inadequately understood. Herein, we investigate the impact of environmental factors on HBM lipid composition in a general population cohort. The study included mothers (All Babies In Southeast Sweden study) whose children later progressed to one or more immune-mediated diseases later in life: type 1 diabetes (n = 9), celiac disease (n = 24), juvenile idiopathic arthritis (n = 9), inflammatory bowel disease (n = 7), hypothyroidism (n = 6), and matched controls (n = 173). Lipidome of HBM was characterized by liquid chromatography combined with high-resolution mass spectrometry. We observed that maternal age, body mass index, diet, and exposure to perfluorinated alkyl substances (PFASs) had a marked impact on breast milk lipidome, with larger changes observed in the milk of those mothers whose children later developed autoimmune diseases. We also observed differences in breast milk lipid composition in those mothers whose offspring later developed autoimmune diseases. Our study suggests that breast milk lipid composition is modified by a complex interaction between genetic and environmental factors, and, importantly, this impact was significantly more pronounced in those mothers whose offspring later developed autoimmune/inflammatory diseases. Our findings also suggest that merely assessing PFAS concentration may not capture the full extent of the impact of chemical exposures; thus, the more comprehensive exposome approach is essential for accurately assessing the impact of PFAS exposure on HBM and, consequently, on the health outcomes of the offspring.
On-line coupling of extraction and chromatographic separation allows the whole analysis to be performed in a closed system. On-line systems are particularly useful when the analytes are labile, the ...amount of sample is limited, or very high sensitivity is required. Many on-line systems have been developed both for liquid and for solid samples. This review discusses the different instruments that have been constructed and the factors that need to be considered in the coupling. Selected illustrative applications are described to illustrate the potential of the on-line systems.
Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was ...detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease.
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•Mfn2 binds directly and specifically to phosphatidylserine (PS)•Hepatic Mfn2 deficiency causes a reduced transfer of PS from ER to mitochondria•Mfn2 ablation in liver causes a NASH-like phenotype and liver cancer•A defective transfer of PS from ER to mitochondria causes liver disease
The mitochondrial protein mitofusin 2 binds and transfers phosphatidylserine across mitochondria-ER contacts, and perturbation of this process leads to aberrant lipid metabolism and liver diseases like NASH, NAFLD, and cancer.
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