Search

Amyotrophic lateral sclerosis (ALS) is a complex, fatal neurodegenerative disease. Disease pathophysiology is incompletely understood but evidence suggests gut dysbiosis occurs in ALS, linked to impaired gastrointestinal integrity, immune system dysregulation and altered metabolism. Gut microbiome and plasma metabolome have been separately investigated in ALS, but little is known about gut microbe-plasma metabolite correlations, which could identify robust disease biomarkers and potentially shed mechanistic insight. Here, gut microbiome changes were longitudinally profiled in ALS and correlated to plasma metabolome. Gut microbial structure at the phylum level differed in ALS versus control participants, with differential abundance of several distinct genera. Unsupervised clustering of microbe and metabolite levels identified modules, which differed significantly in ALS versus control participants. Network analysis found several prominent amplicon sequence variants strongly linked to a group of metabolites, primarily lipids. Similarly, identifying the features that contributed most to case versus control separation pinpointed several bacteria correlated to metabolites, predominantly lipids. Mendelian randomization indicated possible causality from specific lipids related to fatty acid and acylcarnitine metabolism. Overall, the results suggest ALS cases and controls differ in their gut microbiome, which correlates with plasma metabolites, particularly lipids, through specific genera. These findings have the potential to identify robust disease biomarkers and shed mechanistic insight into ALS. [ABSTRACT FROM AUTHOR]

Objective A nontargeted metabolomics approach was established to characterize serum metabolic profile in type 3c diabetes mellitus (T3cDM) secondary to chronic pancreatitis and compare with T2DM. Methods Forty patients were recruited for metabolite analysis based on liquid chromatography-mass spectrometry. Cluster heatmap and KEGG metabolic pathway enrichment analysis were used to analyze the specific and differential metabolites. The receiver operating characteristics (ROCs) were generated and correlation analysis with clinical data was conducted. Results Metabolites including sphingosine, lipids, carnitine, bile acid, and hippuric acid were found to be different between T2DM and T3cDM, mainly enriched in bile acid biosynthesis, fatty acid biosynthesis, and sphingolipid metabolic pathways. The ROCs were generated with an area under the curve of 0.907 (95% confidence interval, 0.726–1) for the model with 15 metabolites. Conclusion T3cDM is characterized by increased sphingosine, carnitine, bile acid, and most lipids, providing novel biomarkers for clinical diagnosis and a future direction in research on pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Due to differences in carbon assimilation pathways between plants, there are subtle but distinct variations in the carbon isotope ratios of foods and animal products throughout the food supply. Although it is well understood that the carbon isotope ratio composition of the diet influences that of the consumers' tissues, the application of natural abundance carbon isotope ratio analysis in nutrition has long been underappreciated. Over the past decade, however, several studies have investigated the utility of carbon isotope ratio analysis for evaluation of nutritional biomarker status, primarily focusing on its application as an objective indicator of sugar and animal protein intake. More recently, research investigating the application of natural abundance measurements has been extended to study fatty acid metabolism and has yielded encouraging results. Collectively, data from large-scale observational studies and experimental animal studies highlight the potential for carbon isotope ratio analysis as an additional and effective tool to study diet and metabolism. The purpose of this review is to provide an overview of natural abundance carbon isotope ratio analysis, its application to studying nutrition, and an update of the research in the field. [ABSTRACT FROM AUTHOR]

Aims Transcriptional regulation through peroxisome proliferator-activated receptor γ (PPARγ) is critical for an altered lipid metabolism during monocyte to macrophage differentiation. Here, we investigated how 5-aminoimidazole-4-carboxamide riboside (AICAR), an activator of AMP-dependent protein kinase (AMPK), affects PPARγ during monocyte differentiation. Methods and results During the differentiation of THP-1 monocytic cells or primary human monocytes to macrophages, we observed that AICAR inhibited the expression of PPARγ target genes, such as fatty acid-binding protein 4 or CD36. This effect was independent of AICAR conversion to AICAR ribotide and AMPK activation. While AICAR increased PPARγ mRNA expression that paralleled differentiation, it inhibited PPARγ protein synthesis without affecting PPARγ protein stability. Monocytes differentiated to macrophages in the presence of AICAR revealed an attenuated uptake of oxidized low-density lipoprotein (oxLDL) and reduced oxLDL-triggered c-Jun N-terminal kinase (JNK) activation. JNK and endoplasmic reticulum stress responses to the saturated fatty acid palmitate were attenuated as well, an effect mimicked by the knockdown of PPARγ. Although PPARγ has been reported to support alternative macrophage activation, AICAR did not inhibit interleukin-4-induced gene expression in differentiating monocytes. Conclusion Inhibition of PPARγ-dependent gene expression during monocyte differentiation may contribute to an AICAR-elicited macrophage phenotype characterized by reduced inflammatory responses to modified lipoproteins and saturated fatty acids. [ABSTRACT FROM AUTHOR]

One key adaptation that Mycobacterium tuberculosis established to survive long term in vivo is a reliance on lipids as an energy source. M. tuberculosis H37Rv has 36 fadD genes annotated as putative fatty acyl-coenzyme A (CoA) synthetase genes, which encode enzymes that activate fatty acids for metabolism. One such gene, fadD5 (Rv0166), is located within the mce1 operon, a cluster of genes associated withM. tuberculosis persistence. We disrupted the putative fatty acid-binding site of fadD5 in H37Rv M. tuberculosis. No significant differences were found in the growth of the mutant and wild-type strains in vitro in nutrient-rich broth or in activated RAW264.7 cells. However, the fadD5 mutant was diminished in growth in minimal medium containing mycolic acid but not other long-chain fatty acids. C57BL/6 mice infected with the fadD5 mutant survived significantly longer than those infected with the wild type, and the mutant never attained the plateau phase of infection in mouse lungs. Infection in the steady-state phase was maintained for up to 168 days at a level that was 1- 2 logs less than that noted in the wild type. These observations raise the rather intriguing possibility that FadD5 may serve to recycle mycolic acids for the long-term survival of the tubercle bacilli. [ABSTRACT FROM AUTHOR]

Two experiments were conducted with lactating Angus × Gelbvieh beef cows to determine the effects of postpartum lipid supplementation, BCS at parturition, and day of lactation on fatty acid profiles in plasma, adipose tissue, and milk. In Exp. 1, 36 primiparous cows (488 ± 10 kg of initial BW; 5.5 ± 0.02 initial BCS) were given ad libitum access to hay and assigned randomly to a low-fat (control) supplement or supplements with cracked, high-linoleate safflower seeds (linoleate) or cracked, high-oleate safflower seeds (oleate) from d 3 to 90 of lactation. Diets were formulated to be isonitrogenous and isocaloric; safflower seed diets provided 5% of DMI as fat. Plasma and milk samples were collected on d 30, 60, and 90 of lactation. Adipose tissue biopsies were collected near the tail-head region of cows on d 45 and 90 of lactation. In Exp. 2, 3-yr-old cows achieving a BCS of 4 ± 0.07 (479 ± 36 kg of BW) or 6 ± 0.07 (580 ± 53 kg of BW) at parturition were used in a 2-yr experiment (n = 36/yr). Beginning 3 d postpartum through d 61 of lactation, cows were fed diets similar to those of Exp. 1. Adipose tissue and milk samples were collected on d 30 and 60, and plasma was collected on d 31 and 61 of lactation. Responses to postpartum dietary treatment were comparable in both experiments. Cows fed linoleate and oleate had greater (P < 0.001) total fatty acid concentrations in plasma than cows fed control. Except for 15:1, milk fatty acids with <18 carbons were greatest (P ≤ 0.01) for cows fed control, whereas milk from cows fed linoleate had the greatest (P ≤ 0.02) 18:1trans-11, 18:2n-6, and cis-9, trans-11 CLA. Milk from cows fed oleate had the greatest (P < 0.001) 18:1cis-9. In Exp. 1, total fatty acid concentrations in adipose tissue samples decreased at d 90 compared with d 45 of lactation, but the fatty acid profile of cow adipose tissue was not affected (P = 0.14 to 0.80) by dietary treatment. In Exp. 2, the percentage of cis-9, trans-11 CLA in adipose tissue of cows with a BCS of 6 decreased (P = 0.001) from d 30 to 60 of lactation. Plasma and milk fatty acid composition reflected alterations in postpartum diet. Less medium-chain fatty acids and more 18-carbon fatty acids in milk were indicative of reduced de novo fatty acid synthesis in the mammary gland of beef cows fed lipid supplements; however, the metabolic demands of lactation prevented the deposition of exogenously derived fatty acids in adipose tissue through d 90 of lactation. [ABSTRACT FROM AUTHOR]

Lipid metabolism and the effect of Pb2+ and Cu2+ on this process was studied in the moss Rhytidiadelphus squarrosus collected from both a lead‐contaminated and a non‐contaminated site. Total radiolabelling of lipids from [1‐14C]acetate was similar in both populations and Cu or Pb (1 μM, 10 μM) did not cause much alteration in acute exposure experiments. However, there were significant qualitative changes. Of the major labelled neutral lipid classes, samples from the lead‐polluted site showed a decrease in labelling of triacylglycerols and an increase in wax esters. Acute lead exposure caused similar effects. Cu caused a decrease in the labelling of wax esters and an increase in diacylglycerols. These data suggest that heavy metals cause a change in carbon flux through the acylation reactions associated with the Kennedy pathway. R. squarrosus obtained from the Pb‐contaminated site also showed changes in polar lipid labelling compared to the uncontaminated site. The labelling of phosphatidylcholine was more than halved and replaced by increased labelling of other zwitterionic lipids. The chloroplast glycerolipids were also increasingly labelled. Acute exposure to Pb, however, caused little alteration of labelling patterns within 24 h. R. squarrosus contains high levels of polyunsaturated fatty acids (PUFAs), but moss obtained from the Pb‐polluted site had significantly less PUFAs containing three or more double bonds. Such samples, when incubated with [1‐14C]acetate also showed decreased PUFA labelling. By contrast, acute exposure to Pb produced different results. These data provide a foundation for examining lipid metabolism in bryophytes and the effects of pollution in this important class of organism. The results also emphasize that acute and chronic exposure to heavy metals may produce different effects and that caution must be exercised in extrapolating data from one system to another. [ABSTRACT FROM PUBLISHER]