PubMed

Nat Food. 2023 Mar;4(3):257-266. doi: 10.1038/s43016-023-00717-w. Epub 2023 Mar 13.ABSTRACTPopulation-level nutritional assessments often rely on self-reported data, which increases the risk of recall bias. Here, we demonstrate that wastewater-based epidemiology can be used for near real-time population dietary assessments. Neighbourhood-level, untreated wastewater samples were collected monthly from within an urban population in the south-western United States from August 2017 to July 2019. Using liquid chromatography-tandem mass spectrometry, we identify recurring seasonal dynamics in phytoestrogen consumption, including dietary changes linked to the winter holiday season. Using 16S ribosomal RNA gene amplicon sequencing, we demonstrated the feasibility of detecting sewage-derived human gut bacterial taxa involved in phytoestrogen metabolism, including Bifidobacterium, Blautia and Romboutsia. Combined metabolomic and genomic wastewater analysis can inform nutritional assessments at population scale, indicating wastewater-based epidemiology as a promising tool for actionable and cost-effective data collection to support public health nutrition.PMID:37118274 | DOI:10.1038/s43016-023-00717-w

Nat Aging. 2022 Nov;2(11):1024-1039. doi: 10.1038/s43587-022-00311-y. Epub 2022 Nov 17.ABSTRACTAlzheimer's disease (AD) is the most common form of dementia without effective clinical treatment. Here, we show that intermittent fasting (IF) improves cognitive functions and AD-like pathology in a transgenic AD mouse model (5XFAD). IF alters gut microbial composition with a significant enrichment in probiotics such as Lactobacillus. The changes in the composition of the gut microbiota affect metabolic activities and metabolite production. Metabolomic profiling analysis of cecal contents revealed IF leads to a decreased carbohydrate metabolism (for example, glucose) and an increased abundance in amino acids (for example, sarcosine and dimethylglycine). Interestingly, we found that the administration of IF-elevated sarcosine or dimethylglycine mimics the protective effects of IF in 5XFAD mice, including the amelioration of cognitive decline, amyloid-β (Aβ) burden and glial overactivation. Our findings thus demonstrate an IF regimen is a potential approach to prevent AD progression, at least through the gut-microbiota-metabolites-brain axis, and constitutes an innovative AD therapeutic avenue.PMID:37118092 | DOI:10.1038/s43587-022-00311-y

Nat Aging. 2022 Nov;2(11):979. doi: 10.1038/s43587-022-00316-7.NO ABSTRACTPMID:37118079 | DOI:10.1038/s43587-022-00316-7

Nat Aging. 2022 May;2(5):438-452. doi: 10.1038/s43587-022-00193-0. Epub 2022 Apr 14.ABSTRACTA better understanding of the biological and environmental variables that contribute to exceptional longevity has the potential to inform the treatment of geriatric diseases and help achieve healthy aging. Here, we compared the gut microbiome and blood metabolome of extremely long-lived individuals (94-105 years old) to that of their children (50-79 years old) in 116 Han Chinese families. We found extensive metagenomic and metabolomic remodeling in advanced age and observed a generational divergence in the correlations with socioeconomic factors. An analysis of quantitative trait loci revealed that genetic associations with metagenomic and metabolomic features were largely generation-specific, but we also found 131 plasma metabolic quantitative trait loci associations that were cross-generational with the genetic variants concentrated in six loci. These included associations between FADS1/2 and arachidonate, PTPA and succinylcarnitine and FLVCR1 and choline. Our characterization of the extensive metagenomic and metabolomic remodeling that occurs in people reaching extreme ages may offer new targets for aging-related interventions.PMID:37118062 | DOI:10.1038/s43587-022-00193-0

Arch Toxicol. 2023 Apr 29. doi: 10.1007/s00204-023-03495-3. Online ahead of print.ABSTRACTIntestinal cells are continuously exposed to food constituents while adapting to peristaltic movement and fluid shear stress. Oleic acid (OA) and palmitic acid (PA) are among the most prevalent fatty acids with respect to dietary lipids. Despite the central importance of dietary lipids for a balanced diet, awareness about potential detrimental effects related to excessive consumption is increasing; this includes toxicity, metabolic deregulation, and, particularly for cancer cells, a benefit from the uptake of fatty acids related to promotion of metastasis. Expanding on this, we started elucidating the effects of OA and PA (25-500 µM) on non-transformed human intestinal epithelial cells (HCEC-1CT) in comparison to colon carcinoma cells (HCT116), with regard to the mechanosensory apparatus. Hence, intestinal cells' motility is on the one side essential to ensure adaption to peristaltic movement and barrier function, but also to enable metastatic progression. Incubation with both OA and PA (≥ 25 µM) significantly decreased membrane fluidity of HCT116 cells, whereas the effect on HCEC-1CT was more limited. Application of rhodamine-labelled PA demonstrated that the fatty acid is incorporated into the plasma membrane of HCT116, which could not be observed in the non-tumorigenic cell line. Down-streaming into the intracellular compartment, a pronounced rearrangement of actin cytoskeleton was evident in both cell lines (OA and PA; 25 and 100 µM). This was accompanied by a variation of translocation efficiency of the mechanosensitive co-transcription factor YAP1, albeit with a stronger effect seen for PA and the cancer cells. Untargeted proteomic analysis confirmed that exposure to OA and PA could alter the response capacity of HCT116 cells to fluid shear stress. Taken together, OA and PA were able to functionally modulate the mechanosensory apparatus of intestinal cells, implying a novel role for dietary fatty acids in the regulation of intestinal pathophysiology.PMID:37117602 | DOI:10.1007/s00204-023-03495-3

Sci Rep. 2023 Apr 28;13(1):6942. doi: 10.1038/s41598-023-34181-0.ABSTRACTThe objective of this study was to determine the influence of a total-mixed ration including unsalable carrots at 45% DM on the rumen microbiome; and the plasma, rumen and liver metabolomes. Carrots discarded at processing were investigated as an energy-dense substitute for barley grain in a conventional feedlot diet, and improved feed conversion efficiency by 25%. Here, rumen fluid was collected from 34 Merino lambs at slaughter (n = 16 control; n = 18 carrot) after a feeding period of 11-weeks. The V4 region of the 16S rRNA gene was sequenced to profile archaeal and bacterial microbe communities. Further, a comprehensive, targeted profile of known metabolites was constructed for blood plasma, rumen fluid and biopsied liver metabolites using a gas chromatography mass spectrometry (GC-MS) metabolomics approach. An in vitro batch culture was used to characterise ruminal fermentation including gas and methane (CH4) production. In vivo rumen microbial community structure of carrot fed lambs was dissimilar (P < 0.01; PERMANOVA), and all measures of alpha diversity were greater (P < 0.01), compared to those fed the control diet. Unclassified genera in Bacteroidales (15.9 ± 6.74% relative abundance; RA) were more abundant (P < 0.01) in the rumen fluid of carrot-fed lambs, while unclassified taxa in the Succinivibrionaceae family (11.1 ± 3.85% RA) were greater (P < 0.01) in the control. The carrot diet improved in vitro ruminal fermentation evidenced as an 8% increase (P < 0.01) in DM digestibility and a 13.8% reduction (P = 0.01) in CH4 on a mg/ g DM basis, while the control diet increased (P = 0.04) percentage of propionate within total VFA by 20%. Fourteen rumen fluid metabolites and 27 liver metabolites were influenced (P ≤ 0.05) by diet, while no effect (P ≥ 0.05) was observed in plasma metabolites. The carrot diet enriched (impact value = 0.13; P = 0.01) the tyrosine metabolism pathway (acetoacetic acid, dopamine and pyruvate), while the control diet enriched (impact value = 0.42; P ≤ 0.02) starch and sucrose metabolism (trehalose and glucose) in rumen fluid. This study demonstrated that feeding 45% DM unsalable carrots diversified bacterial communities in the rumen. These dietary changes influenced pathways of tyrosine degradation, such that previous improvements in feed conversion efficiency in lambs could be explained.PMID:37117259 | DOI:10.1038/s41598-023-34181-0

Nat Commun. 2023 Apr 28;14(1):2461. doi: 10.1038/s41467-023-37031-9.ABSTRACTMultidimensional measurements using state-of-the-art separations and mass spectrometry provide advantages in untargeted metabolomics analyses for studying biological and environmental bio-chemical processes. However, the lack of rapid analytical methods and robust algorithms for these heterogeneous data has limited its application. Here, we develop and evaluate a sensitive and high-throughput analytical and computational workflow to enable accurate metabolite profiling. Our workflow combines liquid chromatography, ion mobility spectrometry and data-independent acquisition mass spectrometry with PeakDecoder, a machine learning-based algorithm that learns to distinguish true co-elution and co-mobility from raw data and calculates metabolite identification error rates. We apply PeakDecoder for metabolite profiling of various engineered strains of Aspergillus pseudoterreus, Aspergillus niger, Pseudomonas putida and Rhodosporidium toruloides. Results, validated manually and against selected reaction monitoring and gas-chromatography platforms, show that 2683 features could be confidently annotated and quantified across 116 microbial sample runs using a library built from 64 standards.PMID:37117207 | DOI:10.1038/s41467-023-37031-9

Nat Commun. 2023 Apr 28;14(1):2449. doi: 10.1038/s41467-023-37626-2.ABSTRACTHuman health is determined by the interaction of our environment with the genome, epigenome, and microbiome, which shape the transcriptomic, proteomic, and metabolomic landscape of cells and tissues. Precision environmental health is an emerging field leveraging environmental and system-level ('omic) data to understand underlying environmental causes of disease, identify biomarkers of exposure and response, and develop new prevention and intervention strategies. In this article we provide real-life illustrations of the utility of precision environmental health approaches, identify current challenges in the field, and outline new opportunities to promote health through a precision environmental health framework.PMID:37117186 | DOI:10.1038/s41467-023-37626-2

Trends Cell Biol. 2023 Apr 26:S0962-8924(23)00070-3. doi: 10.1016/j.tcb.2023.03.013. Online ahead of print.ABSTRACTA long-standing question in cancer biology has been why oxygenated tumors ferment the majority of glucose they consume to lactate rather than oxidizing it in their mitochondria, a phenomenon known as the 'Warburg effect.' An abundance of evidence shows not only that most cancer cells have fully functional mitochondria but also that mitochondrial activity is important to proliferation. It is therefore difficult to rationalize the metabolic benefit of cancer cells switching from respiration to fermentation. An emerging perspective is that rather than mitochondrial metabolism being suppressed in tumors, as is often suggested, mitochondrial activity increases to the level of saturation. As such, the Warburg effect becomes a signature of excess glucose being released as lactate due to mitochondrial overload.PMID:37117116 | DOI:10.1016/j.tcb.2023.03.013

J Hepatol. 2023 Apr 26:S0168-8278(23)00241-6. doi: 10.1016/j.jhep.2023.04.018. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Acute liver failure (ALF) has a high mortality. Alterations in albumin structure and function have been shown to correlate with outcomes in cirrhosis. We undertook a bio-molecular analysis of albumin to determine its correlation with hepatocellular injury and early mortality in ALF.METHOD: Altogether 225 subjects (200-ALF, 25 healthy controls) were enrolled. Albumin was purified from baseline plasma of the training cohort (ALF-40; survivors-8, non-survivors-32, HC-5) and analysed for modifications, functionality, and bound multi-omics signatures and validated in a test cohort [160-ALF; survivors-53, non-survivors-107 and 20-HC].RESULTS: In ALF patients, albumin is more oxidized and glycosylated with a distinct multi-omics profile than controls; more so in non-survivors (p<0.05). In non-survivors, albumin showed increased (p<0.05, FDR<0.01) proteins associated with inflammation, Advanced Glycation End Product; metabolites linked to arginine, proline metabolism, bile acid, and mitochondrial breakdown products. Increased bacterial taxa [Listeria, Clostridium, and others] correlated with lipids [triglycerides (4:0/12:0/12:0) and phosphatidylserine (39:0)] and metabolites (Porphobilinogen, nicotinic acid) in non-survivors (r2>0.7). Multiomics signature-based probability of detection (POD) for non-survival was>90% and showed direct correlation with albumin functionality and clinical parameters (r2>0.85). POD metabolites built on top 5 metabolites; Nicotinic Acid, L-Acetyl carnitine, L-carnitine, Pregnenolone-sulfate, and N-(3-Hydroxybutanoyl)-L-homoserine lactone showed diagnostic efficiency of 98%(AUC=0.98[0.95-1.0]) and segregate ALF patients predisposed to early mortality (log-rank<0.05). On validation using HRMS and five machine learning algorithms in test cohort-1 (plasma and paired one-drop blood), the metabolome panel showed >92% accuracy/sensitivity and specificity for prediction of mortality.CONCLUSION: In ALF, the albumin is hyperoxidised and substantially dysfunctional. Our study outlines distinct 'albuminome' signatures capable of segregating ALF patients predisposed to early mortality or requiring emergency liver transplantation.IMPACTS AND IMPLICATION: Here, we reported the bio-molecular MAP of albumin in Distinct and linked to severity and outcome in acute liver failure (ALF) patients. Detailed structural, functional and Albumin-omics analysis in ALF patients led to the identification and classification of albumin bound biomolecules which could segregate ALF patients predisposed to early mortality. More importantly we found albumin bound metabolites indicative of mitochondrial damage and hyper-inflammation as putative indicator of <30 days mortality in ALF patients. This preclinical study validates the utility of albuminome analysis for understanding the pathophysiology and development of poor outcome indicators in ALF patients.PMID:37116716 | DOI:10.1016/j.jhep.2023.04.018

Environ Pollut. 2023 Apr 26:121730. doi: 10.1016/j.envpol.2023.121730. Online ahead of print.ABSTRACTThe widespread use of phthalates (PAEs) has drawn increasing attention due to their endocrine disruption and reproductive toxicity, while the steroid metabolome is essential for follicular development. However, the mechanism by which PAE exposure affects ovarian reserve through the steroid metabolome remains unclear. This study recruited 264 childbearing-age women in Tianjin (China) from April 2019 to August 2020 in a cross-sectional design. Target metabolome analysis of 16 steroids was performed in follicular fluid (FF) to compare diminished ovarian reserve (DOR) against normal ovarian reserve (NOR) women and differential steroids were identified using binary logistic analyses. Further analysis of eleven PAE metabolites (mPAEs) in FF was conducted, and the retrieved oocyte number (RON) representing ovarian reserve was counted. Multiple linear regression and quantile-based g-computation (qgcomp) models were used to associate individual mPAEs and mPAE mixture with the DOR-related differential steroids in FF. Mediation analysis was used to discuss the mediating effect of DOR-related steroids on the association between mPAEs and RON. Androstenedione (A4), corticosterone (CORT), cortisol (COR) and cortisone were significantly down-regulated in FF from women with DOR. Nine mPAEs with detection frequencies greater than 60% and median concentrations of 0.02-4.86 ng/mL were incorporated into statistical models. Negative associations with COR and CORT were found for mono-ethyl phthalate (mEP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), and mono-2-ethylhexyl phthalate (mEHP). A positive association with cortisone was found for mEOHP, mEHP, monobutyl phthalate (mBP), and mono (2-isobutyl) phthalate (miBP). The qgcomp and mediation analyses revealed that mEP and mEOHP not only significantly contributed to the decline of COR and CORT in the mixed exposure but also indirectly reduced RON through the mediating effects of COR and CORT. In conclusion, PAE exposure may decrease ovarian reserve by downregulating COR and CORT.PMID:37116568 | DOI:10.1016/j.envpol.2023.121730

Environ Pollut. 2023 Apr 26:121729. doi: 10.1016/j.envpol.2023.121729. Online ahead of print.ABSTRACTAflatoxins B1 (AFB1), a type I carcinogen widely present in the environment, not only poses a danger to animal husbandry, but also poses a potential threat to human reproductive health, but its mechanism is still unclear. To address this question, multi-omics were performed on porcine Sertoli cells and mice testis. The data suggest that AFB1 induced testicular damage manifested as decreased expression of GJA1, ZO1 and OCCLUDIN in mice (p < 0.01) and inhibition of porcine Sertoli cell proliferation. Transcriptomic analysis suggested changes in noncoding RNA expression profiles that affect the cell cycle-related Ras/PI3K/Akt signaling pathway after AFB1 exposure both in mice and pigs. Specifically, AFB1 caused abnormal cell cycle of testis with the characterization of decreased expressions of CCNA1, CCNB1 and CDK1 (p < 0.01). Flow cytometry revealed that the G2/M phase was significantly increased after AFB1 exposure. Meanwhile, AFB1 downregulated the expressions of Ras, PI3K and AKT both in porcine Sertoli cell (p < 0.01) and mice testis (p < 0.01). Metabolome analysis verified the alterations in the PI3K/Akt signaling pathway (p < 0.05). Moreover, the joint analysis of metabolome and microbiome found that the changes of metabolites were correlated with the expression of flora. In conclusion, we have demonstrated that AFB1 impairs spermatogenesis via the cell cycle-related Ras/PI3K/Akt signaling and gut imbalance.PMID:37116564 | DOI:10.1016/j.envpol.2023.121729

Cancer Cell. 2023 Apr 13:S1535-6108(23)00131-9. doi: 10.1016/j.ccell.2023.04.005. Online ahead of print.ABSTRACTWu et al. report that patients with hematologic malignancies have reduced immunity against SARS-CoV-2 Omicron subvariants and Sotrovimab retains neutralizing capacity against all tested Omicron subvariants.PMID:37116490 | DOI:10.1016/j.ccell.2023.04.005

Cancer Cell. 2023 Apr 24:S1535-6108(23)00117-4. doi: 10.1016/j.ccell.2023.04.001. Online ahead of print.ABSTRACTIn pancreatic ductal adenocarcinoma (PDAC) patients, we show that response to radiation therapy (RT) is characterized by increased IL-2Rβ and IL-2Rγ along with decreased IL-2Rα expression. The bispecific PD1-IL2v is a PD-1-targeted IL-2 variant (IL-2v) immunocytokine with engineered IL-2 cis targeted to PD-1 and abolished IL-2Rα binding, which enhances tumor-antigen-specific T cell activation while reducing regulatory T cell (Treg) suppression. Using PD1-IL2v in orthotopic PDAC KPC-driven tumor models, we show marked improvement in local and metastatic survival, along with a profound increase in tumor-infiltrating CD8+ T cell subsets with a transcriptionally and metabolically active phenotype and preferential activation of antigen-specific CD8+ T cells. In combination with single-dose RT, PD1-IL2v treatment results in a robust, durable expansion of polyfunctional CD8+ T cells, T cell stemness, tumor-specific memory immune response, natural killer (NK) cell activation, and decreased Tregs. These data show that PD1-IL2v leads to profound local and distant response in PDAC.PMID:37116489 | DOI:10.1016/j.ccell.2023.04.001

Nat Food. 2021 Apr;2(4):223. doi: 10.1038/s43016-021-00273-1.NO ABSTRACTPMID:37118468 | DOI:10.1038/s43016-021-00273-1

Nat Aging. 2022 Mar;2(3):254-263. doi: 10.1038/s43587-022-00174-3. Epub 2022 Feb 17.ABSTRACTSkeletal muscle is greatly affected by aging, resulting in a loss of metabolic and physical function. However, the underlying molecular processes and how (lack of) physical activity is involved in age-related metabolic decline in muscle function in humans is largely unknown. Here, we compared, in a cross-sectional study, the muscle metabolome from young to older adults, whereby the older adults were exercise trained, had normal physical activity levels or were physically impaired. Nicotinamide adenine dinucleotide (NAD+) was one of the most prominent metabolites that was lower in older adults, in line with preclinical models. This lower level was even more pronounced in impaired older individuals, and conversely, exercise-trained older individuals had NAD+ levels that were more similar to those found in younger individuals. NAD+ abundance positively correlated with average number of steps per day and mitochondrial and muscle functioning. Our work suggests that a clear association exists between NAD+ and health status in human aging.PMID:37118369 | DOI:10.1038/s43587-022-00174-3

Nat Aging. 2021 Aug;1(8):666-676. doi: 10.1038/s43587-021-00093-9. Epub 2021 Aug 9.ABSTRACTThe gut microbiota is increasingly recognized as an important regulator of host immunity and brain health. The aging process yields dramatic alterations in the microbiota, which is linked to poorer health and frailty in elderly populations. However, there is limited evidence for a mechanistic role of the gut microbiota in brain health and neuroimmunity during aging processes. Therefore, we conducted fecal microbiota transplantation from either young (3-4 months) or old (19-20 months) donor mice into aged recipient mice (19-20 months). Transplant of a microbiota from young donors reversed aging-associated differences in peripheral and brain immunity, as well as the hippocampal metabolome and transcriptome of aging recipient mice. Finally, the young donor-derived microbiota attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host. Our results reveal that the microbiome may be a suitable therapeutic target to promote healthy aging.PMID:37117767 | DOI:10.1038/s43587-021-00093-9

Nat Food. 2021 Jul;2(7):541-542. doi: 10.1038/s43016-021-00309-6.NO ABSTRACTPMID:37117689 | DOI:10.1038/s43016-021-00309-6

Nat Aging. 2021 Sep;1(9):810-825. doi: 10.1038/s43587-021-00105-8. Epub 2021 Sep 13.ABSTRACTAging is accompanied by a general decline in the function of many cellular pathways. However, whether these are causally or functionally interconnected remains elusive. Here, we study the effect of mitochondrial-nuclear communication on stem cell aging. We show that aged mesenchymal stem cells exhibit reduced chromatin accessibility and lower histone acetylation, particularly on promoters and enhancers of osteogenic genes. The reduced histone acetylation is due to impaired export of mitochondrial acetyl-CoA, owing to the lower levels of citrate carrier (CiC). We demonstrate that aged cells showed enhanced lysosomal degradation of CiC, which is mediated via mitochondrial-derived vesicles. Strikingly, restoring cytosolic acetyl-CoA levels either by exogenous CiC expression or via acetate supplementation, remodels the chromatin landscape and rescues the osteogenesis defects of aged mesenchymal stem cells. Collectively, our results establish a tight, age-dependent connection between mitochondrial quality control, chromatin and stem cell fate, which are linked together by CiC.PMID:37117628 | DOI:10.1038/s43587-021-00105-8

Nat Aging. 2021 Dec;1(12):1127-1136. doi: 10.1038/s43587-021-00141-4. Epub 2021 Dec 20.ABSTRACTUnderstanding the physiological origins of age-related cognitive decline is of critical importance given the rising age of the world's population1. Previous work in animal models has established a strong link between cognitive performance and the microbiota2-5, and it is known that the microbiome undergoes profound remodeling in older adults6. Despite growing evidence for the association between age-related cognitive decline and changes in the gut microbiome, the mechanisms underlying such interactions between the brain and the gut are poorly understood. Here, using fecal microbiota transplantation (FMT), we demonstrate that age-related remodeling of the gut microbiota leads to decline in cognitive function in mice and that this impairment can be rescued by transplantation of microbiota from young animals. Moreover, using a metabolomic approach, we found elevated concentrations of δ-valerobetaine, a gut microbiota-derived metabolite, in the blood and brain of aged mice and older adults. We then demonstrated that δ-valerobetaine is deleterious to learning and memory processes in mice. At the neuronal level, we showed that δ-valerobetaine modulates inhibitory synaptic transmission and neuronal network activity. Finally, we identified specific bacterial taxa that significantly correlate with δ-valerobetaine levels in the brain. Based on our findings, we propose that δ-valerobetaine contributes to microbiota-driven brain aging and that the associated mechanisms represent a promising target for countering age-related cognitive decline.PMID:37117525 | DOI:10.1038/s43587-021-00141-4