PubMed

Aging Cell. 2023 May 2:e13848. doi: 10.1111/acel.13848. Online ahead of print.ABSTRACTGut microbiota associated with longevity plays an important role in the adaptation to damaging stimuli accumulated during the aging process. The mechanism by which the longevity-associated microbiota protects the senescent host remains unclear, while the metabolites of the gut bacteria are of particular interest. Here, an integrated analysis of untargeted metabolomics and 16S rRNA gene sequencing was used to characterize the metabolite and microbiota profiles of long-lived individuals (aged ≥90 years) in comparison to old-elderly (aged 75-89 years), young-elderly (aged 60-74 years), and young to middle-aged (aged ≤59 years) individuals. This novel study constructed both metabolite and microbiota trajectories across aging in populations from Jiaoling county (the seventh longevity town of the world) in China. We found that the long-lived group exhibited remarkably differential metabolomic signatures, highlighting the existence of metabolic heterogeneity with aging. Importantly, we also discovered that long-lived individuals from the familial longevity cohort harbored a microbiome distinguished from that of the general population. Specifically, we identified that the levels of a candidate metabolite, pinane thromboxane A2 (PTA2), which is positively associated with aging, were consistently higher in individuals with familial longevity and their younger descendants than in those of the general population. Furtherly, functional analysis revealed that PTA2 potentiated the efficiency of microglial phagocytosis of β-amyloid 40 and enhanced an anti-inflammatory phenotype, indicating a protective role of PTA2 toward host health. Collectively, our results improve the understanding of the role of the gut microbiome in longevity and may facilitate the development of strategies for healthy aging.PMID:37132117 | DOI:10.1111/acel.13848

PeerJ. 2023 Apr 27;11:e15017. doi: 10.7717/peerj.15017. eCollection 2023.ABSTRACTGlass sponges (Hexactinellida) constitute important parts of ecosystems on the deep-sea floor worldwide. However, they are still an understudied group in terms of their diversity and systematics. Here, we report on new specimens collected during RV Sonne expedition SO254 to the New Zealand region, which has recently emerged as a biodiversity hotspot for hexactinellids. Examination of the material revealed several species new to science or so far unknown from this area. While formal taxonomic descriptions of a fraction of these were published earlier, we here briefly report on the morphology of the remaining new species and use the collection to greatly expand the molecular phylogeny of the group as established with ribosomal DNA and cytochrome oxidase subunit I markers. In addition, we provide a chemical fingerprinting analysis on a subset of the specimens to investigate if the metabolome of glass sponges contains phylogenetic signal that could be used to supplement morphological and DNA-based approaches.PMID:37131989 | PMC:PMC10149058 | DOI:10.7717/peerj.15017

bioRxiv. 2023 Apr 20:2023.04.18.537350. doi: 10.1101/2023.04.18.537350. Preprint.ABSTRACTLKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD + degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD + . Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)-key downstream effectors of LKB1- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer.SIGNIFICANCE: Loss-of-function mutations in the LKB1 tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.PMID:37131623 | PMC:PMC10153147 | DOI:10.1101/2023.04.18.537350

Metabolomics. 2023 May 3;19(5):49. doi: 10.1007/s11306-023-02013-x.ABSTRACTINTRODUCTION: Tandem mass spectrometry (TMS) has emerged an important screening tool for various metabolic disorders in newborns. However, there is inherent risk of false positive outcomes. Objective To establish analyte-specific cutoffs in TMS by integrating metabolomics and genomics data to avoid false positivity and false negativity and improve its clinical utility.METHODS: TMS was performed on 572 healthy and 3000 referred newborns. Urine organic acid analysis identified 23 types of inborn errors in 99 referred newborns. Whole exome sequencing was performed in 30 positive cases. The impact of physiological changes such as age, gender, and birthweight on various analytes was explored in healthy newborns. Machine learning tools were used to integrate demographic data with metabolomics and genomics data to establish disease-specific cut-offs; identify primary and secondary markers; build classification and regression trees (CART) for better differential diagnosis; for pathway modeling.RESULTS: This integration helped in differentiating B12 deficiency from methylmalonic acidemia (MMA) and propionic acidemia (Phi coefficient=0.93); differentiating transient tyrosinemia from tyrosinemia type 1 (Phi coefficient=1.00); getting clues about the possible molecular defect in MMA to initiate appropriate intervention (Phi coefficient=1.00); to link pathogenicity scores with metabolomics profile in tyrosinemia (r2=0.92). CART model helped in establishing differential diagnosis of urea cycle disorders (Phi coefficient=1.00).CONCLUSION: Calibrated cut-offs of different analytes in TMS and machine learning-based establishment of disease-specific thresholds of these markers through integrated OMICS have helped in improved differential diagnosis with significant reduction of the false positivity and false negativity rates.PMID:37131043 | DOI:10.1007/s11306-023-02013-x

Metabolomics. 2023 May 2;19(5):47. doi: 10.1007/s11306-023-02011-z.ABSTRACTPURPOSE: Dengue is a mosquito vector-borne disease caused by the dengue virus, which affects 125 million people globally. The disease causes considerable morbidity. The disease, based on symptoms, is classified into three characteristic phases, which can further lead to complications in the second phase. Molecular signatures that are associated with the three phases have not been well characterized. We performed an integrated clinical and metabolomic analysis of our patient cohort and compared it with omics data from the literature to identify signatures unique to the different phases.METHODS: The dengue patients are recruited by clinicians after standard-of-care diagnostic tests and evaluation of symptoms. Blood from the patients was collected. NS1 antigen, IgM, IgG antibodies, and cytokines in serum were analyzed using ELISA. Targeted metabolomics was performed using LC-MS triple quad. The results were compared with analyzed transcriptomic data from the GEO database and metabolomic data sets from the literature.RESULTS: The dengue patients displayed characteristic features of the disease, including elevated NS1 levels. TNF-α was found to be elevated in all three phases compared to healthy controls. The metabolic pathways were found to be deregulated compared to healthy controls only in phases I and II of dengue patients. The pathways represent viral replication and host response mediated pathways. The major pathways include nucleotide metabolism of various amino acids and fatty acids, biotin, etc. CONCLUSION: The results show elevated TNF-α and metabolites that are characteristic of viral infection and host response. IL10 and IFN-γ were not significant, consistent with the absence of any complications.PMID:37130982 | DOI:10.1007/s11306-023-02011-z

Metabolomics. 2023 May 2;19(5):48. doi: 10.1007/s11306-023-02008-8.ABSTRACTINTRODUCTION: Pink pepper is a worldwide used spice that corresponds to the berries of two species, Schinus terebinthifolia Raddi or S. molle L. (Anacardiaceae). Toxic and allergic reactions by ingestion or contact with these plants were reported, and classical in vitro studies have highlighted the cytotoxic properties of apolar extracts from the fruits.OBJECTIVES: Perform a non-targeted screening of 11 pink pepper samples for the detection and identification of individual cytotoxic substances.METHODS: After reversed-phase high-performance thin-layer chromatography (RP-HPTLC) separation of the extracts and multi-imaging (UV/Vis/FLD), cytotoxic compounds were detected by bioluminescence reduction from luciferase reporter cells (HEK 293 T-CMV-ELuc) applied directly on the adsorbent surface, followed by elution of detected cytotoxic substance into atmospheric-pressure chemical ionization high-resolution mass spectrometry (APCI-HRMS).RESULTS: Separations for mid-polar and non-polar fruit extracts demonstrated the selectivity of the method to different substance classes. One cytotoxic substance zone was tentatively assigned as moronic acid, a pentacyclic triterpenoid acid.CONCLUSION: The developed non-targeted hyphenated RP-HPTLC-UV/Vis/FLD-bioluminescent cytotoxicity bioassay-FIA-APCI-HRMS method was successfully demonstrated for cytotoxicity screening (bioprofiling) and respective cytotoxin assignment.PMID:37130976 | DOI:10.1007/s11306-023-02008-8

Nat Biotechnol. 2023 May 2. doi: 10.1038/s41587-023-01805-9. Online ahead of print.NO ABSTRACTPMID:37130959 | DOI:10.1038/s41587-023-01805-9

Sci Rep. 2023 May 2;13(1):7127. doi: 10.1038/s41598-023-34279-5.ABSTRACTTogether with environmental factors, physiological maturity at birth is a major determinant for neonatal survival and postnatal development in mammalian species. Maturity at birth is the outcome of complex mechanisms of intra-uterine development and maturation during the end of gestation. In pig production, piglet preweaning mortality averages 20% of the litter and thus, maturity is a major welfare and economic concern. Here, we used both targeted and untargeted metabolomic approaches to provide a deeper understanding of the maturity in a model of lines of pigs divergently selected on residual feed intake (RFI), previously shown to have contrasted signs of maturity at birth. Analyses were conducted on plasma metabolome of piglets at birth and integrated with other phenotypic characteristics associated to maturity. We confirmed proline and myo-inositol, previously described for their association with delayed growth, as potential markers of maturity. Urea cycle and energy metabolism were found more regulated in piglets from high and low RFI lines, respectively, suggesting a better thermoregulation ability for the low RFI (with higher feed efficiency) piglets.PMID:37130953 | DOI:10.1038/s41598-023-34279-5

Food Chem. 2023 Apr 25;422:136206. doi: 10.1016/j.foodchem.2023.136206. Online ahead of print.ABSTRACTSuperficial scald is a physiological disorder of fruit, which is easy to occur during long-term cold storage after harvest. Different preharvest bagging treatments (no bagging, polyethylene bagging and non-woven fabric bagging) were used to explore the occurrence mechanism of superficial scald. UHPLC-MS analysis, GC-MS analysis and RNA-seq revealed the influence of the wax of 'Chili' on the occurrence of superficial scald. The wax content and wax components (Lupeol, lup-20(29)-en-3-one, heptacosane, 9-octadecenoic acid, eicosanoic acid, cis-11-eicosenoic acid) were significantly higher in the fruit bagged with non-woven fabric (NWF, with low incidence of superficial scald) than that in fruit bagged with polyethylene (PE, high incidence of superficial scald). Transcriptomics and qRT-PCR data identified a wax synthesis gene, PbKCS10, which exhibited high expression levels in fruit with low of superficial scald. The results of gene function showed that PbKCS10 reduced the occurrence of superficial scald by increasing the wax formation.PMID:37130451 | DOI:10.1016/j.foodchem.2023.136206

Anal Chem. 2023 May 2. doi: 10.1021/acs.analchem.2c05480. Online ahead of print.ABSTRACTAccurate discrimination and classification of unknown species are the basis to predict its characteristics or applications to make correct decisions. However, for biogenic solutions that are ubiquitous in nature and our daily lives, direct determination of their similarities and disparities by their molecular compositions remains a scientific challenge. Here, we explore a standard and visualizable ontology, termed "biogenic solution map", that organizes multifarious classes of biogenic solutions into a map of hierarchical structures. To build the map, a novel 4-dimensional (4D) fingerprinting method based on data-independent acquisition data sets of untargeted metabolomics is developed, enabling accurate characterization of complex biogenic solutions. A generic parameter of metabolic correlation distance, calculated based on averaged similarities between 4D fingerprints of sample groups, is able to define "species", "genus", and "family" of each solution in the map. With the help of the "biogenic solution map", species of unknown biogenic solutions can be explicitly defined. Simultaneously, intrinsic correlations and subtle variations among biogenic solutions in the map are accurately illustrated. Moreover, it is worth mentioning that samples of the same analyte but prepared by alternative protocols may have significantly different metabolic compositions and could be classified into different "genera".PMID:37130068 | DOI:10.1021/acs.analchem.2c05480

Am J Chin Med. 2023 Apr 28:1-26. doi: 10.1142/S0192415X23500441. Online ahead of print.ABSTRACTDeveloping effective and safe lipid-lowering drugs is highly urgent. This study aims to investigate the effectiveness and underlying mechanisms of Gynostemma pentaphyllum (GP) in the treatment of hyperlipidemia. First, a meta-analysis was performed to determine the lipid-lowering effects of GP. Thereafter, hyperlipidemia was induced in mice using a high-fat diet (HFD) and was subsequently treated with Gynostemma pentaphyllum extract (GPE) by daily gavage for 12 weeks. The body weight, tissue weight, blood lipid level, and liver lipid level were determined. Additionally, mouse serum samples were subjected to metabolomic profiling and feces were collected at different time points for metagenomic analysis via 16S rDNA sequencing. A total of 15 out of 1520 studies were retrieved from six databases. The pooled results of the meta-analysis showed that GP effectively reduced triglyceride levels and increased high-density lipoprotein cholesterol (both [Formula: see text]). Animal experiments revealed that GPE administration significantly reduced body weight, ameliorated high blood lipid levels, limited lipid deposition, and improved insulin resistance. Furthermore, GPE treatment markedly changed the intestinal microbiota structure and constitution of tryptophan metabolites. In conclusion, our results confirm the lipid-lowering effect of GP, which may be partly attributable to regulation of the intestinal microbiota and tryptophan metabolism.PMID:37129524 | DOI:10.1142/S0192415X23500441

Microbiol Spectr. 2023 Apr 27:e0313222. doi: 10.1128/spectrum.03132-22. Online ahead of print.ABSTRACTHeptose metabolites including ADP-d-glycero-β-d-manno-heptose (ADP-heptose) are involved in bacterial lipopolysaccharide and cell envelope biosynthesis. Recently, heptoses were also identified to have potent proinflammatory activity on human cells as novel microbe-associated molecular patterns. The gastric pathogenic bacterium Helicobacter pylori produces heptose metabolites, which it transports into human cells through its Cag type 4 secretion system. Using H. pylori as a model, we have addressed the question of how proinflammatory ADP-heptose biosynthesis can be regulated by bacteria. We have characterized the interstrain variability and regulation of heptose biosynthesis genes and the modulation of heptose metabolite production by H. pylori, which impact cell-autonomous proinflammatory human cell activation. HldE, a central enzyme of heptose metabolite biosynthesis, showed strong sequence variability between strains and was also variably expressed between strains. Amounts of gene transcripts in the hldE gene cluster displayed intrastrain and interstrain differences, were modulated by host cell contact and the presence of the cag pathogenicity island, and were affected by carbon starvation regulator A (CsrA). We reconstituted four steps of the H. pylori lipopolysaccharide (LPS) heptose biosynthetic pathway in vitro using recombinant purified GmhA, HldE, and GmhB proteins. On the basis of one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry, the structures of major reaction products were identified as β-d-ADP-heptose and β-heptose-1-monophosphate. A proinflammatory heptose-monophosphate variant was also identified for the first time as a novel cell-active product in H. pylori bacteria. Separate purified HldE subdomains and variant HldE allowed us to uncover additional strain variation in generating heptose metabolites. IMPORTANCE Bacterial heptose metabolites, intermediates of lipopolysaccharide (LPS) biosynthesis, are novel microbe-associated molecular patterns (MAMPs) that activate proinflammatory signaling. In the gastric pathogen Helicobacter pylori, heptoses are transferred into host cells by the Cag type IV secretion system, which is also involved in carcinogenesis. Little is known about how H. pylori, which is highly strain variable, regulates heptose biosynthesis and downstream host cell activation. We report here that the regulation of proinflammatory heptose production by H. pylori is strain specific. Heptose gene cluster activity is modulated by the presence of an active cag pathogenicity island (cagPAI), contact with human cells, and the carbon starvation regulator A. Reconstitution with purified biosynthesis enzymes and purified bacterial lysates allowed us to biochemically characterize heptose pathway products, identifying a heptose-monophosphate variant as a novel proinflammatory metabolite. These findings emphasize that the bacteria use heptose biosynthesis to fine-tune inflammation and also highlight opportunities to mine the heptose biosynthesis pathway as a potential therapeutic target against infection, inflammation, and cancer.PMID:37129481 | DOI:10.1128/spectrum.03132-22

J Agric Food Chem. 2023 May 2. doi: 10.1021/acs.jafc.3c00559. Online ahead of print.ABSTRACTRice direct seeding technology has been considered as a promising alternative to traditional transplanting because of its advantages in saving labor and water. However, the poor emergence and seedling growth caused by chill stress are the main bottlenecks in wide-scale adoption of direct-seeded rice in Heilongjiang Province, China. Here, we found that natural plant growth regulator guvermectin (GV) effectively improved rice seed germination and seedling growth under chilling stress. Results from 2 year field trials showed that seed-soaking with GV not only enhanced the emergence rate and seedling growth but also increased the panicle number per plant and grain number per panicle, resulting in 9.0 and 6.8% increase in the yield of direct-seeded rice, respectively. Integrative physiological, transcriptomic, and metabolomic assays revealed that GV promoted seed germination under chilling stress mainly by enhancing the activities of α-amylase and antioxidant enzymes (superoxide dismutase, peroxidase, and catalase), increasing the contents of soluble sugar and soluble protein, improving the biosynthesis of glutathione and flavonoids, as well as activating gibberellin-responsive transcription factors and inhibiting the abscisic acid signaling pathway. These findings indicate that seed-soaking with GV has good potential to improve seedling establishment and yield of direct-seeded rice even under chilling stress.PMID:37129443 | DOI:10.1021/acs.jafc.3c00559

Elife. 2023 May 2;12:e82502. doi: 10.7554/eLife.82502.ABSTRACTHearing and vision sensory systems are tuned to the natural statistics of acoustic and electromagnetic energy on earth and are evolved to be sensitive in ethologically relevant ranges. But what are the natural statistics of odors, and how do olfactory systems exploit them? Dissecting an accurate machine learning model (Lee et al., 2022) for human odor perception, we find a computable representation for odor at the molecular level that can predict the odor-evoked receptor, neural, and behavioral responses of nearly all terrestrial organisms studied in olfactory neuroscience. Using this olfactory representation (principal odor map [POM]), we find that odorous compounds with similar POM representations are more likely to co-occur within a substance and be metabolically closely related; metabolic reaction sequences (Caspi et al., 2014) also follow smooth paths in POM despite large jumps in molecular structure. Just as the brain's visual representations have evolved around the natural statistics of light and shapes, the natural statistics of metabolism appear to shape the brain's representation of the olfactory world.PMID:37129358 | DOI:10.7554/eLife.82502

Am J Physiol Gastrointest Liver Physiol. 2023 May 2. doi: 10.1152/ajpgi.00017.2023. Online ahead of print.ABSTRACTThe use of probiotics, prebiotics and synbiotics has become an important therapy in numerous gastrointestinal diseases in recent years. Modifying the gut microbiota, this therapeutic approach helps to restore a healthy microbiome. Nonalcoholic fatty liver disease and alcohol-associated liver disease are among the leading causes of chronic liver disease worldwide. A disrupted intestinal barrier, microbial translocation and an altered gut microbiome metabolism, or metabolome, are crucial in the pathogenesis of these chronic liver diseases. As pro-, pre- and synbiotics modulate these targets, they were identified as possible new treatment options in liver disease. In this review, we highlight the current findings on clinical and mechanistic effects of this therapeutic approach in nonalcoholic fatty liver disease and alcohol-associated liver disease.PMID:37129252 | DOI:10.1152/ajpgi.00017.2023

J Proteome Res. 2023 May 2. doi: 10.1021/acs.jproteome.2c00430. Online ahead of print.ABSTRACTGestational Diabetes Mellitus (GDM) results in complications affecting both mothers and their offspring. Metabolomic analysis across pregnancy provides an opportunity to better understand GDM pathophysiology. The objective was to conduct a metabolomics analysis of first and third trimester plasma samples to identify metabolic differences associated with GDM development. Forty pregnant women with overweight/obesity from a multisite clinical trial of a lifestyle intervention were included. Participants who developed GDM (n = 20; GDM group) were matched with those who did not develop GDM (n = 20; Non-GDM group). Plasma samples collected at the first (10-16 weeks) and third (28-35 weeks) trimesters were analyzed with ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Cardiometabolic risk markers, dietary recalls, and physical activity metrics were also assessed. Four medium-chain acylcarnitines, lauroyl-, octanoyl-, decanoyl-, and decenoylcarnitine, significantly differed over the course of pregnancy in the GDM vs Non-GDM group in a group-by-time interaction (p < 0.05). Hypoxanthine and inosine monophosphate were elevated in the GDM group (p < 0.04). In both groups over time, bile acids and sorbitol increased while numerous acylcarnitines and α-hydroxybutyrate decreased (p < 0.05). Metabolites involved in fatty acid oxidation and purine degradation were altered across the first and third trimesters of GDM-affected pregnancies, providing insight into metabolites and metabolic pathways altered with GDM development.PMID:37129248 | DOI:10.1021/acs.jproteome.2c00430

Anal Chem. 2023 May 2. doi: 10.1021/acs.analchem.2c05783. Online ahead of print.ABSTRACTAs metabolomics grows into a high-throughput and high demand research field, current metrics for the identification of small molecules in gas chromatography-mass spectrometry (GC-MS) still require manual verification. Though steps have been taken to improve scoring metrics by combining spectral similarity (SS) and retention index (RI), the problem persists. A large body of literature has analyzed and refined SS scores, but few studies have explicitly studied improvements to RI scores. Here, we examined whether uninvestigated assumptions of the RI score are valid and propose ways to improve them. Query RIs were matched to library RI with a generous window of ±35 to avoid unintentional removal of valid compound identifications. Each match was manually verified as a true positive (TP), true negative, or unknown. Metabolites with at least 30 TP identifications were included in downstream analyses, resulting in a total of 87 metabolites from samples of varying complexity and type (e.g., amino acid mixtures, human urine, fungal species, and so on.). Our results showed that the RI score assumptions of normality, consistent variance across metabolites, and a mean error centered at 0 are often violated. We demonstrated through a cross-validation analysis that modifying these underlying assumptions according to empirical metabolite-specific distributions improved the TP and negative rankings. Further, we statistically determined the minimum number of samples required to estimate distributional parameters for scoring metrics. Overall, this work proposes a robust statistical pipeline to reduce the time bottleneck of metabolite identification by improving RI scores and thus minimize the effort to complete manual verification.PMID:37129113 | DOI:10.1021/acs.analchem.2c05783

Phytochem Anal. 2023 May 2. doi: 10.1002/pca.3229. Online ahead of print.ABSTRACTINTRODUCTION: Natural products and metabolomics are intrinsically linked through efforts to analyze complex mixtures for compound annotation. Although most studies that aim for compound identification in mixtures use MS as the main analysis technique, NMR has complementary advances that are worth exploring for enhanced structural confidence.OBJECTIVE: This review aimed to showcase a portfolio of the main tools available for compound identification using NMR.MATERIALS AND METHODS: COLMAR, SMART-NMR, MADByTE, and NMRfilter are presented using examples collected from real samples from the perspective of a natural product chemist. Data are also made available through Zenodo so that readers can test each case presented here.CONCLUSION: The acquisition of 1 H NMR, HSQC, TOCSY, HSQC-TOCSY, and HMBC data for all samples and fractions from a natural products study is strongly suggested. The same is valid for MS analysis to create a bridged analysis between both techniques in a complementary manner. The use of NOAH supersequences has also been suggested and demonstrated to save NMR time.PMID:37128872 | DOI:10.1002/pca.3229

Exp Physiol. 2023 May 1. doi: 10.1113/EP091127. Online ahead of print.NO ABSTRACTPMID:37128718 | DOI:10.1113/EP091127

Biotechnol J. 2023 May 1:e2300052. doi: 10.1002/biot.202300052. Online ahead of print.ABSTRACTIn order to find a more effective way to obtain docosahexaenoic acid (DHA) rich lipid from Schizochytrium sp., a widespread propionate wastewater (PW) is used. PW is a common industrial and domestic wastewater, and transforming it into valuable products is a potential treatment method. Schizochytrium sp. is a rapidly growing oleaginous organism, which has been used commercially for DHA production. Herein, PW is completely used for DHA production by Schizochytrium sp. by genetic engineering and fermentation optimization, which can alleviate the increasingly tense demand for water resources and environmental pollution caused by industrial wastewater. Firstly, the methylmalonyl-CoA mutase (MCM) was overexpressed in Schizochytrium sp. to enhance the metabolism of propionate, then the engineered strain of OMCM can effectively use propionate. Then, the effects of PW with different concentration of propionate were investigated, and results showed that OMCM can completely replace clean water with PW containing 5 g/L propionate. Furthermore, in the fed-batch fermentation, the OMCM obtained the highest biomass of 113.4 g/L and lipid yield of 64.4 g/L in PW condition, which is 26.8% and 51.7% higher than that of WT in PW condition. Moreover, to verify why overexpression of MCM can promote DHA and lipid accumulation, the comparative metabolomics, ATP production level, the antioxidant system, and the transcription of key genes were investigated. Results showed that ATP induced by PW condition could drive the synthesis of DHA, and remarkably improve the antioxidant capacity of cells by enhancing the carotenoids production. Therefore, PW can be used as an effective and economical substrate and water source for Schizochytrium sp. to accumulate biomass and DHA. This article is protected by copyright. All rights reserved.PMID:37128672 | DOI:10.1002/biot.202300052