Professional Education


  • Ph.D, Uppsala University, Chemistry (2023)
  • M.MedSc, Uppsala University, Biomedicine (2019)

Stanford Advisors


All Publications


  • Rapid and Bifunctional Chemoselective Metabolome Analysis of Liver Patient Samples Using the Reagent 4-Nitrophenyl-2H-azirine. Angewandte Chemie (International ed. in English) Lin, W., Gerullat, L., Braadland, P. R., Fournier, A., Hov, J. R., Globisch, D. 2024: e202318579

    Abstract

    Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts that has been associated with diverse metabolic carboxylic acids. Mass spectrometric techniques are the method of choice for their analysis. However, the broad investigation of this metabolite class remains challenging. Derivatization of carboxylic acids represents a strategy to overcome these limitations but available methods suffer from diverse analytical challenges. Herein, we have designed a novel strategy introducing 4-nitrophenyl-2H-azirine as a new chemoselective moiety for the first time for carboxylic acid metabolites. This moiety was selected as it rapidly forms a stable amide bond and also generates a new ketone, which can be analyzed by our recently developedquant-SCHEMA method specific for carbonyl metabolites. Optimization of this new method revealed a high reproducibility and robustness, which was utilized to validate 102 metabolic carboxylic acids using authentic synthetic standard conjugates in human plasma samples including nine metabolites that were newly detected. Using this sequential analysis of the carbonyl- and carboxylic acid-metabolomes revealed alterations of the ketogenesis pathway, which demonstrates the vast benefit of our unique methodology. We anticipate that the developed azirine moiety with rapid functional group transformation will find broad application in diverse chemical biology research fields.

    View details for DOI 10.1002/anie.202318579

    View details for PubMedID 38235602

  • Identification of nutritional biomarkers through highly sensitive and chemoselective metabolomics. Food chemistry Lin, W., Mellinghaus, K., Rodriguez-Mateos, A., Globisch, D. 2023; 425: 136481

    Abstract

    The importance of a healthy diet for humans is known for decades. The elucidation of key molecules responsible for the beneficial and adverse dietary effects is slowly developing as the tools are missing. Carbonyl-containing metabolites are a common bioproducts through conversion of diet by the microbiome. In here, we have utilized our recently developed mass spectrometric methodology based on chemoselective conjugation of carbonyl-metabolites. The method has been applied for urine sample analysis from a dietary (poly)phenol intervention study (N = 78 individuals) for the first time. We have identified a series of carbonyl-metabolites of dietary origin and the chemical structure was validated for 30 metabolites. Our sensitive analysis led to the discovery of four unknown dietary markers with high sensitivity and selectivity (AUC > 0.91). Our chemical metabolomics method has been successfully applied for large-scale analysis and provides the basis for targeted metabolomics to identify unknown nutritional and disease-related biomarkers.

    View details for DOI 10.1016/j.foodchem.2023.136481

    View details for PubMedID 37276670

  • Chemoselective bicyclobutane-based mass spectrometric detection of biological thiols uncovers human and bacterial metabolites. Chemical science Kaur, A., Lin, W., Dovhalyuk, V., Driutti, L., Di Martino, M. L., Vujasinovic, M., Löhr, J. M., Sellin, M. E., Globisch, D. 2023; 14 (20): 5291-5301

    Abstract

    Sulfur is an essential element of life. Thiol-containing metabolites in all organisms are involved in the regulation of diverse biological processes. Especially, the microbiome produces bioactive metabolites or biological intermediates of this compound class. The analysis of thiol-containing metabolites is challenging due to the lack of specific tools, making these compounds difficult to investigate selectively. We have now developed a new methodology comprising bicyclobutane for chemoselective and irreversible capturing of this metabolite class. We utilized this new chemical biology tool immobilized onto magnetic beads for the investigation of human plasma, fecal samples, and bacterial cultures. Our mass spectrometric investigation detected a broad range of human, dietary and bacterial thiol-containing metabolites and we even captured the reactive sulfur species cysteine persulfide in both fecal and bacterial samples. The described comprehensive methodology represents a new mass spectrometric strategy for the discovery of bioactive thiol-containing metabolites in humans and the microbiome.

    View details for DOI 10.1039/d3sc00224a

    View details for PubMedID 37234898

    View details for PubMedCentralID PMC10207876

  • Sensitive quantification of short-chain fatty acids combined with global metabolomics in microbiome cultures. Chemical communications (Cambridge, England) Lin, W., García, F. R., Norin, E. L., Kart, D., Engstrand, L., Du, J., Globisch, D. 2023; 59 (39): 5843-5846

    Abstract

    The microbiome has been identified to have a key role for the physiology of their human host. One of the major impacts is the clearance of bacterial pathogens. We have now developed a chemoselective probe methodology for the absolute quantification of short-chain fatty acids at low nM concentrations, with high reproducibility and spiked isotope labelled internal standards. Immobilization to magnetic beads allows for separation from the matrix and the tagged metabolites upon bioorthogonal cleavage can be analyzed via UHPLC-MS. The major advantage of our sensitive method is the simple combination with global metabolomics analysis as only a small sample volume is required. We have applied this chemical metabolomics strategy for targeted SCFA analysis combined with global metabolomics on gut microbiome co-cultures with Salmonella and investigated the effect of antibiotic treatment.

    View details for DOI 10.1039/d3cc01223a

    View details for PubMedID 37098752

  • A frame-shift mutation in COMTD1 is associated with impaired pheomelanin pigmentation in chicken. PLoS genetics Bi, H., Tranell, J., Harper, D. C., Lin, W., Li, J., Hellström, A. R., Larsson, M., Rubin, C. J., Wang, C., Sayyab, S., Kerje, S., Bed'hom, B., Gourichon, D., Ito, S., Wakamatsu, K., Tixier-Boichard, M., Marks, M. S., Globisch, D., Andersson, L. 2023; 19 (4): e1010724

    Abstract

    The biochemical pathway regulating the synthesis of yellow/red pheomelanin is less well characterized than the synthesis of black/brown eumelanin. Inhibitor of gold (IG phenotype) is a plumage colour variant in chicken that provides an opportunity to further explore this pathway since the recessive allele (IG) at this locus is associated with a defect in the production of pheomelanin. IG/IG homozygotes display a marked dilution of red pheomelanin pigmentation, whilst black pigmentation (eumelanin) is only slightly affected. Here we show that a 2-base pair insertion (frame-shift mutation) in the 5th exon of the Catechol-O-methyltransferase containing domain 1 gene (COMTD1), expected to cause a complete or partial loss-of-function of the COMTD1 enzyme, shows complete concordance with the IG phenotype within and across breeds. We show that the COMTD1 protein is localized to mitochondria in pigment cells. Knockout of Comtd1 in a mouse melanocytic cell line results in a reduction in pheomelanin metabolites and significant alterations in metabolites of glutamate/glutathione, riboflavin, and the tricarboxylic acid cycle. Furthermore, COMTD1 overexpression enhanced cellular proliferation following chemical-induced transfection, a potential inducer of oxidative stress. These observations suggest that COMTD1 plays a protective role for melanocytes against oxidative stress and that this supports their ability to produce pheomelanin.

    View details for DOI 10.1371/journal.pgen.1010724

    View details for PubMedID 37068079

    View details for PubMedCentralID PMC10138217

  • Differential regulation of oxidative stress, microbiota-derived, and energy metabolites in the mouse brain during sleep. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Vallianatou, T., Lin, W., Bèchet, N. B., Correia, M. S., Shanbhag, N. C., Lundgaard, I., Globisch, D. 2021; 41 (12): 3324-3338

    Abstract

    Sleep has evolved as a universal core function to allow for restorative biological processes. Detailed knowledge of metabolic changes necessary for the sleep state in the brain is missing. Herein, we have performed an in-depth metabolic analysis of four mouse brain regions and uncovered region-specific circadian variations. Metabolites linked to oxidative stress were altered during sleep including acylcarnitines, hydroxylated fatty acids, phenolic compounds, and thiol-containing metabolites. These findings provide molecular evidence of a significant metabolic shift of the brain energy metabolism. Specific alterations were observed for brain metabolites that have previously not been associated with a circadian function including the microbiome-derived metabolite ergothioneine that suggests a regulatory function. The pseudopeptide β-citryl-glutamate has been linked to brain development and we have now discovered a previously unknown regioisomer. These metabolites altered by the circadian rhythm represent the foundation for hypothesis-driven studies of the underlying metabolic processes and their function.

    View details for DOI 10.1177/0271678X211033358

    View details for PubMedID 34293940

    View details for PubMedCentralID PMC8669215

  • Chemoselective and Highly Sensitive Quantification of Gut Microbiome and Human Metabolites. Angewandte Chemie (International ed. in English) Lin, W., Conway, L. P., Vujasinovic, M., Löhr, J. M., Globisch, D. 2021; 60 (43): 23232-23240

    Abstract

    The microbiome has a fundamental impact on the human host's physiology through the production of highly reactive compounds that can lead to disease development. One class of such compounds are carbonyl-containing metabolites, which are involved in diverse biochemical processes. Mass spectrometry is the method of choice for analysis of metabolites but carbonyls are analytically challenging. Herein, we have developed a new chemical biology tool using chemoselective modification to overcome analytical limitations. Two isotopic probes allow for the simultaneous and semi-quantitative analysis at the femtomole level as well as qualitative analysis at attomole quantities that allows for detection of more than 200 metabolites in human fecal, urine and plasma samples. This comprehensive mass spectrometric analysis enhances the scope of metabolomics-driven biomarker discovery. We anticipate that our chemical biology tool will be of general use in metabolomics analysis to obtain a better understanding of microbial interactions with the human host and disease development.

    View details for DOI 10.1002/anie.202107101

    View details for PubMedID 34339587

    View details for PubMedCentralID PMC8597006

  • Squaric acid as a new chemoselective moiety for mass spectrometry-based metabolomics analysis of amines. RSC chemical biology Lin, W., Yang, Z., Kaur, A., Block, A., Vujasinovic, M., Löhr, J. M., Globisch, D. 2021; 2 (5): 1479-1483

    Abstract

    The investigation of microbiome-derived metabolites is important to understand metabolic interactions with their human host. New methodologies for mass spectrometric discovery of undetected metabolites with unknown bioactivity are required. Herein, we introduce squaric acid as a new chemoselective moiety for amine metabolite analysis in human fecal samples.

    View details for DOI 10.1039/d1cb00132a

    View details for PubMedID 34704052

    View details for PubMedCentralID PMC8496035

  • Rapid Preparation of a Large Sulfated Metabolite Library for Structure Validation in Human Samples. Metabolites Correia, M. S., Lin, W., Aria, A. J., Jain, A., Globisch, D. 2020; 10 (10)

    Abstract

    Metabolomics analysis of biological samples is widely applied in medical and natural sciences. Assigning the correct chemical structure in the metabolite identification process is required to draw the correct biological conclusions and still remains a major challenge in this research field. Several metabolite tandem mass spectrometry (MS/MS) fragmentation spectra libraries have been developed that are either based on computational methods or authentic libraries. These libraries are limited due to the high number of structurally diverse metabolites, low commercial availability of these compounds, and the increasing number of newly discovered metabolites. Phase II modification of xenobiotics is a compound class that is underrepresented in these databases despite their importance in diet, drug, or microbiome metabolism. The O-sulfated metabolites have been described as a signature for the co-metabolism of bacteria and their human host. Herein, we have developed a straightforward chemical synthesis method for rapid preparation of sulfated metabolite standards to obtain mass spectrometric fragmentation pattern and retention time information. We report the preparation of 38 O-sulfated alcohols and phenols for the determination of their MS/MS fragmentation pattern and chromatographic properties. Many of these metabolites are regioisomers that cannot be distinguished solely by their fragmentation pattern. We demonstrate that the versatility of this method is comparable to standard chemical synthesis. This comprehensive metabolite library can be applied for co-injection experiments to validate metabolites in different human sample types to explore microbiota-host co-metabolism, xenobiotic, and diet metabolism.

    View details for DOI 10.3390/metabo10100415

    View details for PubMedID 33081284

    View details for PubMedCentralID PMC7603051

  • Difluoromethylation of Dicyanoalkylidenes by Electrophilic <i>S</i>-(Difluoromethyl)sulfonium Salt: Efficient Construction of Difluoromethylated All-carbon-substituted Centers CHEMICAL JOURNAL OF CHINESE UNIVERSITIES-CHINESE Qin, W., Lin, W., Li, X., Xiong, W., Liu, G. 2020; 41 (10): 2230-2238
  • Sensitive mass spectrometric analysis of carbonyl metabolites in human urine and fecal samples using chemoselective modification. The Analyst Lin, W., Conway, L. P., Block, A., Sommi, G., Vujasinovic, M., Löhr, J. M., Globisch, D. 2020; 145 (11): 3822-3831

    Abstract

    Metabolites with ketone or aldehyde functionalities comprise a large proportion of the human metabolome, most notably in the form of sugars. However, these reactive molecules are also generated through oxidative stress or gut microbiota metabolism and have been linked to disease development. The discovery and structural validation of this class of metabolites over the large concentration range found in human samples is crucial to identify their links to pathogenesis. Herein, we have utilized an advanced chemoselective probe methodology alongside bioinformatic analysis to identify carbonyl-metabolites in urine and fecal samples. In total, 99 metabolites were identified in urine samples and the chemical structure for 40 metabolites were unambiguously validated using a co-injection procedure. We also describe the preparation of a metabolite-conjugate library of 94 compounds utilized to efficiently validate these ketones and aldehydes. This method was used to validate 33 metabolites in a pooled fecal sample extract to demonstrate the potential for rapid and efficient metabolite detection over a wide metabolite concentration range. This analysis revealed the presence of six metabolites that have not previously been detected in either sample type. The constructed library can be utilized for straightforward, large-scale, and expeditious analysis of carbonyls in any sample type.

    View details for DOI 10.1039/d0an00150c

    View details for PubMedID 32393929

  • Investigation of host-microbiota co-metabolism as a new strategy for biomarker discovery: New chemical biology tools for metabolomics analysis Correia, M., Conway, L., Lin, W., Ballet, C., Garg, N., Globisch, D. AMER CHEMICAL SOC. 2019
  • Chemoselective probe for detailed analysis of ketones and aldehydes produced by gut microbiota in human samples. Chemical communications (Cambridge, England) Conway, L. P., Garg, N., Lin, W., Vujasinovic, M., Löhr, J. M., Globisch, D. 2019; 55 (62): 9080-9083

    Abstract

    New strategies are required for the discovery of unknown bioactive molecules produced by gut microbiota in the human host. Herein, we utilize a chemoselective probe immobilized to magnetic beads for analysis of carbonyls in human fecal samples. We identified 112 metabolites due to femtomole analysis and an increased mass spectrometric sensitivity by up to six orders of magnitude.

    View details for DOI 10.1039/c9cc04605d

    View details for PubMedID 31287110

  • Selective <i>O</i>-difluoromethylation of 1,3-diones using S-(difluoromethyl) sulfonium salt CHINESE CHEMICAL LETTERS Liu, G., Li, X., Qin, W., Lin, W., Lin, L., Chen, J., Liu, J. 2019; 30 (8): 1515-1518