Introduction
Biography of Professor Jean-Louis GUEANT
Jean-Louis Guéant, MD, PhD, DSc and specialized in Hepato-Gastroenterology is Professor of Biochemistry-Molecular Biology (PU-PH CE2) at Université de Lorraine.
He is Director of UMR-S Inserm 1256 “Nutrition-Genetics-Environmental Exposure” at the University of Lorraine and coordinator of the Federation of Clinical Research ARRIMAGE of the University hospital centers of the region Grand Est.
In the University Regional Hospital of Nancy, he is Head of the Department of Biochemistry-Molecular Biology and Nutrition and has a clinical activity in the department of Hepato-Gastroenterology, National Reference Center of inherited Metabolic Diseases.
In France, he is President of the section of Medical Biochemistry-Molecular Biology, Physiology, Cell Biology and Nutrition of the National Committee of Universities, President of the National Commission of Medical Biology, and Titular Member of the National Academy of Medicine. He is national coordinator of the teaching program in Genetics and Molecular Medicine (FST MD specialization)
He has organized/chaired five international congresses since 2010, including two SRC FASEB conferences (chair SRC Epigenomics in Health and diseases in 2021 and co-chair “The Folate, Vitamin B12, and One-Carbon Metabolism” in 2022 and is chair of the forthcoming 2024 FASEB SRC on the same topic and is regularly invited to international conferences as speaker and session chair. He is member of the editorial board of Hum Genet, Nutrients and Vitamins and Hormones.
His scientific production includes 459 articles in Pub Med, with an H index at 71 and 19500 cites, with publications in N Engl J Med, The Lancet, Science, Nature Comm, Cell Rep Medicine, Nature Rev Disease Primers, PNAS, Ann Intern Med, Gastroenterology, Gut, J Hepatology, Nucleic acid Research, Allergy, J Allergy Clin Immunol, Blood, etc…
He ranked as the top world expert in the items vitamin B 12 deficiency and Methionine synthase and second in the item of vitamin B deficiencies in expertscape (https://expertscape.com/). He has described key mechanisms of digestive transport and metabolism of vitamin B12 and folate, the influence of the one carbon metabolism on the epigenome, cellular stress, energy metabolism and fetal programming in rare and complex metabolic diseases and a new type of B12 rare metabolic disease produced by an epimutation in the MMACHC gene promoter and named “Epi-cblC.” He has also dissected genetic predictors and mechanisms of allergic drug reactions,
He has Supervised 41 PhD Theses and is co-author of 5 patents.
He has received the Distinguish Scientist Award of the Sigrid Juselius Foundation (Finland), the AGAF award of the American Gastroenterological Association, and the “Prix Elise Cailleret” of the French National Academy of Medicine.
Scientific contributions in the past five years
The foetal effects of the deficiency in methyl donors during pregnancy and lactation on metabolic disorders related to obesity are linked to decreased expression and activity of sirtuins. We have shown that the maternal deficiency in methyl donors (MDD, vitamin B12 and folate) during pregnancy and lactation of rodents produces a low birth weight and an epigenomic Sirt1-dependent dysregulation of mitochondrial energy production and fatty acid oxidation in offspring (Kosgei et al, 2021, Cells, Battaglia et al, Nucleic Acid Research, 2018, Harb et al. 2021, J Nutr Biochem). We investigated the cardiovascular consequences of MDD foetal programming (iMDD) of rat pups along life. Developmental programming by iMDD produces cardiomyopathy in female offspring exposed to HF. (Li et al, Mol Nutr Food Res, 2021). MDD fetal programming produces altered integrity and remodeling of ascending aorta during aging and irreversible MARS-associated homocysteinylation of key proteins of extracellular matrix and elastin homeostasis (Ballint et al, ATVB, 2021).
The links between methyl donors status and one carbon metabolism with metabolic disorders related to obesity. We explored the deficit in vitamin B12 vs other micronutrients during the follow-up of the ALPDEPI/OBESEPI cohort of cases with bariatric surgery under systematic multivitamin/trace elements supplementation and to determine whether it was influenced by clinical, metabolic characteristics at surgery. We shwoed that the worsening of B12 deficit rate in the 18-24 months follow-up depends in part to low liver storage capacity of B12 at time of bariatric surgery (Antoine et al, Clin Nutr, 2021). Age and high RBC folate were independently associated with the number of metabolic syndrome components. Our findings challenge the benefit of folate fortified food in severe obesity, in particular in patients with a deficit of vitamin B12 (Li et al, Clin Nutr, 2018). We evaluated the association of intermediate (30–50 and 50-100 μmol/L) and severe (> 100 μmol/L) HHcy related to vitamin deficiencies and/or inherited disorders with CVD outcomes in a retrospective cross-sectional study on 1006 consecutive patients who underwent a homocysteine assay in CHRU Nancy. Our study points out the importance of diagnosing and treating nutritional deficiencies and inherited disorders to reverse intermediate/severe HHcy associated with CVD outcomes (Levy et al, Am J Clin Nutr, 2021).
The deficiency in methyl donors during pregnancy and lactation produces early and long term effects in brain. The stimulation of neurogenesis improves the cognitive status of aging rats subjected to gestational and perinatal MDD (Pourié G, et al, Int J Mol Sci. 2020). MDD during gestation and lactation in rats affects the expression of neuropeptides and related receptors in the hypothalamus (Saber cherif et al Int J Mol Sci. 2019) and sex and age differences in the deleterious effects on neuronal layer integrity in growing young rats (Hassan et al Int J Mol Sci. 2019). Wnt signaling pathways are dysregulated in rat female cerebellum following early MDD (Willekens J et al, Mol Neurobiol. 2019). MDD deficiency during pregnancy and lactation resulted in growth retardation, delayed ossification, brain atrophy and cognitive deficits, along with altered brain level of let-7a, miR-34a and miR-23a, in weaned pups. the continuation of folate supplementation after birth may help to ameliorate neurological symptoms (Geoffroy A, et al., Int J Mol Sci. 2019). We showed that N-homocysteinylation of cell proteins by MARS is a key mechanism of fetal programing and aging, We studied the cellular consequences of the increased cellular homocysteine produced by impaired MS activity, in particular the N- homocysteinylation of functional proteins involved in tau and Map1 proteins, and other proteins involved in cytoskeleton and cell signaling in human brains and our rat model (Bossenmeyer-Pourié C et al. 2019, J Pathol).
The dissection of the molecular mechanisms of inherited disorders of the one carbon metabolism highlights a mislocalization of RNA binding proteins and altered splicing and methylation of RNA. (Battaglia-Hsu et al. 2018, Nucle Acid Research). The mislocalization of HuR triggers the decreased expression of SIRT1 and other genes involved in brain development, neuroplasticity, myelin formation, and brain aging, in the transcriptomic analysis of TO cells (Battaglia-Hsu et al. 2018, Nucleic Acid Research, Ghemrawi et al. 2019, Cell Death Dis). The RNA motifs associated with the differential splicing highlight a role of RBP such as HuR and HNRNPL. Proteomic analysis confirmed that mRNA processing was significantly disturbed (Rashka et al. 2020).
Cd320 KO mouse is a model for studying the pathomechanisms of brain outcomes and behavorial deficits of IECM. The Cd320-/- mouse model presented with impaired learning memory that could be alleviated by a moderate stress with increased plasma cortisol, compared to wild type animals (Dreumont et al. 2021). At the molecular level, the glucocorticoid nuclear receptor (GR)/PPAR-gamma co-activator-1 alpha (PGC-1α) pathway is impaired, with decreased expression of GR, decreased methylation of GR and PGC1- α and decreased dimerization and interaction of GR with PGC1-α (Dreumont et al. 2021). m6A methylation in mRNA could be one of the contributing mechanisms that underlie the neurological manifestations produced by vitamin B12 deficiency (Mosca et al, Mol Nutr Food Res, 2021).
We evaluated the rescue of the mislocalization of RBP by SIRT1 agonists as potential strategy in the treatment of severe cases of IECM who are resistant to classical treatments. The SIRT1 activating compounds inhibit ER stress and rescues RBP and mRNA mislocalization and IRF3 splicing in patient fibroblasts (Ghemrawi et al. 2019). SRT1720 and SRT2104 decrease cellular stress and RBP mislocalization and improves the deficient hippocampo-dependent learning ability in Mtr KO mice compared to wild type mice. These data open perspectives for the use of SIRT1 activating compounds as a novel therapeutic strategy to treat IECM especially for patients with poor response to conventional therapy (Ghemrawi et al., 2019).
The EFFET randomized placebo-controlled trial of folinic acid in autism spectrum disorders. The EFFET randomized placebo-controlled trial (NCT02551380) study showed significant efficacy of folinic acid with an oral formulation that is readily available (Renard et al, Biochimie, 2020).
The discovery of an inherited disorder of the one carbon metabolism due to an epimutation. The cblC disease is due to mutations in the MMACHC gene and is the most frequent inborn disorder of cobalamin metabolism (IDCM) (Greene,..Guéant et al. Nature Dis Primers, 2017). We discovered a new IDCM that we named epi-cblC. Using DNA methylome profiling, we identified an MMACHC epimutation that was present in three generations and in the sperm of the fathers of two cases. We subsequently found it in five other patients from Europe and the United States (Guéant et al. Nature Communication, 2018). The antisense aberrant transcription through the promoter produces a cis epimutation in the MMACHC/CCDCD163P promoter and the TESK2 promoter neighboring CCDC163P with subsequent MMACHC and TESK2 transcriptional silencing (Guéant et al. Nature communication 2018 and Oussalah et al, Clin Epigenetics, 2022). To date, Epi-cblC has been diagnosed in 20 cases worldwide, including 11 new cases identified by newborn screening in Tuscany (Cavicchi et al. Clin Epigenetics, 2021), and 2 new cases from China. Among the Italian cases, one had a homozygous MMACHC epimutation related to a PRDX1 c.515-1G>T homozygous mutation. In one of the two cases from China, no PRDX1 variant was detected in the second epi-cblC, suggesting to consider the hypothesis that the epimutation could be also triggered by a non-genetic mechanism (Guéant et al, Human Genetics, 2021). The comparison of epigrams of two monozygotic twins suggest that the aberrant transcription could also be influenced by post-zygotic environmental exposures (Guéant et al, Human Genetics, 2021).
Epigenomics, one carbon metabolism and Cancer. Methionine dependency is a metabolic profile characteristic of many cancer cells, which unlike non-cancerous cell lines cannot survive in a medium supplemented with homocysteine but lacking methionine (Gueant et al. Biochimie, 2020). Previous studies from our and other groups have showed that methionine dependency is linked to cancer stemness, in glioblastoma cells (Zgheib et al, Cell Death Dis, 2019). We showed also that methionine dependency can be produced by epigenetic mechanisms and that a cellular stress like ionising irradiation may lead to epigenetic alteration linked to methionine dependency and increased cancer stemness capacity, cell cycle and division, sustained angiogenesis, tissue invasion, and metastasis. These results provide insight on shared adaptive mechanisms of the epigenome in cancerous cell lines in response to IR. Future experiments should focus on the tryptic association between IRs, the initiation of a radioresistance phenotype, and their interaction with methionine dependency as a hallmark of metabolic adaptation in cancer (Siblini et al, Clin Epigenetics, 2021).
Epigenomics and hepatocellular carcinoma. Liver cancer represents a global health challenge, with an estimated annual incidence of over one million cases by 2025. In a proof of concept study, we demonstrated that the circulating plasma epigenetic biomarker mSEPT9 (HCC Blood test®, approved by the FDA) had good diagnostic performances for the detection and exclusion of diagnosis of HCC in cirrhotic patients (Oussalah et al, EBioMedicine 2018).
Genetics and environmental exposure in inherited metabolic and developmental disorders. Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism in Europe. We provide evidence on the combination of evolutionary and adaptive events in populations with distinct ancestries, which may explain the overdominance of some genetic variants on PAH (Oussalah et al, EBioMedicine, 2020).
Genetic determinants of drug allergy. We showed that GNAI2 is a Significant predictor of NSAID-induced hypersensitivity in genome-wide high density genotyping of immune loci performed in two case-control populations from Spain. (Blanca et al, Allergy, 2020).
Nonimmediate (delayed)-allergic reactions to penicillins are common and some of them can be life-threatening. The genetic factors influencing these reactions are unknown/poorly known/poorly understood. We assessed the genetic predictors of a delayed penicillin allergy that cover the HLA loci. We showed that the HLA-DRB3 locus is strongly associated with an increased risk of delayed penicillin hypersensitivity, at least in Southwestern Europe (Romano et al, Allergy, 2021).
Metabolic pathomechanism of Covid-19 severity. In the context of the pandemy, we aim to contribute to the general effort to better know the assessment of the disease and the need for biomarkers predictors of severity, during the containment. Neutrophils participate in the first-line host response against viral infections. Neutrophils have an arsenal of defensive strategies which include the release of elastase from neutrophils (NE) and the formation and release of extracellular neutrophils (Neutrophil Extracellular Traps, NET). NETs are histone-DNA components of dying neutrophils, primarily degraded by DNase 1 and DNase 1L3. Blood levels of MPO-DNA and free DNA are increased in SARS-CoV-2 infection, including outpatient cases diagnosed in the first week of infection (Guéant et al. Allergy, March 2020). We carried out subsequently a multicenter study in 155 cases, recruited consecutively from a screening center, local hospitals and two regional university hospitals in France. NE and histone-DNA were associated with ICU admission, lung injury. NE was an independent predictor of multi-organ injury and COVID-19 CT score. These results highlight the involvement of the exacerbation of innate neutrophil immunity in severe and systemic manifestations of COVID-19 (Guéant et al, Allergy, June 2020). We were among the first to show a significant association between kidney dysfunction and the risk of COVID-19-related acute respiratory failure and death (Oussalah et al, EBiomedicine, 2020). This concerns in particular Fanconi syndrome (Kormann R et al, Clin Kidney J, 2020). In patients with severe COVID-19, data were scarce and conflicting as to whether chronic use of angiotensin converting enzyme inhibitors (ACEIs) or an angiotensin receptor antagonist (ARA) influences the severity of the course of the disease. Patients chronically treated with ACEI / ARA and with severe COVID-19 have an increased risk of acute kidney injury. In these patients, the increase in urea associated with the use of ACEI / ARA could predict the development of acute respiratory failure (Oussalah et al, Clin Infect Dis, 2020).
Selection of 15 publications from the past 5 years (with JCR IF 2021):
1.Broséus J, Hergalant S, Vogt J, Tausch E, Kreuz M, Mottok A, Schneider C, Dartigeas C, Roos-Weil D, Quinquenel A, Moulin C, Ott G, Blanchet O, Tomowiak C, Lazarian G, Rouyer P, Chteinberg E, Bernhart SH, Tournilhac O, Gauchotte G, Lomazzi S, Chapiro E, Nguyen-Khac F, Chery C, Davi F, Hunault M, Houlgatte R, Rosenwald A, Delmer A, Meyre D, Béné MC, Thieblemont C, Lichter P, Ammerpohl O, Guéant JL; ICGC MMML-Seq Consortium. Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis. Nat Commun. 2023 ;19;14(1):309. (IF: 17.7)
2.Wiedemann A, Oussalah A, Lamireau N, Théron M, Julien M, Mergnac JP, Augay B, Deniaud P, Alix T, Frayssinoux M, Feillet F, Guéant JL. Clinical, phenotypic and genetic landscape of case reports with genetically proven inherited disorders of vitamin B12 metabolism: A meta-analysis. Cell Rep Med. 2022;3(7):100670. (IF: 17)
3.Li Y, Tan Z, Zhang Y, Zhang Z, Hu Q, Liang K, Jun Y, Ye Y, Li YC, Li C, Liao L, Xu J, Xing Z, Pan Y, Chatterjee SS, Nguyen TK, Hsiao H, Egranov SD, Putluri N, Coarfa C, Hawke DH, Gunaratne PH, Tsai KL, Han L, Hung MC, Calin GA, Namour F, Guéant JL, Muntau AC, Blau N, Sutton VR, Schiff M, Feillet F, Zhang S, Lin C, Yang L. A noncoding RNA modulator potentiates phenylalanine metabolism in mice. Science. 2021;373(6555):662-673. (IF: 41.8)
4.Balint B, Hergalant S, Camadro JM, Blaise S, Vanalderwiert L, Lignières L, Guéant-Rodriguez RM, Guéant JL. Fetal Programming by Methyl Donor Deficiency Produces Pathological Remodeling of the Ascending Aorta. Arterioscler Thromb Vasc Biol. 2021;41(6):1928-1941. (IF: 10.5)
5.Levy J, Rodriguez-Guéant RM, Oussalah A, Jeannesson E, Wahl D, Ziuly S, Guéant JL. Cardiovascular manifestations of intermediate and major hyperhomocysteinemia due to vitamin B12 and folate deficiency and/or inherited disorders of one-carbon metabolism: a 3.5-year retrospective cross-sectional study of consecutive patients. Am J Clin Nutr. 2021;113(5):1157-1167. (IF: 8.5). With Editorial
6.Oussalah A, Gleye S, Clerc Urmes I, Laugel E, Callet J, Barbé F, Orlowski S, Malaplate C, Aimone-Gastin I, Caillierez BM, Merten M, Jeannesson E, Kormann R, Olivier JL, Rodriguez-Guéant RM, Namour F, Bevilacqua S, Losser MR, Levy B, Kimmoun A, Gibot S, Thilly N, Frimat L, Schvoerer E, Guéant JL. Long-term ACE Inhibitor/ARB Use Is Associated With Severe Renal Dysfunction and Acute Kidney Injury in Patients With Severe COVID-19: Results From a Referral Center Cohort in the Northeast of France. Clin Infect Dis. 2020;71(9):2447-2456. (IF: 21)
7.Oussalah A, Jeannesson-Thivisol E, Chéry C, Perrin P, Rouyer P, Josse T, Cano A, Barth M, Fouilhoux A, Mention K, Labarthe F, Arnoux JB, Maillot F, Lenaerts C, Dumesnil C, Wagner K, Terral D, Broué P, De Parscau L, Gay C, Kuster A, Bédu A, Besson G, Lamireau D, Odent S, Masurel A, Rodriguez-Guéant RM, Feillet F, Guéant JL,* Namour F.* Population and evolutionary genetics of the PAH locus to uncover overdominance and adaptive mechanisms in phenylketonuria: Results from a multiethnic study. EBioMedicine. 2020 Jan;51:102623. *Equal contribution (IF: 11.2)
8.Guéant JL, Guéant-Rodriguez RM, Fromonot J, Oussalah A, Louis H, Chery C, Gette M, Gleye S, Callet J, Raso J, Blanchecotte F, Lacolley P, Guieu R, Regnault V. Elastase and exacerbation of neutrophil innate immunity are involved in multi-visceral manifestations of COVID-19.
Allergy. 2021;76(6):1846-1858. (IF: 14.7)
9.Blanca M, Oussalah A, Cornejo-García JA, Blanca-López N, Guéant-Rodriguez RM, Doña I, Mayorga C, Chery C, Rouyer P, Carmona FD, Bossini Castillo L, Canto G, Martin J, Torres MJ, Guéant JL. GNAI2 variants predict nonsteroidal anti-inflammatory drug hypersensitivity in a genome-wide study. Allergy. 2020;75(5):1250-1253. (IF: 14.7)
10.Oussalah A, Gleye S, Urmes IC, Laugel E, Barbé F, Orlowski S, Malaplate C, Aimone-Gastin I, Caillierez BM, Merten M, Jeannesson E, Kormann R, Olivier JL, Rodriguez-Guéant RM, Namour F, Bevilacqua S, Thilly N, Losser MR, Kimmoun A, Frimat L, Levy B, Gibot S, Schvoerer E, Guéant JL. The spectrum of biochemical alterations associated with organ dysfunction and inflammatory status and their association with disease outcomes in severe COVID-19: A longitudinal cohort and time-series design study. EClinicalMedicine. 2020 Oct;27:100554. (IF:17)
11.Ghemrawi R, Arnold C, Battaglia-Hsu SF, Pourie G, Trinh I, Bassila C, Rashka C, Wiedemann, A, Flayac J, Robert A, Dreumont N, Feillet F, Gueant JL* and Coelho D*. SIRT1 activation rescues the mislocalization of RNA-binding proteins and cognitive defects induced by inherited cobalamin disorders. Metabolism. 2019;101:153992. *Equal contribution (IF: 13.9)
12.Battaglia-Hsu SF, Ghemrawi R, Coelho D, Dreumont N, …Guéant JL. Inherited disorders of cobalamin metabolism disrupt nucleocytoplasmic transport of mRNA through impaired methylation/phosphorylation of ELAVL1/HuR. Nucleic Acids Res. 2018;46:7844-7857. (IF: 19.2)
13.Guéant JL, Chéry C, Oussalah A, Nadaf J, …..Rosenblatt DS. APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients. Nature Commun. 2018;9:67. (IF: 17.7)
14.Oussalah A, Rischer S, Bensenane M, Conroy G, Filhine-Tresarrieu P, Debard R, Forest-Tramoy D, Josse T, Reinicke D, Garcia M, Luc A, Baumann C, Ayav A, Laurent V, Hollenbach M, Ripoll C, Guéant-Rodriguez RM, Namour F, Zipprich A, Fleischhacker M, Bronowicki JP, Guéant JL. Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma. EBioMedicine. 2018 Apr;30:138-147. (IF: 11.2)
15.Green R, Allen LH, Bjørke-Monsen AL, Brito A, Guéant JL, et al. Vitamin B(12) deficiency. Nature Rev Dis Primers. 2017;3:17040. (IF : 65.0)
Recent and ongoing Research Support of NGERE Inserm 1256 with JL Guéant as PI or co-P or PI WP
- European project UE HDHL – Nutrition & the Epigenome (2019-2022) : Total 860 k€, N-GERE 250 k€
- European project DrNanoDall (2021-2023) : Total 670 k€, N-GERE 174 k€
- Project ANR international NUTTMed (2018-2022): total 710 k€, N-GERE 230 k€
- Project OMAGE (2019-2022), total 1.1k€
- University of excellence I-site GEENAGE 460 k€ (2017-2020)
- Project ANR EoiGONE (2023-2025). Total 450 k€, N-GERE 270 k€
- Other grants (FRM, JL, UL, Inotrem), 250 k€
