These are my personal notes from the 12th International Conference on One-carbon metabolism, B Vitamins and Homocysteine, arranged in Tarragona, Spain, June 9-13.

Return to home.

Take-homes

  • Folate supplementation is effective in reducing NTD, but likely just in a genetically susceptible subset of the population (Amanda MacFarlane)
  • RCTs of tHcy lowering were not powered to detect an expected risk decrease of 10% (Paul Jacques)
  • There is no such thing as a hepatic B12 store maintaining B12 function for years (Ebba Nexø)

Sunday

Honorary lectures

Methionine Synthase - the beating heart in a complex system

Anne Molloy

  • Methyltransferases has higher affinity for SAH compared to SAM
  • Impossible to develop an animal model of B12-deficiency related neuropathy, so far.
  • Without MS, folate is diverted to mTHF, which has no known way to go (The methyl folate trap)
    • High methionin partly ameliorates the folate trap, due to SAM-inhibition of MTHFR

Epigenetics and DNA methylation in health and disease

Manel Esteller

  • Genome - Epigenome - Transcriptome - Epitranskriptome - Proteome
  • As we age we lose methylation, increasing the expression of many genes
  • DNA methylation is a good marker of biological age

Metabolomics implicates amino acid metabolism as a key node in cardiometabolic disease pathogenesis

Chris Newgard

  • Metabolomic flux analysis (“fluxomics”) - stable isotope tracers
  • BCAA and insulin resistance (Newgard 2009)
  • What are the cellular and metabolic mechanisms?
    • WHen BCCA is high, glycine is depleted by driving the pyruvate-alanine cycle. BCAA restriction improves insulin sensitivity and restore glycine in zucker rats (White 2016)
  • Is manipulation of BCAA metabolism a viable target for treatment?
    • Inhibition of BCKDH or overexpression of PPM1K reduces hepaatic triglyceride accumulation (White2018)
  • Review paper: Branched-chain amino acids in disease (White 2019 )

Monday

Plenary session 1: A Multidiciplinary approach to understanding one-carbon metabolism from the nucleus to the clinic

Folate-dependent molecular mechanisms and metabolic disorders

Sergey Krupenko

  • Formaldehyde detoxification in human cells generates formate, which is a meaningful source of one-carbon units (Burgos-Barragan 2017)
  • Folate might regulate histone demethylation, with a mechanism similar to DMGDH and SARDH (Luka 2011,Luka 2014, Garcia 2016)
  • Cytosolic THF accumulates in absence of mitochondrially produced formate (Zheng 2018)
  • ALDH1L1 catalyzed 10-formylTHF to THF conversion. This enzyme is hypermethylated and silenced during cancer.
  • 40% of NADPH is produced in one-carbon metabolism, including from ALDH1L1 (Fan 2014)

The role of perturbed B-vitamin status in the development of pathogeneic mechanisms: evidence from animal studies

Amanda MacFarlane

Criticism of animal studies

  • Failure to predict human responses
    • Folate-deficient mice do not develop NTD (Heid 1992). Folate-sensitive NTD are underpinned by gene-diet interactions, where susceptible individuals develop NTD when folate deficient. Mouse data supports that folate supplementatuin is effective in the subset of susceptible individuals.
    • Animal models refine our understanding of the underlying mechanisms. For instance through knockout-models.
  • Don’t reflect nutrient-disease relationships
    • Folate deficiency increases colon cancer in SHMT-/- mice, but not in wild-type (MacFarlane 2008, 2009)
  • Not reproducible duet to different study design
    • Different strains respond differently. Studies often includes male animals only etc.
    • Different tissues might respond in different, often opposite, ways. Depending on which tissue is studied, the observations may differ.
    • Control diet and supplementation dose differ vastly
    • Inconsistent reporting and often lack of transparency

The role of B-vitamins in health and disease: the snakes and ladders of evidence from human observational studies and trials

Paul Jacques

  • RCTs and observational studies often do noe address the same research question

Nutritional interventions vs observational studies

  • Inherent differences
    • random assignment
  • Incidental differences
    • Secondary vs primary prevention
      • Different subjects in secondary (high risk) vs primary (low risk) prevention
      • Interventions are expected to yield an effect in the short term, prevention in the long-term
      • Drugs yield large effect sizes for the individual, vs small effects in primary prevention
      • Background exposure, common in primary prevention - everybody eat
    • Modeling
      • High vs low (observational studies). The difference from low to high may be large and important.
      • High vs average (intervention). The differences between average and high exposure may be less pronounced, making it difficult to find differences when recruiting from the general population with average intakes.

Homocysteine and CVD

  • Observational studies
    • 25% lower tHcy associated with reduced risk (Homocysteine studies collaboration)
    • Stroke mortality rate dramatically decreased after folate fortification (Yang 2006). Similar data for CVD mortality were not published.
  • RCT
    • All but one (CSSPP) performed in sick populations (secondary prevention)
    • Based on the observational studies, we should expect a maximum of 10% decrease in risk with 25% reduction in tHcy. None of the performed studies have sufficient power to identify this effect size. (Bostom 2009)
    • Folate supplementation decreases risk among patients without previous CVD or with low plasma folate levels (Li 2009)

The multidiciplinary making of the MTHFR story: Past, present and future

Joshua Miller

  • Discovery of MTHFR (Donaldson 1962)
  • Meta-analyses of MTHFR C677T and disease risk (bilde)
  • Internet mythology
    • Folic acid is toxic/doesn’t work for individuals with the MTHFR mutations
  • MTHFR cannot be seen in isolation
    • Folic acid is converted to DHF, but folic acid also inhibits DHFR, reducing conversion to THF
    • DHF inhibits MTHFR, can accumulating DHF reduce MTHFR activity?
    • MTHFR should be seen in context of folic acid supplementation, choline/betaine/B12 status etc

Plenary session 2: Pre-natalfunction/dysfunction of folate and one-carbon metabolism

One-carbon metabolism: Linking nutritional biochemistry to epigenetic programming of life-time development

Kevin Sinclair

  • Paternal low-protein diet led to global hypomethylation in offspring of BL/6 mice (Watkins 2014, 2018)

Tuesday

Plenary session 4

Transsulfuration and further downstream catabolism of H2S

Victor Kozich

  • H2S can be endogenously synthesized, produced by the gut microbiota and ingested.
    • 5 enzymyes produce H2S, including CBS and CGL
  • H2S is catablized in mitochondria, by condensing with glutathione. The end product is sulfate.

Wednesday

Plenary session 7

Revisiting treatment and prevention of vitamin B12 deficiency

Ebba Nexo

  • Guesstimate of 3 mg total B12 content
  • Bariatric surgery and B12 status, data published (Kornerup 2019)
  • There are no such thing as a liver store maintaining B12 status for a long time. Depletion starts once absorption decreases.
  • Severely impaired B12 status should be normalized in a 2-step procedure, first normalizing with high doses and then maintain with lower dose.
  • Rat studies show that OH- and CN-B12 differ. OH-B12 is better converted to AdoCbl, CN-B12 mainly accumulates in kidney.
    • Plasma B12 should not be taken too seriously
  • Mahalle 2019, unpublished data. Indian people supplemented with OH or CN-B12, 2x2.8 µg/day. Plasma B12 increases much more after CN-B12, but the biomarkers are similarly affected.
  • Increased plasma B12 does not imply superiority of CN-B12

Achieving optimal folate status for health

Helene McNulty

  • Folic acid is fully oxidized and in monoglutamate form, while food folate are reduced and in polyglutamate form. Hence, folic acid are more bioavailable.
  • The potential to optimise folate status with natural folates are very limited

Thursday

Plenary session 9

Homocysteine: From disease biomarker to disease prevention

David Smith

  • Tyranny of dogma,
    • Cholesterol was prioritized - Homocysteine is dead
    • Kilmer McCully lost his job at Harvard
  • Tyranny of systematic reviews and meta-analysis, combining different studies
  • Basic errors like ignoring changes in placebo group, nutrient status, sub grups and intereactions
  • Homocysteine in 2019 - associated with the risk of everything
  • HOPE-2 reported a beneficial effect of B-vitamins on stroke, but it was hidden in the supplement because the finding was hard to explain…
  • Subgroup analyses founded in biology is important (Spence and Stampfer 2011)
  • tHcy is dose-response associated with cerebral small vessel disease and dementia (Nam 2019, Beydoun 2014 and Smith 2018)
  • All studies on B-vitamins should stratify for omega-3-status

Choline supplementation does not promote atherosclerosis in CETP-expressing male ApoE-knockout mice

Heidi Collins

  • Mice does not have CETP
  • In mice modified to express CETP, choline did not increase atherosclerosis, despite a dose-response increse in TMAO.

Micronutrients, anaemia and cognitive functions: findings from the TUDA study

Eamon Laird

  • Anaemia and cognitive impairment doesn’t differ between gender, but increases with age
  • Older adults with anaemia is more likely to have cognitive impairment