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Vitamin B₁₂ is a limiting factor for induced cellular plasticity and tissue repair.

ABSTRACT: Transient reprogramming by the expression of OCT4, SOX2, KLF4 and MYC (OSKM) is a therapeutic strategy for tissue regeneration and rejuvenation, but little is known about its metabolic requirements. Here we show that OSKM reprogramming in mice causes a global depletion of vitamin B₁₂ and molecular hallmarks of methionine starvation. Supplementation with vitamin B₁₂ increases the efficiency of reprogramming both in mice and in cultured cells, the latter indicating a cell-intrinsic effect. We show that the epigenetic mark H3K36me3, which prevents illegitimate initiation of transcription outside promoters (cryptic transcription), is sensitive to vitamin B₁₂ levels, providing evidence for a link between B₁₂ levels, H3K36 methylation, transcriptional fidelity and efficient reprogramming. Vitamin B₁₂ supplementation also accelerates tissue repair in a model of ulcerative colitis. We conclude that vitamin B₁₂, through its key role in one-carbon metabolism and epigenetic dynamics, improves the efficiency of in vivo reprogramming and tissue repair.

SUBMITTER: Kovatcheva M

PROVIDER: S-EPMC10663163 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Vitamin B12 is a limiting factor for induced cellular plasticity and tissue repair.

Kovatcheva Marta M Melendez Elena E Chondronasiou Dafni D Pietrocola Federico F Bernad Raquel R Caballe Adrià A Junza Alexandra A Capellades Jordi J Holguín-Horcajo Adrián A Prats Neus N Durand Sylvere S Rovira Meritxell M Yanes Oscar O Stephan-Otto Attolini Camille C Kroemer Guido G Serrano Manuel M

Nature metabolism 20231116 11

Transient reprogramming by the expression of OCT4, SOX2, KLF4 and MYC (OSKM) is a therapeutic strategy for tissue regeneration and rejuvenation, but little is known about its metabolic requirements. Here we show that OSKM reprogramming in mice causes a global depletion of vitamin B12 and molecular hallmarks of methionine starvation. Supplementation with vitamin B12 increases the efficiency of reprogramming both in mice and in cultured cells, the latter indicating a cell-int ...[more]

PMID: 37973897

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Project description:Vitamin B12 (cobalamin, herein B12) is a key cofactor for most organisms being involved in essential metabolic processes. In microbial communities, B12 is often scarce, largely because only few prokaryotes can synthesize B12 de novo and are thus considered B12-prototrophs. B12-auxotrophy is mostly manifested by the absence of the B12-independent methionine synthase, MetE. Here, we focus on bacteria that we classified as facultative B12 consumers as they encode both B12-independent and -dependent (MetH) methionine synthases yet largely cannot synthesize B12 de novo. The genus Vibrio belongs to this group, and our work shows that upon B12 supply growth of Vibrio campbellii is accelerated and autoinducer-2 (AI-2) concentrations are enhanced. We speculate that methionine synthesis efficiency, dependent on B12 availability, is linked to AI-2 synthesis. The precursor for AI-2 synthesis is S-adenosyl-L-homocysteine (SAH), which in turn requires methionine as a precursor. In almost all Vibrio species studied, btuF (B12-binding protein), which is required for B12 uptake, and cobD (Adenosylcobinamide-phosphate synthase), which enables remodeling of B12-like compounds, are encoded on the same operon as pfs (or mtnN, Adenosylhomocysteine nucleosidase), the first enzyme in the two-step AI-2 synthesis reaction. Transcriptomic analyses show that virulence factors, such as toxin synthesis, fimbriae formation, and activation of the type-6 secretion system, which have been shown to be regulated by quorum sensing via AI-2, are significantly upregulated in V. campbellii when B12 is available. Our results demonstrate that V. campbellii is a facultative B12 consumer and indicate that B12 availability affects AI-2 levels and thus potentially virulence factor regulation.IMPORTANCEMetabolites play a key role in microbial metabolism and communication. While vitamin B12 is an essential cofactor for important enzymatic reactions, autoinducer-2 mediates interspecies signaling and can regulate the expression of genes that are crucial for virulence and survival. In our study, we hypothesize and present findings how these two important metabolites are linked in Vibrio species. Vibrio campbellii grows without B12 but at an accelerated rate when B12 is present, and we detect higher AI-2 values in cultures with B12 amendment. Transcriptome analyses show how vitamin B12 availability significantly upregulates gene expression of virulence factors such as toxin synthesis, fimbrial formation, and activation of the type-6 secretion system in V. campbellii.

Project description:The early life gut microbiome affects the developing brain, and therefore may serve as a target to support neurodevelopment of children living in stressful and under-resourced environments, such as Black youth living on the South Side of Chicago, for whom we observe racial disparities in health. Microbiome compositions/functions key to multiple neurodevelopmental facets have not been studied in Black children, a vulnerable population due to racial disparities in health; thus, a subsample of Black infants living in urban, low-income neighborhoods whose mothers participated in a prenatal nutrition study were recruited for testing associations between composition and function of the gut microbiome (16S rRNA gene sequencing, shotgun metagenomics, and targeted metabolomics of fecal samples) and neurodevelopment (developmental testing, maternal report of temperament, and observed stress regulation). Two microbiome community types, defined by high Lachnospiraceae or Enterobacteriaceae abundance, were discovered in this cohort from 16S rRNA gene sequencing analysis; the Enterobacteriaceae-dominant community type was significantly negatively associated with cognition and language scores, specifically in male children. Vitamin B12 biosynthesis emerged as a key microbiome function from shotgun metagenomics sequencing analysis, showing positive associations with all measured developmental skills (i.e., cognition, language, motor, surgency, effortful control, and observed stress regulation). Blautia spp. also were identified as substantial contributors of important microbiome functions, including vitamin B12 biosynthesis and related vitamin B12-dependent microbiome functions, anti-inflammatory microbial surface antigens, competitive mechanisms against pathobionts, and production of antioxidants. The results are promising with respect to the potential for exploring therapeutic candidates, such as vitamin B12 nutritional or Blautia spp. probiotic supplementation, to support the neurodevelopment of infants at risk for experiencing racial disparities in health.

Project description:Vitamin B12 is synthesized only by certain bacteria and archaeon, but not by plants. The synthesized vitamin B12 is transferred and accumulates in animal tissues, which can occur in certain plant and mushroom species through microbial interaction. In particular, the meat and milk of herbivorous ruminant animals (e.g. cattle and sheep) are good sources of vitamin B12 for humans. Ruminants acquire vitamin B12, which is considered an essential nutrient, through a symbiotic relationship with the bacteria present in their stomachs. In aquatic environments, most phytoplankton acquire vitamin B12 through a symbiotic relationship with bacteria, and they become food for larval fish and bivalves. Edible plants and mushrooms rarely contain a considerable amount of vitamin B12, mainly due to concomitant bacteria in soil and/or their aerial surfaces. Thus, humans acquire vitamin B12 formed by microbial interaction via mainly ruminants and fish (or shellfish) as food sources. In this review, up-to-date information on vitamin B12 sources and bioavailability are also discussed. Impact statement To prevent vitamin B12 (B12) deﬁciency in high-risk populations such as vegetarians and elderly subjects, it is necessary to identify foods that contain high levels of B12. B12 is synthesized by only certain bacteria and archaeon, but not by plants or animals. The synthesized B12 is transferred and accumulated in animal tissues, even in certain plant tissues via microbial interaction. Meats and milks of herbivorous ruminant animals are good sources of B12 for humans. Ruminants acquire the essential B12 through a symbiotic relationship with bacteria inside the body. Thus, we also depend on B12-producing bacteria located in ruminant stomachs. While edible plants and mushrooms rarely contain a considerable amount of B12, mainly due to concomitant bacteria in soil and/or their aerial surfaces. In this mini-review, we described up-to-date information on B12 sources and bioavailability with reference to the interaction of microbes as B12-producers.

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Vitamin B₁₂ is a limiting factor for induced cellular plasticity and tissue repair.

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Vitamin B<sub>12</sub> is a limiting factor for induced cellular plasticity and tissue repair.

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