Microbiota-mediated inflammation and antimicrobial defense in the intestine.

The diverse microbial populations constituting the intestinal microbiota promote immune development and differentiation, but because of their complex metabolic requirements and the consequent difficulty culturing them, they remained, until recently, largely uncharacterized and mysterious. In the last decade, deep nucleic acid sequencing platforms, new computational and bioinformatics tools, and full-genome characterization of several hundred commensal bacterial species facilitated studies of the microbiota and revealed that differences in microbiota composition can be associated with inflammatory, metabolic, and infectious diseases, that each human is colonized by a distinct bacterial flora, and that the microbiota can be manipulated to reduce and even cure some diseases. Different bacterial species induce distinct immune cell populations that can play pro- and anti-inflammatory roles, and thus the composition of the microbiota determines, in part, the level of resistance to infection and susceptibility to inflammatory diseases. This review summarizes recent work characterizing commensal microbes that contribute to the antimicrobial defense/inflammation axis.

A Missing Link to Vitamin B12 Metabolism.

Nearly 3% of the human population carries bi-allelic loss-of-function variants in the gene encoding CLYBL. While largely healthy, these individuals exhibit reduced circulating vitamin B12 levels. In this issue of Cell, Shen and colleagues uncover the metabolic role of CLYBL, linking its function to B12 metabolism and the immunomodulatory metabolite, itaconate.

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression.

Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2+ and α-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer. PAPERCLIP.

Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy.

Dormant hematopoietic stem cells (dHSCs) are atop the hematopoietic hierarchy. The molecular identity of dHSCs and the mechanisms regulating their maintenance or exit from dormancy remain uncertain. Here, we use single-cell RNA sequencing (RNA-seq) analysis to show that the transition from dormancy toward cell-cycle entry is a continuous developmental path associated with upregulation of biosynthetic processes rather than a stepwise progression. In addition, low Myc levels and high expression of a retinoic acid program are characteristic for dHSCs. To follow the behavior of dHSCs in situ, a Gprc5c-controlled reporter mouse was established. Treatment with all-trans retinoic acid antagonizes stress-induced activation of dHSCs by restricting protein translation and levels of reactive oxygen species (ROS) and Myc. Mice maintained on a vitamin A-free diet lose HSCs and show a disrupted re-entry into dormancy after exposure to inflammatory stress stimuli. Our results highlight the impact of dietary vitamin A on the regulation of cell-cycle-mediated stem cell plasticity. VIDEO ABSTRACT.

Nutrition, inflammation and cancer.

Quantitative and qualitative aspects of nutrition have a profound effect on leukocytes and thereby affect proinflammatory carcinogenic effects or anticancer immune responses. As a result, nutrition affects the incidence, natural progression and therapeutic response of malignant diseases, both in humans and in preclinical animal models. Here we discuss the molecular mechanisms through which alimentary cues modulate metabolic, microbial and neuroendocrine circuitries and thus affect the probability of developing premalignant lesions that progress to clinically manifested disease and the response to therapeutic intervention. We examine each of the connections that compose the triangle of nutrition, immunological and inflammatory reactions and cancer while focusing on the mechanistic aspects of these relationships.

Vitamin A mediates conversion of monocyte-derived macrophages into tissue-resident macrophages during alternative activation.

It remains unclear whether activated inflammatory macrophages can adopt features of tissue-resident macrophages, or what mechanisms might mediate such a phenotypic conversion. Here we show that vitamin A is required for the phenotypic conversion of interleukin 4 (IL-4)-activated monocyte-derived F4/80intCD206+PD-L2+MHCII+ macrophages into macrophages with a tissue-resident F4/80hiCD206-PD-L2-MHCII-UCP1+ phenotype in the peritoneal cavity of mice and during the formation of liver granulomas in mice infected with Schistosoma mansoni. The phenotypic conversion of F4/80intCD206+ macrophages into F4/80hiCD206- macrophages was associated with almost complete remodeling of the chromatin landscape, as well as alteration of the transcriptional profiles. Vitamin A-deficient mice infected with S. mansoni had disrupted liver granuloma architecture and increased mortality, which indicates that failure to convert macrophages from the F4/80intCD206+ phenotype to F4/80hiCD206- may lead to dysregulated inflammation during helminth infection.

Structural and mechanistic basis of the central energy-converting methyltransferase complex of methanogenesis.

Methanogenic archaea inhabiting anaerobic environments play a crucial role in the global biogeochemical material cycle. The most universal electrogenic reaction of their methane-producing energy metabolism is catalyzed by N    5-methyl-tetrahydromethanopterin: coenzyme M methyltransferase (MtrABCDEFGH), which couples the vectorial Na+ transport with a methyl transfer between the one-carbon carriers tetrahydromethanopterin and coenzyme M via a vitamin B12 derivative (cobamide) as prosthetic group. We present the 2.08 Šcryo-EM structure of Mtr(ABCDEFG)3 composed of the central Mtr(ABFG)3 stalk symmetrically flanked by three membrane-spanning MtrCDE globes. Tetraether glycolipids visible in the map fill gaps inside the multisubunit complex. Putative coenzyme M and Na+ were identified inside or in a side-pocket of a cytoplasmic cavity formed within MtrCDE. Its bottom marks the gate of the transmembrane pore occluded in the cryo-EM map. By integrating Alphafold2 information, functionally competent MtrA-MtrH and MtrA-MtrCDE subcomplexes could be modeled and thus the methyl-tetrahydromethanopterin demethylation and coenzyme M methylation half-reactions structurally described. Methyl-transfer-driven Na+ transport is proposed to be based on a strong and weak complex between MtrCDE and MtrA carrying vitamin B12, the latter being placed at the entrance of the cytoplasmic MtrCDE cavity. Hypothetically, strongly attached methyl-cob(III)amide (His-on) carrying MtrA induces an inward-facing conformation, Na+ flux into the membrane protein center and finally coenzyme M methylation while the generated loosely attached (or detached) MtrA carrying cob(I)amide (His-off) induces an outward-facing conformation and an extracellular Na+ outflux. Methyl-cob(III)amide (His-on) is regenerated in the distant active site of the methyl-tetrahydromethanopterin binding MtrH implicating a large-scale shuttling movement of the vitamin B12-carrying domain.

Flexible B12 ecophysiology of Phaeocystis antarctica due to a fusion B12-independent methionine synthase with widespread homologues.

Coastal Antarctic marine ecosystems are significant in carbon cycling because of their intense seasonal phytoplankton blooms. Southern Ocean algae are primarily limited by light and iron (Fe) and can be co-limited by cobalamin (vitamin B12). Micronutrient limitation controls productivity and shapes the composition of blooms which are typically dominated by either diatoms or the haptophyte Phaeocystis antarctica. However, the vitamin requirements and ecophysiology of the keystone species P. antarctica remain poorly characterized. Using cultures, physiological analysis, and comparative omics, we examined the response of P. antarctica to a matrix of Fe-B12 conditions. We show that P. antarctica is not auxotrophic for B12, as previously suggested, and identify mechanisms underlying its B12 response in cultures of predominantly solitary and colonial cells. A combination of proteomics and proteogenomics reveals a B12-independent methionine synthase fusion protein (MetE-fusion) that is expressed under vitamin limitation and interreplaced with the B12-dependent isoform under replete conditions. Database searches return homologues of the MetE-fusion protein in multiple Phaeocystis species and in a wide range of marine microbes, including other photosynthetic eukaryotes with polymorphic life cycles as well as bacterioplankton. Furthermore, we find MetE-fusion homologues expressed in metaproteomic and metatranscriptomic field samples in polar and more geographically widespread regions. As climate change impacts micronutrient availability in the coastal Southern Ocean, our finding that P. antarctica has a flexible B12 metabolism has implications for its relative fitness compared to B12-auxotrophic diatoms and for the detection of B12-stress in a more diverse set of marine microbes.

Nutrient regulation of development and cell fate decisions.

Diet contributes to health at all stages of life, from embryonic development to old age. Nutrients, including vitamins, amino acids, lipids and sugars, have instructive roles in directing cell fate and function, maintaining stem cell populations, tissue homeostasis and alleviating the consequences of aging. This Review highlights recent findings that illuminate how common diets and specific nutrients impact cell fate decisions in healthy and disease contexts. We also draw attention to new models, technologies and resources that help to address outstanding questions in this emerging field and may lead to dietary approaches that promote healthy development and improve disease treatments.

Melatonin and vitamin D, two sides of the same coin, better to land on its edge to improve multiple sclerosis.

Previous studies revealed a latitudinal gradient of multiple sclerosis (MS) prevalence, increasing by moving from the equator to the poles. The duration and quality of an individual's exposure to sunlight vary with latitude. Skin exposure to sunlight activates vitamin D synthesis, while light absence, as perceived by the eyes, activates melatonin synthesis in the pineal gland. Vitamin D or melatonin deficiency/insufficiency or overdose can occur at any latitude due to specific lifestyles and diets. Moving away from the equator, especially beyond 37°, decreases vitamin D while raising melatonin. Furthermore, melatonin synthesis increases in cold habitats like northern countries. Since melatonin's beneficial role was shown in MS, it is expected that northern countries whose individuals have higher endogenous melatonin should show a lower MS prevalence; however, these are ranked with the highest scores. In addition, countries like the United States and Canada have uncontrolled over-the-counter usage. In high latitudes, vitamin D deficiency and a higher MS prevalence persist even though vitamin D is typically compensated for by supplementation and not sunlight. Recently, we found that prolonged darkness increased MS melatonin levels, mimicking the long-term increase in northern countries. This caused a reduction in cortisol and increased infiltration, inflammation, and demyelination, which were all rescued by constant light therapy. In this review, we explain melatonin and vitamin D's possible roles in MS prevalence. The possible causes in northern countries are then discussed. Finally, we suggest strategies to treat MS by manipulating vitamin D and melatonin, preferably with sunlight or darkness, not supplements.

Scribble scrambles parathyroid hormone receptor interactions to regulate phosphate and vitamin D homeostasis.

G protein-coupled receptors, including PTHR, are pivotal for controlling metabolic processes ranging from serum phosphate and vitamin D levels to glucose uptake, and cytoplasmic interactors may modulate their signaling, trafficking, and function. We now show that direct interaction with Scribble, a cell polarity-regulating adaptor protein, modulates PTHR activity. Scribble is a crucial regulator for establishing and developing tissue architecture, and its dysregulation is involved in various disease conditions, including tumor expansion and viral infections. Scribble co-localizes with PTHR at basal and lateral surfaces in polarized cells. Using X-ray crystallography, we show that colocalization is mediated by engaging a short sequence motif at the PTHR C-terminus using Scribble PDZ1 and PDZ3 domain, with binding affinities of 31.7 and 13.4 µM, respectively. Since PTHR controls metabolic functions by actions on renal proximal tubules, we engineered mice to selectively knockout Scribble in proximal tubules. The loss of Scribble impacted serum phosphate and vitamin D levels and caused significant plasma phosphate elevation and increased aggregate vitamin D3 levels, whereas blood glucose levels remained unchanged. Collectively these results identify Scribble as a vital regulator of PTHR-mediated signaling and function. Our findings reveal an unexpected link between renal metabolism and cell polarity signaling.

Micro but mighty-Micronutrients in the epigenetic regulation of adaptive immune responses.

Micronutrients are essential small molecules required by organisms in minute quantity for survival. For instance, vitamins and minerals, the two major categories of micronutrients, are central for biological processes such as metabolism, cell replication, differentiation, and immune response. Studies estimated that around two billion humans worldwide suffer from micronutrient deficiencies, also known as "hidden hunger," linked to weakened immune responses. While micronutrients affect the immune system at multiple levels, recent studies showed that micronutrients potentially impact the differentiation and function of immune cells as cofactors for epigenetic enzymes, including the 2-oxoglutarate-dependent dioxygenase (2OGDD) family involved in histone and DNA demethylation. Here, we will first provide an overview of the role of DNA methylation in T cells and B cells, followed by the micronutrients ascorbate (vitamin C) and iron, two critical cofactors for 2OGDD. We will discuss the emerging evidence of these micronutrients could regulate adaptive immune response by influencing epigenetic remodeling.

Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit.

BACKGROUND: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

The taste of vitamin C in Drosophila.

Vitamins are essential micronutrients, but the mechanisms of vitamin chemoreception in animals are poorly understood. Here, we provide evidence that vitamin C doubles starvation resistance and induces egg laying in Drosophila melanogaster. Our behavioral analyses of genetically engineered and anatomically ablated flies show that fruit flies sense vitamin C via sweet-sensing gustatory receptor neurons (GRNs) in the labellum. Using a behavioral screen and in vivo electrophysiological analyses of ionotropic receptors (IRs) and sweet-sensing gustatory receptors (GRs), we find that two broadly tuned IRs (i.e., IR25a and IR76b) and five GRs (i.e., GR5a, GR61a, GR64b, GR64c, and GR64e) are essential for vitamin C detection. Thus, vitamin C is directly detected by the fly labellum and requires at least two distinct receptor types. Next, we expand our electrophysiological study to test attractive tastants such as sugars, carboxylic acids, and glycerol. Our analysis elucidates the molecular basis of chemoreception in sweet-sensing GRNs.

Vitamin D did not reduce multiple sclerosis disease activity after a clinically isolated syndrome.

Low serum levels of 25-hydroxyvitamin D [25(OH)D] and low sunlight exposure are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomized 1:1:1:1 to placebo, 1000, 5000 or 10 000 international units (IU) of oral vitamin D3 daily within each study centre (n = 23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the hazard ratios (95% confidence interval) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions and use of steroids, the hazard ratios (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); and 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome.

Vitomics: A novel paradigm for examining the role of vitamins in human biology.

The conventional view of vitamins reflects a diverse group of small molecules that facilitate critical aspects of metabolism and prevent potentially fatal deficiency syndromes. However, vitamins also contribute to the shaping and maintenance of the human phenome over lifecycle and evolutionary timescales, enabling a degree of phenotypic plasticity that operates to allow adaptive responses that are appropriate to key periods of sensitivity (i.e., epigenetic response during prenatal development within the lifecycle or as an evolved response to environmental challenge over a great many lifecycles). Individually, vitamins are important, but their effect is often based on nutrient-nutrient (vitamin-vitamin), nutrient-gene (vitamin-gene), and gene-gene interactions, and the environmental influence of shifting geophysical cycles, as well as evolving cultural practices. These ideas will be explored within what I refer to as the "adaptive vitome (vitomics)" paradigm.

Convergent total synthesis of (+)-calcipotriol: A scalable, modular approach to vitamin D analogs.

A convergent approach for the total synthesis of calcipotriol (brand name: Dovonex), a proven vitamin D analog used for the treatment of psoriasis, and medicinally relevant synthetic analogs is described. A complete approach, not wedded to semisynthesis, toward both the A-ring and CD-ring is reported. From a retrosynthetic standpoint, hidden symmetry within the decorated A-ring is disclosed, which allowed for scalable quantities of this advanced intermediate. In addition, a radical retrosynthetic approach is described, which highlights an electrochemical reductive coupling as well as an intramolecular hydrogen atom transfer Giese addition to establish the 6,5-transcarbon skeleton found in the vitamin D family. Finally, a late-stage decarboxylative cross-coupling approach allowed for the facile preparation of various C20-arylated derivatives that show promising biological activity in an initial bioassay.

Life cycle and functional genomics of the unicellular red alga Galdieria for elucidating algal and plant evolution and industrial use.

Sexual reproduction is widespread in eukaryotes; however, only asexual reproduction has been observed in unicellular red algae, including Galdieria, which branched early in Archaeplastida. Galdieria possesses a small genome; it is polyextremophile, grows either photoautotrophically, mixotrophically, or heterotrophically, and is being developed as an industrial source of vitamins and pigments because of its high biomass productivity. Here, we show that Galdieria exhibits a sexual life cycle, alternating between cell-walled diploid and cell wall-less haploid, and that both phases can proliferate asexually. The haploid can move over surfaces and undergo self-diploidization or generate heterozygous diploids through mating. Further, we prepared the whole genome and a comparative transcriptome dataset between the diploid and haploid and developed genetic tools for the stable gene expression, gene disruption, and selectable marker recycling system using the cell wall-less haploid. The BELL/KNOX and MADS-box transcription factors, which function in haploid-to-diploid transition and development in plants, are specifically expressed in the haploid and diploid, respectively, and are involved in the haploid-to-diploid transition in Galdieria, providing information on the missing link of the sexual life cycle evolution in Archaeplastida. Four actin genes are differently involved in motility of the haploid and cytokinesis in the diploid, both of which are myosin independent and likely reflect ancestral roles of actin. We have also generated photosynthesis-deficient mutants, such as blue-colored cells, which were depleted in chlorophyll and carotenoids, for industrial pigment production. These features of Galdieria facilitate the understanding of the evolution of algae and plants and the industrial use of microalgae.

Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women : Postintervention Follow-up of a Randomized Clinical Trial.

BACKGROUND: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited. OBJECTIVE: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial. DESIGN: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611). SETTING: A multicenter (n = 40) trial across the United States. PARTICIPANTS: 36 282 postmenopausal women with no history of breast or colorectal cancer. INTERVENTION: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D3 daily or placebo. MEASUREMENTS: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use. RESULTS: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality. LIMITATION: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled. CONCLUSION: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

Causes and consequences of impaired methionine synthase activity in acquired and inherited disorders of vitamin B12 metabolism.

Methyl-Cobalamin (Cbl) derives from dietary vitamin B12 and acts as a cofactor of methionine synthase (MS) in mammals. MS encoded by MTR catalyzes the remethylation of homocysteine to generate methionine and tetrahydrofolate, which fuel methionine and cytoplasmic folate cycles, respectively. Methionine is the precursor of S-adenosyl methionine (SAM), the universal methyl donor of transmethylation reactions. Impaired MS activity results from inadequate dietary intake or malabsorption of B12 and inborn errors of Cbl metabolism (IECM). The mechanisms at the origin of the high variability of clinical presentation of impaired MS activity are classically considered as the consequence of the disruption of the folate cycle and related synthesis of purines and pyrimidines and the decreased synthesis of endogenous methionine and SAM. For one decade, data on cellular and animal models of B12 deficiency and IECM have highlighted other key pathomechanisms, including altered interactome of MS with methionine synthase reductase, MMACHC, and MMADHC, endoplasmic reticulum stress, altered cell signaling, and genomic/epigenomic dysregulations. Decreased MS activity increases catalytic protein phosphatase 2A (PP2A) and produces imbalanced phosphorylation/methylation of nucleocytoplasmic RNA binding proteins, including ELAVL1/HuR protein, with subsequent nuclear sequestration of mRNAs and dramatic alteration of gene expression, including SIRT1. Decreased SAM and SIRT1 activity induce ER stress through impaired SIRT1-deacetylation of HSF1 and hypomethylation/hyperacetylation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), which deactivate nuclear receptors and lead to impaired energy metabolism and neuroplasticity. The reversibility of these pathomechanisms by SIRT1 agonists opens promising perspectives in the treatment of IECM outcomes resistant to conventional supplementation therapies.