Elevated serum methylmalonic acid (MMA), a marker of cobalamin (vitamin B12) deficiency, has been linked to cancer progression. However, the impact of MMA or cobalamin on mortality risk in cancer survivors remains unknown.
To explore the relationship between MMA, serum, dietary, and supplement of cobalamin, MMA metabolism-related genes, and poor prognosis in adult cancer survivors.
We analyzed data from 1988 cancer survivors aged ≥20 y. Patients were selected from the National Health and Nutrition Examination Survey and followed up until December 31, 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for mortality risk assessment. Genomic analysis identified MMA metabolism-related genes linked to early death in a 33-cancer-type cohort from The Cancer Genome Atlas.
Among 1988 participants, 872 deaths occurred over a 10-year follow-up. Higher serum MMA levels were significantly linked to increased long-term mortality risk (tertile 3 compared with tertile 1: adjusted HR: 1.37; 95% CI: 1.11, 1.70; P-trend < 0.001). No associations were found between serum, dietary, and supplement of cobalamin and cancer survivor mortality (each P-trend > 0.143). However, MMA-associated mortality was notable in patients without deficiency. When combining cobalamin and MMA categories, multivariate-adjusted HR (95% CI) for all-cause mortality was 2.06 (95% CI: 1.60, 2.65) in participants with >250 nmol/L and cobalamin >295.1 pmol/L compared with those with MMA ≤250 nmol/L and cobalamin >295.1 pmol/L. Moreover, reduced transcriptional levels of MMA metabolism-related genes, indicating decreased mitochondrial MMA metabolism capability, are linked to an unfavorable prognosis in certain cancer types.
Serum MMA was associated with long-term mortality risk in adult cancer survivors, which was more significant among individuals with higher levels of serum cobalamin. These findings suggest that mortality related to MMA was attributed to the insufficient flux of MMA metabolism, not cobalamin deficiency.

The use of omeprazole as a preventive treatment for gastrointestinal ulcers in veterinary medicine has been questioned during previous years. The aim of the present study is to assess the long-term effect of omeprazole on cobalamin and serum gastrin levels in healthy dogs. Eighteen healthy dogs were included: 10 in the control group and 8 in the omeprazole group. Three samples were collected: before starting the treatment (T0), 30 days after the start of treatment (T1), and at 60 days (T2). The mean cobalamin value (ng/L) in the control group was 481.4 (±293.70) at T0, 481.4 (±170.21) at T1, and 513.2 (±174.50) at T2. In the omeprazole group, the values were 424.62 (±161.57) at T0, 454.5 (±160.96) at T1, and 414.87 (±127.90) at T2. No statistically significant changes were detected in cobalamin levels between the three-time period in both study groups. These results agree with previous findings in felines but contrast with human medicine studies. The median gastrin values (pg/mL) in the control group were 62.45 [30.17-218.75] at T0, 76.06 [30.67-199.87] at T1, and 63.02 [35.81-176.06] at T2. The median gastrin value in the omeprazole group was 67.59 [55.96-101.60] at T0, 191.77 [75.31-1901.77] at T1, and 128.16 [43.62-1066.46] at T2. Statistically significant differences were detected (p = 0.008), indicating an increase in gastrin levels after initiating treatment with omeprazole. In conclusion, the increased levels of gastrin observed in this population underscore the importance of conducting a comprehensive clinical assessment to identify potential gastrointestinal disorders, particularly in consideration of the usage of omeprazole as a preventive treatment.

Catalysis by radical enzymes dependent on coenzyme B12 (AdoCbl) relies on the reactive primary 5\'-deoxy-5\'adenosyl radical, which originates from reversible Co-C bond homolysis of AdoCbl. This bond homolysis is accelerated roughly 1012-fold upon binding the enzyme substrate. The structural basis for this activation is still strikingly enigmatic. As revealed here, a displaced firm adenosine binding cavity in substrate-loaded glutamate mutase (GM) causes a structural misfit for intact AdoCbl that is relieved by the homolytic Co-C bond cleavage. Strategically interacting adjacent adenosine- and substrate-binding protein cavities provide a tight caged radical reaction space, controlling the entire radical path. The GM active site is perfectly structured for promoting radical catalysis, including \"negative catalysis\", a paradigm for AdoCbl-dependent mutases.
Glutamate mutase (GM) catalyses the interconversion of glutamate and 3‐methylaspartate. It binds its B12‐cofactor AdoCbl with an essential misfit for its Ado‐group, liberating the clamped down aggressive Ado‐radical in a tight reaction space to even promote “negative catalysis”. A “simply stretched” AdoCbl‐homolog, in contrast, fits GM, freezing up the intriguing functional structure of this enzyme.

BACKGROUND: In the Western world, there has been a notable rise in the popularity of plant-based, meat-reduced flexitarian diets. Nevertheless, there is insufficient data on the nutritional status of individuals following this dietary pattern. The aim of this study was to investigate the intake and endogenous status of various nutrients in a healthy German adult study population consisting of flexitarians (FXs), vegans (Vs) and omnivores (OMNs).
METHODS: In this cross-sectional study, dietary intake of 94 non-smoking adults (32 FXs, 33 Vs, 29 OMNs) between 25 and 45 years of age was assessed using 3-day dietary records. In addition, blood samples were collected to determine different endogenous nutrient status markers.
RESULTS: 32%, 82% and 24% of the FXs, Vs, and OMNs respectively reported using dietary supplements. In the FXs, intake of total energy as well as macronutrients and most micronutrients were within the reference range. FXs had higher intakes of fiber, retinol-equ., ascorbic acid, folate-equ., tocopherol-equ., calcium, and magnesium compared to OMNs. However, cobalamin intake in FXs (2.12 µg/d) was below the reference (4 µg/d). Based on 4cB12, 13% of FXs showed a cobalamin undersupply [< -0.5 to -2.5] compared to 10% of OMNs, and 9% of Vs. The median 25(OH)D serum concentrations in FXs, Vs and OMNs were 46.6, 55.6, and 59.6 nmol/L. The prevalence of an insufficient/deficient vitamin-D status [< 49.9 nmol 25(OH)D/L] was highest in FXs (53%), followed by Vs (34%) and OMNs (27%). In FXs and Vs, the supplement takers had better cobalamin and vitamin-D status than non-supplement takers. Anemia and depleted iron stores were found only occasionally in all groups. In women, the prevalence of pre-latent iron deficiency and iron deficiency was highest in FXs (67%) compared to Vs (61%) and OMNs (54%).
CONCLUSIONS: Our findings indicated that all three diets delivered sufficient amounts of most macro- and micronutrients. However, deficiencies in cobalamin, vitamin-D, and iron status were common across all diets. Further studies are needed to investigate the nutrient supply status and health consequences of meat-reduced plant-based diets. The study was registered in the German Clinical Trial Register (number: DRKS 00019887, data: 08.01.2020).

Vitamin B12 and folate are essential micronutrients important for normal infant growth and development.
The aims were to describe vitamin B12 and folate status in pregnant females and their infants according to commonly used status cutoffs and examine the associations between maternal status, maternal supplement use, and breastfeeding and infant status.
Pregnant females were recruited at 18 wk gestation in Bergen, Norway. Maternal vitamin B12 and folate status were measured at gestational weeks 18 (n = 136) and 36 (n = 116), and infant status was measured at ages 3 (n = 73) and 6 (n = 74) mo.
At gestational weeks 18 and 36, respectively, 4.4% and 2.6% of the mothers had plasma cobalamin concentrations <148 pmol/L, 0.7% and 6.9% had methylmalonic acid (MMA) concentrations >0.26 μmol/L, and 3.7% and 30% had folate concentrations <10 nmol/L. None of the females had total homocysteine (t-Hcy) concentrations >13 μmol/L or 3 combined indicator of vitamin B12 (cB12) < -0.5. At 3 and 6 mo, respectively, 4.1% and 5.4% of the infants had cobalamin concentrations <148 pmol/L, 63% and 74% had t-Hcy concentrations >6.5 μmol/L, 59% and 66% had MMA concentrations >0.26 μmol/L, and 47% and 60% had cB12 > -0.5. None of the infants had folate concentrations <10 nmol/L. Several of the vitamin B12 biomarkers in infants were associated with maternal vitamin B12 status during pregnancy. Breastfed infants had lower vitamin B12 status (as indicated by plasma cobalamin, t-Hcy, and cB12) than nonbreastfed infants at both 3 and 6 mo. Use of supplements during pregnancy was associated with better vitamin B12 status among infants at 3 and 6 mo, as indicated by infants\' cobalamin and t-Hcy concentrations.
Subclinical vitamin B12 deficiency among infants was common and associated with maternal vitamin B12 status during pregnancy and breastfeeding. Among the mothers, an increase in biochemical folate deficiency was discovered toward the end of gestation. Further studies are needed to investigate clinical consequences. This trial was registered at clinicaltrials.gov as NCT02610959.

BACKGROUND: The role of diet in the pathogenesis and treatment of chronic enteropathies (CE) in dogs is unresolved.
OBJECTIVE: To compare the ability of diets composed of hydrolyzed fish, rice starch, and fish oil without (HF) or with prebiotics, turmeric, and high cobalamin (HF+) against a limited ingredient diet containing mixed nonhydrolyzed antigens and oils (control) to resolve clinical signs and maintain serum cobalamin and folate concentrations in dogs with nonprotein losing CE (non-PLE). To determine the ability of hydrolyzed fish diets to support recovery and remission in dogs with PLE.
METHODS: Thirty-one client-owned dogs with CE: 23 non-PLE, 8 PLE.
METHODS: Randomized, blinded, controlled trial. Diets were fed for 2 weeks; responders continued for 12 weeks. Nonresponders were crossed over to another diet for 12 weeks. Response was determined by standardized clinical evaluation with long-term follow-up at 26 weeks. Concurrent medications were allowed in PLE.
RESULTS: Nineteen of 23 (83%; 95% confidence interval [CI], 60%-94%) non-PLE CE responded clinically to their initial diet, with no difference between diets (P > .05). Four nonresponders responded to another diet, with sustained remission of 18/18 (100%; 95%CI, 78%-100%) at 26 weeks. Serum cobalamin concentration was increased (P < .05) and maintained by diet. Serum folate concentration decreased posttreatment (P < .05) but was restored by dietary supplementation. Hydrolyzed fish diets supported weight gain, serum albumin concentration, and recovery (P < .05) in dogs with PLE.
CONCLUSIONS: Changing diet, independent of antigen restriction or supplemental ingredients, induced long-term remission in dogs with non-PLE CE. Serum cobalamin and folate concentrations were maintained by diet. Hydrolyzed fish diets supported clinical recovery and remission in PLE.

OBJECTIVE: To examine the extent to which metformin increases the risk of vitamin B12 deficiency and borderline deficiency over time in participants with type 2 diabetes mellitus (T2DM).
METHODS: Using the All of Us database, adults aged ≥18 years with T2DM and a documented history of metformin use were included for the evaluation of B12 deficiency. Those with B12 deficiency before metformin use were excluded. Adjusted logistic regression models were used to evaluate the association between metformin use and long-term metformin use (≥4 years) and the risk of B12 deficiency. We conducted a subgroup analysis comparing differences in borderline B12 deficiency in metformin and non-metformin users.
RESULTS: Of 36 740 participants with T2DM, 6221 (16.9%) had documented metformin use. The mean age of metformin users was 65.3 years. B12 deficiency was confirmed in 464 (7.5%) metformin users, and 1919 of 30 519 participants (6.3%) did not use metformin. Metformin users had a 4.7% increased risk of developing B12 deficiency compared with nonmetformin users (P = .44). Each additional year of metformin use was associated with 5% increased likelihood of deficiency (P < .05). Metformin use for ≥4 years resulted in a 41.0% increased odds of B12 deficiency, compared with those who used <4 years of metformin (P < .05). Metformin use increased the odds of borderline B12 deficiency by 27.0% (P < .05).
CONCLUSIONS: Long-term metformin use was associated with an increased risk of B12 deficiency in patients with T2DM, with compounding risk over time.

Micronutrient deficiencies and stunting are prevalent. We assessed correlates of iron, cobalamin, folate, and vitamin A biomarkers in a cross-sectional study of stunted children aged 12-59 months in eastern Uganda. The biomarkers measured were serum ferritin (S-FE), soluble transferrin receptor (S-TfR), retinol binding protein (S-RBP), plasma cobalamin (P-Cob), methylmalonic acid (P-MMA), and folate (P-Fol). Using linear regression, we assessed socio-demography, stunting severity, malaria rapid test, and inflammation as correlates of micronutrient biomarkers. Of the 750 children, the mean (SD) age was 32.0 (11.7) months, and 45% were girls. Iron stores were depleted (inflammation-corrected S-FE < 12 µg/L) in 43%, and 62% had tissue iron deficiency (S-TfR > 8.3 mg/L). P-Cob was low (<148 pmol/L) and marginal (148-221 pmol/L) in 3% and 20%, and 16% had high P-MMA (>0.75 µmol/L). Inflammation-corrected S-RBP was low (<0.7 µmol/L) in 21% and P-Fol (<14 nmol/L) in 1%. Age 24-59 months was associated with higher S-FE and P-Fol and lower S-TfR. Breastfeeding beyond infancy was associated with lower iron status and cobalamin status, and malaria was associated with lower cobalamin status and tissue iron deficiency (higher S-TfR) despite iron sequestration in stores (higher S-FE). In conclusion, stunted children have iron, cobalamin, and vitamin A deficiencies. Interventions addressing stunting should target co-existing micronutrient deficiencies.

BACKGROUND: Hypercobalaminemia is infrequently reported in companion animals and is considered of low clinical significance. Recent studies have described its association with inflammatory, immune-mediated, endocrine, and neoplastic conditions in dogs and cats.
OBJECTIVE: We aimed to investigate the association between hypercobalaminemia and neoplasia in companion animals and to identify other concurrent diseases or clinicopathologic changes.
METHODS: This is a retrospective, case-control study. Medical records of patients with measured serum cobalamin concentration (2015-2020) and no history of prior supplementation were reviewed. Hypocobalaminemic animals were excluded. Variables were compared between groups (hypercobalaminemic vs. normocobalaminemic) using non-parametric statistics. Data are presented as median (range).
RESULTS: Thirty-five dogs and eight cats were hypercobalaminemic. At baseline, neoplasia was confirmed in 4/35 hypercobalaminemic dogs versus 11/70 control dogs (P = 0.77) and 0/8 hypercobalaminemic cats versus 3/16 control cats (P = 0.53). Cases without neoplasia at baseline were followed for 409 (13-1854) days (dogs, n = 78) and 395 (28-1670) days (cats, n = 21). During follow-up, neoplasia was diagnosed in 4/27 hypercobalaminemic dogs versus 3/51 control dogs (P = 0.23) and 1/8 hypercobalaminemic cats versus 0/13 control cats (P = 0.38). Pancreatitis was more frequent in hypercobalaminemic dogs (P = 0.006). Hypercobalaminemic dogs had higher serum total protein (P = 0.014), globulin (P = 0.001), and CRP (P = 0.032) concentrations and lower serum sodium (P = 0.012) and chloride (P = 0.033) concentrations than controls. Hypercobalaminemic cats had higher serum total protein concentrations than controls (P = 0.008).
CONCLUSIONS: Our results suggest that hypercobalaminemia is not associated with the presence or development of neoplasia in dogs and cats but may be associated with systemic inflammatory conditions, including pancreatitis, in dogs.

BACKGROUND: Pathophysiological mechanisms underlying sex-based differences in diabetes remain poorly understood. Mitochondrial metabolite methylmalonic acid (MMA) accumulation reflects mitochondrial dysfunction which is involved in sex-specific pathophysiological responses biologically. We aimed to investigate the sex-specific associations between mortality risk and MMA in adults with the presence or absence of type 2 diabetes.
METHODS: This cohort study included 24,164 adults (12,123 females and 12,041 males) from the NHANES study during 1999-2014. Both sexes were separately categorized as those with no diabetes, prediabetes, undiagnosed diabetes, and diagnosed diabetes. Circulating MMA level was measured at baseline by mass-spectrometric detection. Mortality status was ascertained from baseline until December 31, 2015.
RESULTS: During a median follow-up of 11.1 years, 3375 deaths were documented. Males had a particularly higher mortality than females in adults with diagnosed diabetes compared to differences in those with no diabetes, prediabetes and undiagnosed diabetes (sex differences in mortality rate per 1000 person-years across diabetic status: 0.62, 1.44, 5.78, and 9.77, p < 0.001). Notably, the sex-specific difference in associations between MMA and mortality was significant only in adults with diagnosed diabetes (p for interaction = 0.028), not in adults with no diabetes and prediabetes. Adjusted HRs (95%CIs) per doubling of MMA for all-cause mortality were 1.19 (1.04-1.37) in females with diagnosed diabetes versus 1.58 (1.36-1.86) in male counterparts. In addition, MMA levels had an insignificant or weak correlation with sex hormone profiles at baseline, regardless of diabetes status and sex.
CONCLUSIONS: Sex difference in mortality risk was especially significant in diagnosed type 2 diabetes. Increasing equivalent exposure to mitochondrial metabolite MMA was associated with a greater excess risk of future mortality in males with diabetes than in females.