Background and purpose: The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in directing folate species towards nucleotide synthesis or DNA methylation. The MTHFR polymorphisms C677T and A1298C have been linked to cancer susceptibility, but the evidence supporting this association has been equivocal. To investigate the individual and joint associations between MTHFR C677T, A1298C, and digestive system cancer in a Chinese hypertensive population, we conducted a population-based case–control study involving 751 digestive system cancer cases and one-to-one matched controls from the China H-type Hypertension Registry Study (CHHRS). Methods: We utilized the conditional logistic regression model to evaluate multivariate odds ratios (ORs) and 95% confidence intervals (CIs) of digestive system cancer. Results: The analysis revealed a significantly lower risk of digestive system cancer in individuals with the CT genotype (adjusted OR: 0.71; 95% CI 0.52, 0.97; P = 0.034) and TT genotype (adjusted OR: 0.57; 95% CI 0.40, 0.82; P = 0.003; P for trend = 0.003) compared to those with the 677CC genotype. Although A1298C did not show a measurable association with digestive system cancer risk, further stratification of 677CT genotype carriers by A1298C homozygotes (AA) and heterozygotes (AC) revealed a distinct trend within these subgroups. Conclusion: These findings indicate a potential protective effect against digestive system cancer associated with the T allele of MTHFR C677T. Moreover, we observed that the presence of different combinations of MTHFR polymorphisms may contribute to varying susceptibilities to digestive system cancer.

Background: Folate deficiency is a global nutritional problem associated with multiple adverse health outcomes, including impaired one-carbon metabolism and elevated homocysteine levels (hyperhomocysteinemia). Gut microbiota-mediated folate biosynthesis has emerged as a promising strategy for improving the host’s folate status. This study aimed to isolate folate-producing probiotic strains, clarify their folate synthesis mechanisms, and evaluate their regulatory effects on folate metabolism and gut microbiota. Methods: High-throughput cultivation and screening were performed to isolate folate-producing candidate probiotics. Whole-genome sequencing analysis, pathway reconstruction, and metabolite profiling in fermented milk were performed to explore folate biosynthesis pathways and microbial cross-feeding interactions. A folate-deficient mouse model was established to evaluate the effects of a candidate probiotic cocktail on serum folate, homocysteine (Hcy) levels, and gut microbiota composition using quantitative PCR (qPCR) and 16S rRNA gene sequencing. Results: High-throughput screening identified 8 high-folate-producing candidate probiotic strains, including Lactiplantibacillus plantarum and Heyndrickxia coagulans , from over 1,000 isolates. Genomic analysis revealed that most commonly used probiotics lacked para-aminobenzoic acid (pABA) biosynthesis genes but retained downstream modules, suggesting a reliance on cross-feeding with pABA-producing gut commensals such as Bacteroides. Metabolite profiling of fermented milk demonstrated that selected strains significantly increased bioactive 5-methyltetrahydrofolate (5-MeTHF) and tetrahydrofolate levels. In vivo , only a high-dose candidate probiotic cocktail significantly elevated serum folate ( p < 0.05) and reduced homocysteine levels ( p < 0.05) in deficient mice. Fecal qPCR confirmed dose-dependent transient persistence of the administered bacterial species. Consistent with the qPCR data, 16S rRNA gene sequences demonstrated significant enrichment of these administered species observed in the high-dose group. Furthermore, beta-diversity analysis found that high-dose candidate probiotic supplementation promoted a shift in the gut microbiota composition toward a normal profile, partially mitigating the dysbiosis induced by the folate-deficient diet. This effect was accompanied by a significant enrichment of potential short-chain fatty acid producers (e.g., Lachnospiraceae and Oscillospiraceae ) and the depletion of potential opportunistic pathogens. Conclusion: This study screened high-folate-producing candidate probiotic strains and demonstrated their ability to synthesize the active form of 5-MeTHF. Moreover, folate-producing candidate probiotic cocktail treatment significantly improved folate status and Hcy metabolism and modulated the gut microbiota by enriching potential beneficial bacterial taxa. These findings suggested that folate-producing probiotics may serve as a promising microbiota-based strategy to improve folate availability and homocysteine metabolism.

Introduction: Previous studies in mostly Western populations, have yielded conflicting findings on the association of vitamin B12 with diabetes risk, in part, due to differences in study design and population characteristics. This study sought to examine the vitamin B12 – diabetes association in Chinese hypertensive adults by both cross-sectional and longitudinal analyses. Research Design and Methods: This report included a total of 16699 participants from the China Stroke Primary Prevention Trial (CSPPT), with pertinent baseline and follow-up data. Diabetes mellitus (DM) was defined as either physician-diagnosed diabetes, the use of glucose-lowering drugs, or fasting blood glucose (FBG) ≥7.0 mmol/L. New-onset diabetes was defined as any new case of onset diabetes during the follow-up period or fasting blood glucose (FBG) ≥7.0 mmol/L at the exit visit. Results: At baseline, there were 1872 (11.2%) diabetic patients; less than 1.5% had clinical B12 deficiency (<148.0 pmol/L). Over a median follow-up period of 4.5 years, there were 1589 (10.7%) cases of new-onset diabetes. Cross-sectional analyses showed a positive association between baseline vitamin B12 levels and FBG levels (β=0.18, 95%CI 0.15-0.21) and diabetes (OR=1.42, 95%CI 1.33-1.51). However, longitudinal analyses showed no association between baseline vitamin B12 and new-onset diabetes or changes in FBG levels. Among a subset of the sample (N=4366) with both baseline and exit B12 measurements, we found a positive association between an increase in B12 and an increase in FBG. Conclusions: In this large Chinese hypertensive population mostly sufficient with vitamin B12, parallel cross-sectional and longitudinal analyses provided new insight into the conflicting findings of previous studies, and these results underscore the need for future studies to consider both baseline vitamin B12 and its longitudinal trajectory in order to better elucidate the role of vitamin B12 in the development of diabetes. Such findings, would have important clinical and public health implications.