Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota.

Restriction of methionine (MR), a sulfur-containing essential amino acid, has been reported to repress cancer growth and improve therapeutic responses in several preclinical settings. However, how MR impacts cancer progression in the context of the intact immune system is unknown. Here we report that while inhibiting cancer growth in immunocompromised mice, MR reduces T cell abundance, exacerbates tumour growth and impairs tumour response to immunotherapy in immunocompetent male and female mice. Mechanistically, MR reduces microbial production of hydrogen sulfide, which is critical for immune cell survival/activation. Dietary supplementation of a hydrogen sulfide donor or a precursor, or methionine, stimulates antitumour immunity and suppresses tumour progression. Our findings reveal an unexpected negative interaction between MR, sulfur deficiency and antitumour immunity and further uncover a vital role of gut microbiota in mediating this interaction. Our study suggests that any possible anticancer benefits of MR require careful consideration of both the microbiota and the immune system.

Longitudinal changes during pregnancy in gut microbiota and methylmercury biomarkers, and reversal of microbe-exposure correlations.

OBJECTIVE: Gut microorganisms contribute to the metabolism of environmental toxicants, including methylmercury (MeHg). Our main objective was to investigate whether associations between biomarkers for prenatal MeHg exposure and maternal gut microbiota differed between early and late gestation. METHODS: Maternal blood and stool samples were collected during early (8.3-17 weeks, n=28) and late (27-36 weeks, n=24) gestation. Total mercury and MeHg concentrations were quantified in biomarkers, and inorganic mercury was estimated by subtraction. The diversity and structure of the gut microbiota were investigated using 16S rRNA gene profiling (n = 52). Biomarkers were dichotomized, and diversity patterns were compared between high/low mercury concentrations. Spearman's correlation was used to assess bivariate associations between MeHg biomarkers (stool, blood, and meconium), and 23 gut microbial taxa (genus or family level, >1% average relative abundance). RESULTS: Within-person and between-person diversity patterns in gut microbiota differed between early/late gestation. The overall composition of the microbiome differed between high/low MeHg concentrations (in blood and stool) during early gestation, but not late gestation. Ten (of 23) taxa were significantly correlated with MeHg biomarkers (increasing or decreasing); however, associations differed, depending on whether the sample was collected during early or late gestation. A total of 43% of associations (69/161) reversed the direction of correlation between early/late gestation. CONCLUSIONS: The time point at which a maternal fecal sample is collected may yield different associations between gut microorganisms and MeHg biomarkers, which may be due in part to remodeling of maternal microbiota during pregnancy. Our results suggest the effectiveness of dietary interventions to reduce prenatal MeHg exposure may differ between early and late gestation.