Z-D-methionine

Background: There are close links between chemotherapy-induced intestinal mucositis and microbiota dysbiosis. Previous studies indicated that D-methionine was an excellent candidate for a chemopreventive agent. Here, we investigated the effects of D-methionine on cisplatin-induced mucositis. Materials and methods: Male Wistar rats (176-200 g, 6 weeks old) were given cisplatin (5 mg/kg) and treated with D-methionine (300 mg/kg). Histopathological, digestive enzymes activity, oxidative/antioxidant status, proinflammatory/anti-inflammatory cytokines in intestinal tissues were measured. Next-generation sequencing technologies were also performed to investigate the gut microbial ecology. Results: D-methionine administration increased villus length and crypt depth and improved digestive enzyme (leucine aminopeptidase, sucrose and alkaline phosphatase) activities in the brush-border membrane of cisplatin-treated rats (p < 0.05). Furthermore, D-methionine significantly attenuated oxidative stress and inflammatory reaction and increased interleukin-10 levels in cisplatin-induced intestinal mucositis (p < 0.05). Cisplatin administration resulted in high relative abundances of Deferribacteres and Proteobacteria and a low diversity of the microbiota when compared with control groups, D-methionine only and cisplatin plus D-methionine. Cisplatin markedly increased comparative abundances of Bacteroides caccae, Escherichia coli, Mucispirillum schaedleri, Bacteroides uniformis and Desulfovibrio C21-c20, while Lactobacillus was almost completely depleted, compared with the control group. There were higher abundances of Lactobacillus, Lachnospiraceae, and Clostridium butyrium in cisplatin plus D-methionine rats than in cisplatin rats. D-methionine treatment alone significantly increased the number of Lactobacillus reuteri. Conclusion: D-methionine protects against cisplatin-induced intestinal damage through antioxidative and anti-inflammatory effects. By enhancing growth of beneficial bacteria (Lachnospiraceae and Lactobacillus), D-methionine attenuates gut microbiome imbalance caused by cisplatin and maintains gut homeostasis.

This experiment was conducted to determine the bioavailability of D-methionine (Met) relative to L-Met for nursery pigs using the slope-ratio assay. A total of 50 crossbred barrows with an initial BW of 13.5 kg (SD = 1.0) were used in an N balance study. A Met-deficient basal diet (BD) was formulated to contain an adequate amount of all amino acids (AA) for 10-20 kg pigs except for Met. The two reference diets were prepared by supplementing the BD with 0.4 or 0.8 g L-Met/kg at the expense of corn starch, and an equivalent concentration of D-Met was added to the BD for the two test diets. The pigs were adapted to the experimental diets for 5 d and then total but separated collection of feces and urine was conducted for 4 d according to the marker-to-marker procedure. Nitrogen intakes were similar across the treatments. Fecal N output was not affected by Met supplementation regardless of source and consequently apparent N digestibility did not change. Conversely, there was a negative linear response (P < 0.01) to Met supplementation with both Met isomers in urinary N output, which resulted in increased retained N (g/4 d) and N retention (% of intake). No quadratic response was observed in any of the N balance criteria. The estimated bioavailability of D-Met relative to L-Met from urinary N output (g/4 d) and N retention (% of intake) as dependent variables using supplemental Met intake (g/4 d) as an independent variable were 87.6% and 89.6%, respectively; however, approximately 95% of the fiducial limits for the relative bioavailability estimates included 100%. In conclusion, with an absence of statistical significance, the present study indicated that the mean relative bioequivalence of D- to L-Met was 87.6% based on urinary N output or 89.6% based on N retention.

Rumen-protected forms of Met contain an equimolar mixture of the D- and L-isomers. Only L-Met can be directly used for protein synthesis, but it is unclear how much of the D-isomer can be transformed into L-Met in ruminants. Four lactating dairy cows, with an average milk yield of 32.4 kg/d, received a basal diet (12.5% crude protein, supplying 1,718 g/d of metabolizable protein) in 12 equal meals per day plus an abomasal infusion of amino acids (590 g/d, casein profile without Met). They were used in 3 consecutive studies to determine utilization of D-Met. First, the cows each received portal vein infusions for d of 5, 10, or 15 g/d of DL-Met in a Youden square. On the last day of each period, 6 arterial samples were collected at 45-min intervals. Concentrations of L- and D-Met were determined on a chiral column by gas chromatography-mass spectrometry. Portal infusion of 5, 10, and 15 g/d of DL-Met increased plasma total Met concentrations (19.7, 25.0, and 34.4±0.6 μM) and the proportion of Met as D (19.4, 30.5, and 37.3±0.7%). The fractional removal of D-Met was 6 to 7 times lower than the fractional removal of L-Met, with mean half-lives of 52 versus 8 min, respectively. Second, the same cows were infused for 8 h with L[methyl-(2)H(3)]Met at 1.3 mmol/h; at 2 h, cows received a bolus injection i.v. of D-[1-(13)C]Met (6.8 mmol), and arterial samples were collected after 10, 20, 30, 40, 60, 90, 120, 150, 180, 240, 300, 360, 420, and 480 min. Expressed relative to L-[(12)C]Met; that is, as tracer:tracee ratios, enrichments of plasma D-[1-(13)C]Met and L-[1-(13)C]Met averaged 1.77±0.14 and 0.144±0.026, respectively, 10 min after the bolus injection and declined exponentially thereafter. A minimum of 75±3% of the D-[1-(13)C]Met was transformed into L-[1-(13)C]Met. Third, the cows received, in a crossover design, an abomasal infusion for D of either DL-Met or L-Met (1g/d) and, on the last day of each experimental period, blood samples were collected simultaneously from arterial, portal, hepatic, and mammary vessels. Arterial total Met concentrations were higher with DL- versus L-Met infusions (37.4 vs. 25.4±0.5 μM), with 37.1±5.0% as D-Met. The mammary gland did not extract any D-Met. Hepatic removal of D-Met was observed, but was numerically lower than the fractional extraction of L-Met. In conclusion, much of the D-Met is transformed into L-Met by the dairy cow but at a slow rate. No uptake of D-Met occurs across the mammary gland but L-Met synthesized from the D-isomer elsewhere in the body can be utilized for milk protein synthesis.