Yearly changes in the composition of gut microbiota in the elderly, and the effect of lactobacilli intake on these changes

Abstract The onset and worsening of some diseases are related to the variation and instability of gut microbiota. However, studies examining the personal variation of gut microbiota in detail are limited. Here, we evaluated the yearly variation of individual gut microbiota in 218 Japanese subjects aged 66–91 years, using Jensen-Shannon distance (JSD) metrics. Approximately 9% of the subjects showed a substantial change, as their formerly predominant bacterial families were replaced over the year. These subjects consumed fermented milk products less frequently than their peers. The relationship between the intake frequencies of fermented milk products containing Lactocaseibacillus paracasei strain Shirota (LcS) and JSD values was also investigated. The intra-individual JSD of subjects ingesting LcS products ≥ 3 days/week over the past 10 years was statistically lower than the < 3 days/week group (P = 0.045). Focusing on subjects with substantial gut microbiota changes, only 1.7% of the subjects were included in the LcS intake ≥ 3 days/week group whereas 11.3% were found in the < 3 days/week group (P = 0.029). These results suggest that about one-tenth of the elderly Japanese could experience a substantial change in their gut microbiota during a 1-year period, and that the habitual intake of probiotics may stabilize their gut microbiota

Discovery of a cystathionine γ-lyase (CSE) selective inhibitor targeting active-site pyridoxal 5′-phosphate (PLP) via Schiff base formation

Abstract D,L-Propargylglycine (PAG) has been widely used as a selective inhibitor to investigate the biological functions of cystathionine γ-lyase (CSE), which catalyzes the formation of reactive sulfur species (RSS). However, PAG also inhibits other PLP (pyridoxal-5′-phosphate)-dependent enzymes such as methionine γ-lyase (MGL) and L-alanine transaminase (ALT), so highly selective CSE inhibitors are still required. Here, we performed high-throughput screening (HTS) of a large chemical library and identified oxamic hydrazide 1 as a potent inhibitor of CSE (IC50 = 13 ± 1 μM (mean ± S.E.)) with high selectivity over other PLP-dependent enzymes and RSS-generating enzymes. Inhibitor 1 inhibited the enzymatic activity of human CSE in living cells, indicating that it is sufficiently membrane-permeable. X-Ray crystal structure analysis of the complex of rat CSE (rCSE) with 1 revealed that 1 forms a Schiff base linkage with the cofactor PLP in the active site of rCSE. PLP in the active site may be a promising target for development of selective inhibitors of PLP-dependent enzymes, including RSS-generating enzymes such as cystathionine β-synthase (CBS) and cysteinyl-tRNA synthetase 2 (CARS2), which have unique substrate binding pocket structures