Background Aging is a natural process that an organism gradually loses its physical fitness and functionality. Great efforts have been made to understand and intervene in this deteriorating process. The gut microbiota affects host physiology, and dysbiosis of the microbial community often underlies the pathogenesis of host disorders. The commensal microbiota also changes with aging; however, the interplay between the microbiota and host aging remains largely unexplored. Here, we systematically examined the ameliorating effects of the gut microbiota derived from the young on the physiology and phenotypes of the aged. Results As the fecal microbiota was transplanted from young mice at 5 weeks after birth into 12-month-old ones, the thickness of the muscle fiber and grip strength were increased, and the water retention ability of the skin was enhanced with thickened stratum corneum. Muscle thickness was also marginally increased in 25-month-old mice after transferring the gut microbiota from the young. Bacteria enriched in 12-month-old mice that received the young-derived microbiota significantly correlated with the improved host fitness and altered gene expression. In the dermis of these mice, transcription of Dbn1 was most upregulated and DBN1-expressing cells increased twice. Dbn1-heterozygous mice exhibited impaired skin barrier function and hydration. Conclusions We revealed that the young-derived gut microbiota rejuvenates the physical fitness of the aged by altering the microbial composition of the gut and gene expression in muscle and skin. Dbn1, for the first time, was found to be induced by the young microbiota and to modulate skin hydration. Our results provide solid evidence that the gut microbiota from the young improves the vitality of the aged.

Background A significant proportion of colorectal cancer (CRC) patients suffer from early recurrence and progression after surgical treatment. Although the gut microbiota is considered as a key player in the initiation and progression of CRC, most prospective studies have been focused on a particular pathobionts such as Fusobacterium nucleatum. Here, we aimed to identify novel prognostic bacteria for CRC by examining the preoperative gut microbiota through 16S ribosomal RNA gene sequencing. Results We collected stool samples from 333 patients with primary CRC within 2 weeks before surgery and followed up the patients for a median of 27.6 months for progression and 43.6 months for survival. The sequence and prognosis data were assessed using the log-rank test and multivariate Cox proportional hazard analysis. The gut microbiota was associated with the clinical outcomes of CRC patients (Pprogress = 0.011, Pdecease = 0.007). In particular, the high abundance of Prevotella, a representative genus of human enterotypes, indicated lower risks of CRC progression (P = 0.026) and decease (P = 0.0056), while the occurrence of Alistipes assigned to Bacteroides sp., Pyramidobacter piscolens, Dialister invisus, and Fusobacterium nucleatum indicated a high risk of progression. A microbiota-derived hazard score considering the five prognostic bacteria accurately predicted CRC progression in 1000 random subsamples; it outperformed widely accepted clinical biomarkers such as carcinoembryonic antigen and lymphatic invasion, after adjustment for the clinicopathological stage (adjusted HR 2.07 [95% CI, 1.61–2.64], P = 7.8e−9, C-index = 0.78). PICRUSt2 suggested that microbial pathways pertaining to thiamine salvage and L-histidine degradation underlie the different prognoses. Conclusions The enterotypical genus Prevotella was demonstrated to be useful in improving CRC prognosis, and combined with the four pathobionts, our hazard score based on the gut microbiota should provide an important asset in predicting medical outcomes for CRC patients.

Nucleotide-sensing Toll-like receptors (TLRs), such as TLR3, 7, and 9, reside in the endolysosomal compartments to avoid activation by host DNA or RNA. Proper intracellular localization and signaling by these TLRs depend on the physical interaction with UNC93B1. Specific amino acid residues in UNC93B1 have been identified to affect the functions of endosolysomal TLRs. However, it is largely unknown how UNC93B1 differentially regulates individual TLRs. Protein N-glycosylation controls folding, maturation, stability, localization and protein-interaction of target glycoproteins. In this study, we examined whether the N-glycosylation of UNC93B1 affects its properties and molecular function. Using mutagenesis, we found that the N251 and N272 residues of UNC93B1 become N-glycosylated. We expressed wild type (WT) and N-glycosylation-defective UNC93B1 mutants (N251Q and N272Q) in UNC93B1-deficient cells and found that signaling of TLR9, but not that of other TLRs, were defective in UNC93B1 N272Q-expressing cells. The N272Q mutation did not affect the protein stability, localization, interaction of UNC93B1 and TLRs, nor did it prevent the CpG DNA-binding of TLR9. Nonetheless, upon CpG DNA stimulation, the recruitment of MyD88 to TLR9 was significantly inhibited in UNC93B1 N272Q-expressing cells compared to WT cells. Consequently, poor phosphorylation and degradation of I_B were observed in UNC93B1 N272Q-expressing cells. Combined, our data show that N-glycosylation of UNC93B1 specifically regulates TLR9 signaling by modulating the recruitment of MyD88 to TLR9.