Intestinal aging is closely associated with gut microbiota dysbiosis and insufficient microbial short-chain fatty acid (SCFAs) production, particularly butyrate. Here, a homogeneous polysaccharide (DOPP) was isolated and purified from the stems of Dendrobium officinale Kimura et Migo, and its structural characteristics and anti-intestinal aging activity were systematically investigated. With a weight-average molecular weight (Mw) of 65.33 kDa, DOPP is a neutral acetylated glucomannan. It was proposed to mainly consist of →4)-β-D-Manp-(1→, →4)-2-O-Ac-β-D-Manp-(1→, →4)-α-D-Glcp-(1→, α-reducing Glcp, and β-reducing Glcp moieties, and to adopt an approximately random-coil chain conformation in aqueous solution. In vivo experiments demonstrated that DOPP administration effectively ameliorated aging phenotypes, enhanced intestinal barrier integrity, and alleviated intestinal inflammaging in naturally aged mice. Mechanistically, DOPP reshaped the gut microbiota by reducing the abundance of aging-associated Bacteroidota and Pseudomonadota while enriching butyrate-producing bacteria, including the Lachnospiraceae NK4A136 group, Roseburia, and Ruminococcus, thereby elevating intestinal SCFAs levels, with butyrate as the major functional component. The elevated SCFAs, predominantly butyrate, promoted functional regulatory T-cell (Treg) differentiation by improving colonic mitochondrial oxidative phosphorylation, thereby correcting the age-related Treg/Th17 immune imbalance. Fecal microbiota transplantation (FMT) further indicated that the anti-intestinal aging effect of DOPP is largely dependent on an intact gut microbiota. Collectively, this study demonstrates that DOPP is a promising functional food ingredient for preventing intestinal aging and provides a scientific basis for the high-value development of Dendrobium officinale.
