This study is the first to report the selective utilization of Dendrobium polysaccharides by Bacteroides uniformis, a human gut commensal bacterium. Using an interdisciplinary synthetic biology approach, researchers identified a unique polysaccharide utilization locus in this bacterium. Structural alignment and molecular docking analyses further revealed that the GH26 enzyme, with conserved catalytic sites (E415/E504) and substrate-binding sites, plays a crucial role in Dendrobium polysaccharide metabolism. This pioneering research uncovers key factors in the utilization of medicinal polysaccharides by the human gut microbiota, emphasizing their highly specific metabolism. It enhances our understanding of their in vivo applications and mechanisms of action, while also highlighting the potential for precise gut microbiota targeting, paving the way for new therapeutic strategies.

The research team systematically mapped the utilization profiles of 20 medicinal polysaccharides across 28 human gut Bacteroides and Parabacteroides species, revealing distinct species-specific utilization patterns. Notably, Dendrobium polysaccharides (DPs), a type of glucomannan, selectively promoted the growth of Bacteroides uniformis DA183. To uncover the genetic mechanism behind this selective utilization, the team conducted transcriptomic analysis and gene knock-out experiments. They identified the key gene cluster PUL34 and the critical enzyme GH26_BuDA183 as essential for DPs metabolism. Sequence alignment further showed that only the genome of B. uniformis DA183 encodes the complete PUL34_BuDA183 gene cluster.

Harnessing medicinal polysaccharides to modulate the gut microbiome has emerged as a promising therapeutic approach for human diseases. Bacteroides and Parabacteroides are the primary consumers of dietary polysaccharides in the human gut. Understanding how these commensal bacteria metabolize medicinal polysaccharides is crucial for developing novel polysaccharide-based prebiotics and therapeutics to enhance human health. However, a comprehensive analysis of gut bacterial utilization of medicinal polysaccharides and its genetic basis remains lacking.

The research team compared the AlphaFold2-predicted structure of Bacteroides uniformis GH26 with the crystal structure of Bacteroides ovatus GH26, revealing conserved catalytic and substrate-binding sites. They expressed and purified the enzyme, confirming its hydrolytic activity against mannans in vitro. Point mutation experiments showed that mutating E415A or E504A abolished activity, confirming their essential catalytic role. Molecular docking simulations further highlighted substrate interactions with catalytic residues.

This study provides a framework for understanding how human gut bacteria utilize plant-derived polysaccharides, with implications for gut microbiome research, carbohydrate-active enzymes, and glycan-based prebiotics and therapeutics.

Source: https://www.um.edu.mo/news-and-press-releases/campus-news/detail/60372/