Dataset Information

Arylsulfamates inhibit colonic Bacteroides growth through lipid kinases and not sulfatases

ABSTRACT: Excessive degradation of the colonic mucin layer by Bacteroides within the human gut microbiota drives inflammatory bowel disease in mice. Bacterial carbohydrate sulfatases are key enzymes in gut colonization, as they are elevated in human inflammatory bowel disease and correlate with disease severity. Selective inhibitors of carbohydrate sulfatases could function as sulfatase-selective drugs, allowing precise control of sulfatase activity while preserving these otherwise beneficial bacteria. Arylsulfamates are covalent inhibitors that target a catalytic formylglycine residue of steroid sulfatases, which is also conserved in carbohydrate sulfatases. Here, using a library of aryl- and carbohydrate sulfamates, we find that they are ineffective against Bacteroides carbohydrate sulfatases yet can inhibit human gut microbiota species grown on sulfated glycans. Leveraging thermal proteome profiling, we identify a lipid kinase as the target responsible for these effects. This work highlights the imperative for developing specific inhibitors targeting carbohydrate sulfatases and unveils the adverse effect that arylsulfamates have on Bacteroides species of the human gut microbiota.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Bacteria Bacteroides Thetaiotaomicron (strain Atcc 29148 / Dsm 2079 / Nctc 10582 / E50 / Vpi-5482)

SUBMITTER: S.S van der Post

LAB HEAD: Sjoerd van der Post

PROVIDER: PXD065411 | Pride | 2025-07-28

REPOSITORIES: Pride

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Arylsulfamates inhibit colonic Bacteroidota growth through a sulfatase-independent mechanism.

Crawford Conor J CJ Tomlinson Charles W E CWE Gunawan Christian C Chen Zongjia Z Byrne Dominic P DP Darby Cosette C Conti Martina L G MLG Larson Tony T Luis Ana S AS Elli Stefano S Yates Edwin A EA Bolam David N DN van der Post Sjoerd S Williams Spencer J SJ Cartmell Alan A

Proceedings of the National Academy of Sciences of the United States of America 20250710 28

Excessive degradation of the colonic mucin layer by <i>Bacteroides</i> within the human gut microbiota drives inflammatory bowel disease (IBD) in mice. Bacterial carbohydrate sulfatases are key enzymes in gut colonization, and they are elevated in human IBD and correlate with disease severity. Selective inhibitors of carbohydrate sulfatases could function as sulfatase-selective drugs, allowing precise control of sulfatase activity while preserving these otherwise beneficial bacteria. Arylsulfama ...[more]

PMID: 40638084

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Project description:The large-scale application of genomic and metagenomic sequencing technologies has yielded a number of insights about the metabolic potential of symbiotic human gut microbes. Bacteria that colonize the mucosal layer that overlies the gut epithelium have access to highly-sulfated polysaccharides (i.e., mucin oligosaccharides and glycosaminoglycans), which they could potentially forage as nutrient sources. To be active, sulfatases must undergo a critical post-translational modification catalyzed in anaerobic bacteria by the AdoMet enzyme anSME (anaerobic Sulfatase-Maturating Enzyme). In the present study, we have tested the role of this pathway in the prominent gut symbiont Bacteroides thetaiotaomicron, which possesses more predicted sulfatases (28) than in the human genome and a single predicted anSME. In vitro studies revealed that deletion of its anSME (BT0238) results in loss of sulfatase activity and impaired ability to use sulfated polysaccharides as carbon sources. Co-colonization of germ-free animals with both isogenic strains, or invasion experiments involving the introduction of one then the other strain, established that anSME activity and the sulfatases that are activated via this pathway, are important fitness factors for B. thetaiotaomicron, especially when mice are fed a simple sugar diet that requires this saccharolytic bacterium to adaptively forage on host glycans as nutrients. Whole genome transcriptional profiling of wild-type and the anSME mutant in vivo revealed that loss of this enzyme alters expression of genes involved in mucin utilization and that this disrupted ability to access mucosal glycans likely underlies the observed dramatic colonization defect. Comparative genomic analysis reveals that 100% of 46 fully sequenced human gut Bacteroidetes contain homologs of BT0238 and genes encoding sulfatases, suggesting that this is an important and evolutionarily conserved feature. Three replicate samples from 4 different biological treatment groups: 1. Wild-type B. thetaiotaomicron from the cecum of gnotobiotic mice fed a simple-sugar diet; 2. chuR mutant B. thetaiotaomicron from the cecum of gnotobiotic mice fed a simple-sugar diet; 3. Wild-type B. thetaiotaomicron from the cecum of gnotobiotic mice fed a plant-rich diet; 4. chuR mutant B. thetaiotaomicron from the cecum of gnotobiotic mice fed a plant-rich diet.

Project description:The human gut microbiota is an important metabolic organ, yet little is known about how its individual species interact, establish dominant positions, and respond to changes in environmental factors such as diet. In this study, gnotobiotic mice were colonized with an artificial microbiota comprising 12 sequenced human gut bacterial species and fed oscillating diets of disparate composition. Rapid, reproducible, and reversible changes in the structure of this assemblage were observed. Time-series microbial RNA-Seq analyses revealed staggered functional responses to diet shifts throughout the assemblage that were heavily focused on carbohydrate and amino acid metabolism. High-resolution shotgun metaproteomics confirmed many of these responses at a protein level. One member, Bacteroides cellulosilyticus WH2, proved exceptionally fit regardless of diet. Its genome encoded more carbohydrate active enzymes than any previously sequenced member of the Bacteroidetes. Transcriptional profiling indicated that B. cellulosilyticus WH2 is an adaptive forager that tailors its versatile carbohydrate utilization strategy to available dietary polysaccharides, with a strong emphasis on plant-derived xylans abundant in dietary staples like cereal grains. Two highly expressed, diet-specific polysaccharide utilization loci (PULs) in B. cellulosilyticus WH2 were identified, one with characteristics of xylan utilization systems. Introduction of a B. cellulosilyticus WH2 library comprising >90,000 isogenic transposon mutants into gnotobiotic mice, along with the other artificial community members, confirmed that these loci represent critical diet-specific fitness determinants. Carbohydrates that trigger dramatic increases in expression of these two loci and many of the organism’s 111 other predicted PULs were identified by RNA-Seq during in vitro growth on 31 distinct carbohydrate substrates, allowing us to better interpret in vivo RNA-Seq and proteomics data. These results offer insight into how gut microbes adapt to dietary perturbations at both a community level and from the perspective of a well-adapted symbiont with exceptional saccharolytic capabilities, and illustrate the value of artificial communities. 611 samples total (221 from experiment 1, 390 from experiment 2). Evaluation of changes in an artificial gut community's structure over time as a result of dietary oscillation.

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