Masi, A. C. | Search bioRxiv

bioRxiv2025

Human milk oligosaccharide metabolism by Clostridium species suppresses inflammation and pathogen growth

Gut microbiome development is strongly impacted by breastmilk and human milk oligosaccharides (HMOs), with short- and long-term health implications. HMO metabolism is best characterised within bifidobacteria, but the full range of other HMO-utilising species remains unknown. This study examined HMO-utilising bacteria that colonise preterm infants (born <32 weeks gestation), their role in microbiome modulation, and their effects on intestinal barrier function. We found that infant-derived Clostridium perfringens, and three other Clostridium species, metabolise HMOs, producing short chain fatty acids, tryptophan catabolites, and other metabolites known to improve host health. C. perfringens inhibited pathobiont growth and supressed inflammation in preterm-derived intestinal organoids. These findings suggest a previously unrecognised role for C. perfringens, specifically those lacking the perfringolysin O gene, in promoting healthy gut development during infancy.

microbiology↗

bioRxiv2024

Single Cell Integration Characterises Metaplasia in Inflammatory Intestinal Diseases

The gastrointestinal (GI) tract consists of connected organs, from the oral cavity to rectum, which function to ensure efficient nutrient uptake and barrier immunity. Diseases of the GI tract affect millions worldwide and as such there are now over 25 published single cell RNA-sequencing (scRNAseq) datasets surveying the GI tract, profiling specific anatomical regions, cell lineages, ages and diseases. To consolidate these efforts, we harmonised and integrated scRNAseq datasets across the whole GI tract from developing and adult human tissues, as well as newly generated data from preterm gut. We uniformly processed 385 samples from 189 healthy controls using a newly developed automated QC approach (scAutoQC). In total, our healthy reference contains [~]1.1 million cells which we annotated to a total of 137 fine-grained cell states. We anchor 13 published and 1 unpublished GI disease datasets covering gastric and colorectal (CRC) cancers, celiac disease, ulcerative colitis (UC) and Crohns disease (CD) to this reference, taking our atlas to a total of 1.6 million cells. We provide our atlas as a valuable resource to the community (available at gutcellatlas.org). Using this resource, we discover epithelial cell metaplasia arising from stem cells across intestinal inflammatory diseases (celiac, UC and CD) and CRC with transcriptional similarity to cells of the gastric and Brunners glands. Whilst previously linked to mucosal healing, we now implicate these cells in inflammation through recruitment of immune cells including T cells and neutrophils, and through direct interactions with T cells. Overall, we discover a shift in paradigm whereby changes in stem cells during inflammation lead to altered mucosal tissue architecture, which in turn contributes to ongoing inflammation. These findings highlight that in addition to barrier function, epithelial cells actively contribute to progression of inflammation which may be a function applicable to other tissues and diseases.

genomics↗