Biology subjects

Sanville, J.

Publications and source records attributed to Sanville, J..

3 recordsLinked to original sources

bioRxiv2025

A genotoxin associated with colorectal cancer linked to gut dysbiosis in children with cystic fibrosis

Cystic fibrosis (CF) substantially alters the gastrointestinal microbiome from an early age, leading to significant changes in microbial composition and functionality. This study explores the physiological and microbiological factors contributing to dysbiosis in children with cystic fibrosis (cwCF), characterized by an increase in potentially pathogenic Escherichia coli and a decrease in beneficial anaerobes such as Bacteroides. In this study, we employed an in vitro medium representative of the nutritional environment of the CF colon to test the role of factors including mucin, fat, bile, pH, antibiotics and features associated with inflammation (e.g., nitrate, sulfate, formate, reactive oxygen species) on growth of clinical isolates of E. coli and Bacteroides spp. We further examined interactions between these two microbes under CF-like conditions to understand modulators of microbial competition, and identified glycerol, a surrogate of increased fat, as a significant driver of altered microbial competition. Finally, we investigated genetic determinants influencing these microbial interactions, with the focus on glycerol metabolism, by performing a transposon mutagenesis screen in E. coli. Results of this screen pointed to the role of colibactin production in mediating this microbial competition; colibactin is a DNA-damaging genotoxin associated with the increased risk of colorectal cancer (CRC) in CF populations. This work enhances our understanding of mechanisms of microbial competition in the CF gut, while potentially enhancing our understanding of colorectal cancer risk in persons with CF through the identification of early-life microbial biomarkers. Significance StatementThe risk of CRC development in CF populations is significantly increased. This study examines the interplay of altered intestinal physiology in the microbial dysbiosis common in the CF gut, implicating the high fat environment in a competition-mediated depletion of immune-modulating Bacteroides. This work identifies candidate features of the young CF intestine and gut microbiome that may contribute to advanced development of CRC in these populations, informing potential therapeutic approaches.

microbiology↗

bioRxiv2025

Profiling Bile Acids in the Stools of Humans and Animal Models of Cystic Fibrosis

Cystic fibrosis (CF) is associated with dysbiosis of the gut microbiome, alterations in intestinal mucus production, aberrant bile acid (BA) metabolism, fat malabsorption, and chronic inflammation. As little is known about BAs in CF, we performed both comprehensive and targeted BA profiling in stool of children with or without CF. Our results reveal that select BA species and metabolites are significantly different between children with CF (cwCF) and healthy controls. There is also a trend towards higher primary cBA and total BA levels for cwCF. Matched bacterial metagenomic analyses showed no change in alpha-diversity between groups in our small cohort, at odds with previous studies, whereas changes in relative abundance of Bacteroides (lower) and E. coli (increased) species is consistent with prior reports. A robust trend was noted toward reduced abundance of bsh gene families (Wilcox test, p = 0.052), a key rate-limiting enzyme required for bacterial synthesis of secondary BAs, in cwCF. Modest changes in both BAs and microbial BA metabolism-related gene abundances may be attributable to small sample sizes, but also suggest likely combination defects in both host and microbial BA metabolic pathways in cwCF. Importantly, although fecal BA profiles from both ferret and mouse CF models showed significant differences from human BA profiles, only the ferret model reproduced significant differences between CF and nonCF animals, highlighting ferrets as a potentially more appropriate model for studying BA in stool in the context of CF. Together, these results provide new insights into CF-related BA dysmetabolism in cwCF, and highlight limitations of CF animal models for BA functional studies. IMPORTANCEChanges in the abundance and/or composition of intestinal bile acids (BAs) may contribute to dysbiosis and altered gastrointestinal physiology in CF. Here, we report shifts in select fecal BA classes and species for children with CF (cwCF). Matched metagenomic analysis suggest possible defects in both host intestinal BA absorption and gut microbial BA metabolism. Additional analyses of mouse and ferret CF stool for BA composition suggest great care must be taken when interpreting BA functional studies using these animal models. Together, this work lays technical and conceptual foundations for interrogating BA-microbe interactions in cwCF.

microbiology↗

bioRxiv2023

An In Vitro Medium for Modeling Gut Dysbiosis Associated with Cystic Fibrosis

The gut physiology of pediatric and adult persons with cystic fibrosis (pwCF) is altered relative to healthy persons. The CF gut is characterized, in part, as having excess mucus, increased fat content, acidic pH, increased inflammation, increased antibiotic perturbation and the potential for increased oxygen availability. These physiological differences shift nutritional availability and the local environment for intestinal microbes, thus likely driving significant changes in microbial metabolism, colonization and competition with other microbes. The impact of any specific change in this physiological landscape is difficult to parse using human or animal studies. Thus, we have developed a novel culture medium representative of the CF gut environment, inclusive of all the aforementioned features. This medium, called CF-MiPro, maintains CF gut microbiome communities, while significantly shifting non-CF gut microbiome communities toward a CF-like microbial profile, characterized by low Bacteroidetes and high Proteobacteria abundance. This medium is able to maintain this culture composition for up to 5 days of passage. Additionally, microbial communities passaged in CF-MiPro produce significantly less immunomodulatory short chain fatty acids (SCFA), including propionate and butyrate, than communities passaged in MiPro, a culture medium representative of healthy gut physiology, confirming not only a shift in microbial composition but altered community function. Our results support the potential for this in vitro culture medium as a new tool for the study of gut dysbiosis in CF. ImportanceCystic fibrosis is an autosomal recessive disease that disrupts ion transport at mucosal surfaces, leading to mucus accumulation and altered physiology of both the lungs and the intestines, among other organs, with the resulting altered environment contributing to an imbalance of microbial communities. Culture media representative of the CF airway have been developed and validated; however, no such medium exists for modeling the CF intestine. Here, we develop and validate a first-generation culture medium inclusive of features that are altered in the CF colon. Our findings suggest this novel medium, called CF-MiPro, as a maintenance medium for CF gut microbiome samples and a flexible tool for studying key drivers of CF-associated gut dysbiosis.

microbiology↗