Biology subjects

Doupe, D. P.

Publications and source records attributed to Doupe, D. P..

3 recordsLinked to original sources

bioRxiv2026

The Transcription Factor Sob Maintains Intestinal Stem Cell Homeostasis to Delay Ageing

Ageing is associated with physiological decline and disrupted tissue homeostasis, often driven by imbalanced stem cell activity. The Drosophila midgut serves as a powerful model for studying epithelial homeostasis and ageing as it exhibits many conserved hallmarks of regulation and deteriorating intestinal stem cell function with age. We have identified the transcription factor encoded by Sister of odd and bowl (Sob) as a conserved marker of intestinal stem/progenitor cells in homeostasis whose expression is lost with age. Premature downregulation of sob shortens lifespan while overexpression in the intestinal stem/progenitor cells is sufficient to extend lifespan, suggesting a critical role in maintaining homeostasis with age. At the cell and tissue level stem/progenitor knockdown and overexpression reveal that Sob maintains homeostasis by regulating both proliferation and lineage specification. In young guts, Sob restricts intestinal stem cell proliferation and promotes enteroendocrine differentiation while limiting excessive enterocyte differentiation. We have also found that the transcription factor Exex, the Notch pathway inhibitor Numb, and the enterocyte differentiation regulator Dawdle act downstream of Sob to regulate proliferation and differentiation. Our findings position Sob as a critical molecular switch linking stem cell dysfunction to gut ageing.

developmental biology↗

bioRxiv2025

Chronic intestinal immune activation reveals separable impacts of inflammation and barrier loss on hallmarks of ageing.

Inflammaging is considered a driver of age-associated pathology across tissues. Similarly, intestinal permeability is a feature of ageing and underlies a range of inflammatory and age-related diseases. Increased intestinal permeability has been described as both a cause and a consequence of inflammation. Both intestinal permeability and inflammation are closely associated with microbial dysbiosis, epithelial dysplasia and mortality but dissecting the complex interplay between these phenotypes remains challenging. Here we genetically induce intestinal immune activation in Drosophila and stratify animals by their intestinal barrier status using the Smurf assay. We demonstrate that intestinal immune activation and barrier failure have distinct impacts on the microbiota. Further, intestinal immune activation drives intestinal barrier failure and mortality even in the absence of the microbiota. Importantly, immune-induced intestinal barrier failure takes time to develop and is closely associated with the onset of mortality. Our work adds to building evidence that the impact of intestinal permeability on the microbiota and on animal health needs to be considered independently of its relationship with inflammation.

physiology↗

bioRxiv2023

Drosophila Undigested Metabolite Profiling reveals age related loss of intestinal amino acid transport regulates longevity

Age-related intestinal decline is marked by altered epithelial architecture, loss of barrier function, elevated stress and immune signalling and changes to the intestinal microbiota. Despite this we do not yet know whether age-related intestinal decline impacts nutrient management, a key function of the intestinal epithelium. In this study we have developed Drosophila Undigested Metabolite Profiling (D.U.M.P.) to assess the impact of intestinal ageing on nutrient absorption/excretion balance. We demonstrate that ageing results in a significant increase in amino acid load in the faecal matter that is largely driven by the microbiota and shortens lifespan. Increased amino acid load is associated with reduced expression of a subset of amino acid transporters. Knockdown of the amino acid transporter slimfast in the intestinal epithelium extends lifespan and confers improved microbial control in aged flies, suggesting reduced transporter expression is protective, preventing cellular uptake of excess amino acids. We conclude that age-related changes to the microbiota are an important determinant of the local nutritional environment, with consequences for health. In addition, age-related decline of the intestinal epithelium may impact its capacity for nutrient absorption. These findings have significant implications for the rational design of anti-ageing nutritional therapies.

physiology↗