Biology subjects

La, J.

Publications and source records attributed to La, J..

4 recordsLinked to original sources

bioRxiv2025

Development of the Early Childhood Duodenum across Ancestry, Geography and Environment

During early childhood, the proximal small intestinal mucosa plays a central role in growth, metabolism, immune priming, and neuronal development. Yet the cellular architecture and environmental responsiveness of the human small intestinal mucosa during this period remain poorly defined. Here, we generate a comprehensive cellular and spatial map of the duodenum from 87 children aged 6 months to 13 years, representing diverse ancestries and geographic contexts. This atlas integrates single-cell transcriptomic and spatial profiling with data on diet, social drivers of health, and environmental exposures. Using these data, we define mucosal cellular composition and chart its developmental trajectory in early childhood. Comparative analyses of children residing in the United States (US) and Pakistan reveal a differentiated enterocyte subset expressing the aquaglyceroporin, AQP10 (AQP10+ enterocyte), that is enriched in children from the US. We show that emergence of this enterocyte state depends on lipid exposure to intestinal stem cells and correlates with dietary fat intake. We also identify a previously-undescribed thyrotropin-releasing hormone (TRH+) enteroendocrine cell and provide evidence for a local endocrine-epithelial-lymphocyte circuit. Our work establishes a detailed framework for pediatric duodenal mucosal development and illuminates how intestinal cellular dynamics are shaped by age and environment.

developmental biology↗

bioRxiv2025

TTC7A organizes glandular lumen formation in the intestine through a Class II phosphatidylinositol 3-kinase

The formation of a single central lumen is a critical step for glandular morphogenesis. Patients with loss of function variants in the chaperone protein TTC7A have multiple lumen formation in colonic crypt glands. We show that trafficking and localization of TTC7A to the plasma membrane is required for directionally specifying the apical membrane with TTC7A patient loss-of-function variants leading to mislocalized membrane and lumen formation. Our experiments show that TTC7A, in early stages of apical membrane development, functions as a molecular chaperone for the Class II phosphatidylinositol 3-kinase, PIK3C2A and is trafficked in Rab11a positive vesicles to generate phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2). We show that the apical specification process is dependent on PIK3C2A dependent generation of PI(3,4)P2 in intestinal epithelia and that defective lumen formation can be rescued by exogenous PI(3,4)P2 or small molecules that modulate phosphoinositide homeostasis.

cell biology↗

bioRxiv2025

SPECTRE-Plex: an automated, fast, high-resolution-enabled approach for multiplexed cyclic imaging and tissue spatial analysis

Mapping the spatial organization of tissues is critical to understanding organ biology in health and disease. Developments in multiplexed antibody-based, fluorescence labelling methods have provided unique insights into tissue microenvironments. However, many current methods have a variety of limitations that reduce their practical utilization. To address this, we developed SPECTRE-Plex; an end-to-end solution based on a series of methods that significantly improve speed, automation, and resolution of cyclic multiplex immunofluorescence imaging.

bioengineering↗

bioRxiv2024

Gut microbiota dysbiosis induced by brain tumor modulates the efficacy of immunotherapy

BackgroundAlthough the influence of gut microbiota on various tumors has gained recognition, the intricate mechanisms underlying their effects on brain tumors remain largely unexplored. In this study, our objective was to unveil pivotal gut microbiota that contribute significantly to the anti-tumor immune response against brain tumors. ResultsDuring the progression of brain tumors, our research uncovered a notable shift in the gut microbiome, as revealed through comprehensive 16S rRNA sequencing analysis. This shift coincided with a substantial decrease in the concentration of tryptophan in fecal samples, indicating a potential link between tryptophan levels and microbiome composition. Intriguingly, dietary supplementation with tryptophan significantly mitigated these microbial alterations, suggesting a restorative effect on the gut microbiota composition. This intervention not only reversed the changes observed in the gut microbiome but also markedly improved survival rates, a phenomenon that was determined to be dependent on the gut microbiota. The mechanism underlying this improvement appears to involve an enhancement in T cell circulation, which in turn boosts the efficacy of immunotherapeutic approaches. Upon further investigation into the specific microbial species that were positively influenced by tryptophan supplementation, some candidates were screened. Among several gut microbiota strains restored by tryptophan supplementation, the most significant is Duncaniella dubosii. Through sole colonization into germ-free mice, we found that the presence of Duncaniella dubosii alone was able to replicate the beneficial effects observed with tryptophan supplementation. ConclusionsThis study highlights Duncaniella dubosiis crucial role in linking tryptophan supplementation to positive shifts in the gut microbiome, immune modulation, and enhanced survival during brain tumor progression. It underscores the complex interaction between diet, microbiota, and immune responses, offering novel insights for boosting cancer immunotherapys success.

microbiology↗