Biology subjects

Bonfini, A.

Publications and source records attributed to Bonfini, A..

4 recordsLinked to original sources

bioRxiv2025

Microbes and diet reshape the intestine via distinct cellular dynamics

BackgroundThe intestine adapts to environmental stimuli by dynamically altering its size. Infections causes shrinkage and subsequent regrowth to original intestinal dimensions, suggesting homeostasis, whereas diet can induce adaptive changes. Whether diet and infection differ in the kinetics, magnitude, or cellular mechanisms that drive intestinal resizing, and whether intestines use a fixed size "memory" versus an adaption to nutrient availability, still remains unclear. ObjectiveTo determine whether intestinal regrowth after infection reflects a fixed "memory" of a target size (homeostasis) or an adaptation to the nutritional state during regrowth, and to identify the cellular modalities that drive infection- and diet-induced resizing. DesignUsing Drosophila melanogaster as a model, we quantified intestinal size, cell size, cell number, and epithelial turnover in response to dietary shifts and oral bacterial infections, both individually and in combination. ResultsInfection-induced atrophy occurred only when the intestine was initially large, and regrowth required nutrient availability. Distinct cellular mechanisms underpinned changes in intestinal size: diet-induced growth in unchallenged intestines was mediated by enterocyte hypertrophy, whereas post-infection regrowth required intestinal stem cell (ISC) proliferation. Consistently, ISC ablation impaired regrowth only after infection. Bacteria functioned both as pathogens and nutrients, triggering intestinal shrinkage when damaging a large organ, but promoting growth when consumed by nutrient-deprived flies. ConclusionIntestinal regrowth after infection reflects a context-dependent, diet-driven adaptation, not a fixed intestinal size memory. Diet and infection engage distinct, stimulus-specific cellular programs to reshape the midgut, revealing a modular logic of organ plasticity with implications for tissue repair and metabolic regulation. Summary boxO_ST_ABSWhat is already known on this topicC_ST_ABS- Intestinal size is regulated by epithelial turnover and responds dynamically to dietary and microbial stimuli. What this study adds- Post-infection intestinal regrowth is governed by dietary input rather than an intrinsic memory of pre-infection intestinal size. - Intestinal resizing is driven by distinct cellular programs: diet-induced intestinal growth occurs independently of stem cells, while post-infection intestinal regrowth requires stem cell proliferation. - Diet, rather than microbes, is the primary driver of intestinal size, while pathogens influence the mode of size change by increasing cellular turnover. - Pathogenic microbes act as both sources of damage and nutrients, influencing organ resizing. How this study might affect research, practice, or policy- Reframes intestinal regeneration as a flexible, context-dependent adaptation rather than a fixed homeostatic process. - Identifies nutritional status as a critical determinant of recovery following intestinal injury. - Offers a conceptual framework for understanding epithelial plasticity in health and disease, emphasizing how the balance of cell size and stem cell activity coordinates adult intestinal size.

developmental biology↗

bioRxiv2023

Wnt/β-catenin signaling within multiple cell types dependent upon kramer regulates Drosophila intestinal stem cell proliferation

The gut epithelium is subject to constant renewal, a process reliant upon intestinal stem cell (ISC) proliferation that is driven by Wnt/{beta}-catenin signaling. Despite the importance of Wnt signaling within ISCs, the relevance of Wnt signaling within other gut cell types and the underlying mechanisms that modulate Wnt signaling in these contexts remain incompletely understood. Using challenge of the Drosophila midgut with a non-lethal enteric pathogen, we examine the cellular determinants of ISC proliferation, harnessing kramer, a recently identified regulator of Wnt signaling pathways, as a mechanistic tool. We find that Wnt signaling within Prospero-positive cells supports ISC proliferation and that kramer regulates Wnt signaling in this context by antagonizing kelch, a Cullin-3 E3 ligase adaptor that mediates Dishevelled polyubiquitination. This work establishes kramer as a physiological regulator of Wnt/{beta}-catenin signaling in vivo and suggests enteroendocrine cells as a new cell type that regulates ISC proliferation via Wnt/{beta}-catenin signaling.

cell biology↗

bioRxiv2021

A transcriptomic atlas of Aedes aegypti reveals detailed functional organization of major body parts and gut regional specializations in sugar-fed and blood-fed adult females

Mosquito vectors transmit numerous pathogens, but large gaps remain in our understanding of their physiology. To facilitate future explorations of mosquito biology, with specific attention to the major vector Aedes aegypti, we have created Aegypti-Atlas (http://aegyptiatlas.buchonlab.com/), an online resource hosting RNAseq profiles of Ae. Aegypti body parts (head, thorax, abdomen, gut, Malpighian tubules, and ovaries), gut regions (crop, proventriculus, anterior and posterior midgut, and hindgut), and a time course of blood meal digestion in the gut. Using Aegypti-Atlas, we provide new insights into the regionalization of gut function, blood feeding response, and immune defenses. We find that the anterior and posterior regions of the mosquito midgut possess clearly delineated digestive specializations which are preserved in the blood-fed state. Blood feeding initiates the sequential transcriptional induction and repression/depletion of multiple cohorts of peptidases throughout blood meal digestion. With respect to defense, immune signaling components, but not recognition or effector molecules, show enrichment in ovaries. Basal expression of antimicrobial peptides is dominated by two genes, holotricin and gambicin, that are expressed in the carcass and the digestive tissues, respectively, in a near mutually exclusive manner. In the midgut, gambicin and other immune effector genes are almost exclusively expressed in the anterior regions, while the posterior midgut exhibits the hallmarks of immune tolerance. Finally, in a cross-species comparison between the midguts of Ae. aegypti and Anopheles gambiae, we observe that regional digestive and immune specializations are closely conserved, indicating that our data may yield inferences that are broadly relevant to multiple mosquito vector species. We further demonstrate that the expression of orthologous genes is highly correlated, with the exception of a species signature comprising a small number of highly/disparately expressed genes. With this work, we show the potential of Aegypti-Atlas to unlock a more complete understanding of mosquito biology.

physiology↗

bioRxiv2020

Single Cell Analysis Reveals Multi-faceted miR-375 Regulation of the Intestinal Crypt

The role of individual miRNAs in small intestinal (SI) epithelial homeostasis is under-explored. In this study, we discovered that miR-375 is among the most enriched miRNAs in intestinal crypts and stem cells (ISCs), especially facultative ISCs. We then showed by multiple manipulations, including CRISPR/Cas9 editing, that miR-375 is strongly suppressed by Wnt-signaling. Single-cell RNA-seq analysis of SI crypt-enriched cells from miR-375 knockout (375-KO) mice revealed elevated numbers of tuft cells and increased expression of pro-proliferative genes in ISCs. Accordingly, the genetic loss of miR-375 promoted resistance to helminth infection and enhanced the regenerative response to irradiation. The conserved effects of miR-375 were confirmed by gain-of-function studies in Drosophila midgut stem cells in vivo. Moreover, functional experiments in enteroids uncovered a regulatory relationship between miR-375 and Yap1 that controls cell survival. Finally, analysis of mouse model and clinical data revealed an inverse association between miR-375 levels and intestinal tumor development. HighlightsO_LImiR-375 is one of the most enriched miRNAs in ISCs, especially facultative ISCs. C_LIO_LImiR-375 modifies tuft cell abundance and pro-proliferative gene expression in ISCs. C_LIO_LILoss of miR-375 in mice enhances the host response to helminth infection and crypt regeneration. C_LIO_LIMouse and human intestinal cancer are associated with reduced miR-375 expression. C_LI eTOC BlurbSethupathy and colleagues show that miR-375 is a Wnt-responsive, ISC-enriched miRNA that serves as a break on intestinal crypt proliferation. They also show that miR-375 modulates tuft cell abundance and pro-proliferative gene expression in ISCs, that miR-375 loss enhances the host response to helminth infection as well as crypt regeneration post-irradiation, and its reduced expression is associated with intestinal cancer.

molecular biology↗