Soutenance de Thèse : Longwei Bai

Le 16 septembre, Longwei Bai de l'équipe de François Leulier soutiendra sa thèse intitulée :

"Gut-derived signals mediate adaptive growth to microbiota and diet in Drosophila larvae"

Abstract:

Juvenile growth is a plastic and adaptive trait, particularly critical under chronic undernutrition which typically leads to reduced growth rates and delayed maturation. Using Drosophila and mouse gnotobiotic models, previous studies have established the evolutionarily conserved influence of the intestinal microbiota and selected Lactiplantibacillus strains on juvenile growth. Building upon this foundation, this thesis aimed to identify the molecular mechanisms underlying microbe-mediated Drosophila adaptive growth under nutritional stress.

Recognizing the intestine as the primary interface for host-microbe interactions, we conducted a comparative analysis of the larval midgut transcriptome in the presence or absence of an intestinal Lactiplantibacillus plantarumWJL (LpWJL) strain representative of the Drosophila microbiota. Among the differentially regulated biological processes identified, Ecdysone signaling emerged as a novel LpWJL-mediated signature within the gut epithelium. Through subsequent functional and morphometrical studies, we demonstrate that, upon bacterial association, intestinal Ecdysone is not rate-limiting for systemic larval growth but is specifically required for the adaptation of midgut tissue growth to the presence of LpWJL. Our results reveal a tissue-specific contribution of the pleiotropic hormone Ecdysone in controlling midgut adaptive growth and maturation.

Extending these investigations, our previous findings also unveiled that the association of undernourished germ-free (GF) Drosophila larvae with selected commensal bacteria, including LpWJL, supports juvenile growth by promoting the systemic activity of Drosophila Insulin-like peptides (DILPs). However, the mechanisms by which gut endocrine functions coordinate with systemic insulin signaling in this context remained elusive.

From our midgut bulk RNA-seq data, we identified Limostatin (Lst), a peptide hormone, as being differentially regulated by LpWJL upon malnutrition. We further demonstrate that lst is specifically induced in a discrete group of enteroendocrine cells (EECs) in the anterior midgut of larvae exposed to environmental stress, particularly when dietary protein and the microbiota are severely altered. Moreover, we found that lst-deficiency or EEC-specific knockdown of lst significantly reduced the delay in larval systemic growth caused by malnutrition. Furthermore, overexpression of lst in EECs significantly inhibited Lp-promoted larval systemic growth upon malnutrition.

More intriguingly, amino acid sensing from the fat body and the resulting systemic insulin intensity are involved in regulating gut-derived lst expression; attenuated insulin signaling in EECs triggers the expression of lst, in line with the inhibition of larval systemic growth upon undernutrition. More intriguingly, we show that lst expression is induced in EECs upon reduced circulating DILP2 levels, and that Lst in turn suppresses DILP2 release from brain Insulin-producing cells (IPCs). This establishes a negative feedback loop that reinforces the inhibition of systemic growth when nutrients are scarce. These findings establish Lst as an adaptive enterokine—a gut-derived peptide hormone that integrates dietary and microbial signals to modulate somatotropic output. Our work reveals that, in addition to the fat body, the intestine acts as a nutrient- and microbiota-sensitive endocrine organ that coordinates systemic growth with environmental input.

In summary, this thesis uncovers Lp-modulated Ecdysone signals targeting enterocytes that distinctly promote larval intestinal tissue growth and identifies Lst-mediated gut endocrine functions that contribute to larval adaptive growth under conditions of malnutrition. Collectively, these findings advance our understanding of microbiota-host interactions for larval developmental adaptation to nutrient stress.