Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila

Abstract

Gut homeostasis is controlled by both immune and developmental mechanisms, and its disruption can lead to inflammatory disorders or cancerous lesions of the intestine. While the impact of bacteria on the mucosal immune system is beginning to be precisely understood, little is known about the effects of bacteria on gut epithelium renewal. Here, we addressed how both infectious and indigenous bacteria modulate stem cell activity in Drosophila. We show that the increased epithelium renewal observed upon some bacterial infections is a consequence of the oxidative burst, a major defense of the Drosophila gut. Additionally, we provide evidence that the JAK-STAT (Janus kinase-signal transducers and activators of transcription) and JNK (c-Jun NH 2 terminal kinase) pathways are both required for bacteria-induced stem cell proliferation. Similarly, we demonstrate that indigenous gut microbiota activate the same, albeit reduced, program at basal levels. Altered control of gut microbiota in immune-deficient or aged flies correlates with increased epithelium renewal. Finally, we show that epithelium renewal is an essential component of Drosophila defense against oral bacterial infection. Altogether, these results indicate that gut homeostasis is achieved by a complex interregulation of the immune response, gut microbiota, and stem cell activity.

EGFR and Notch signaling respectively regulate proliferative activity and multiple cell lineage differentiation of Drosophila gastric stem cells

“…In pMG, damage or bacterial infection can induce expression of Upd-family ligands through JNK, Hippo and/or other unknown mechanisms [10,12,[26][27][28]. These secreted ligands are able to promote ISC proliferation directly and also indirectly through induction of EGFR ligands [11,29,30].…”

Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration

“…Tissue damage induced by feeding flies with chemicals such as dextran sulfate sodium (DSS) or bleomycin, or by bacterial infection can stimulate ISC proliferation and mount a regeneration program in affected midguts [6,7]. Several evolutionarily conserved signaling pathways, including insulin, JNK, JAK-STAT, EGFR, Wg/Wnt and Hippo (Hpo) pathways, have been implicated in the regulation of ISC proliferation during midgut homeostasis and regeneration [5,6,[8][9][10][11][12][13][14][15][16][17][18]. All these pathways have been implicated in human cancers; therefore, investigating the mechanisms underlying the control of ISC proliferation in the Drosophila midgut may have important implications for human diseases.…”

Le dialogue microbiote-cellules souches

“…Plusieurs études réalisées chez la drosophile ont montré que le microbiote intestinal jouait un rôle important dans la régulation de la prolifération des CSI [25]. Cette régulation semble en grande partie relayée par les entérocytes qui, en réponse au stimulus bactérien, activent la prolifération des CSI via la signalisation JAK/ STAT (Janus kinases/signal transducers and activators of transcription) [28,29], ou la signalisation Redox (oxydo-réduction), à la suite de l'activation de NOX1 (NADPH oxydase 1), un complexe enzymatique membranaire exprimé par les cellules épithéliales et responsable de la libération de ROS (reactive oxygen species) [30]. Le pic oxydatif résultant de l'activation de NOX1 a éga-lement été impliqué dans la cytoprotection des CSI.…”