Commensal microbiota-induced redox signaling activates proliferative signals in the intestinal stem cell microenvironment

Abstract

A distinct taxon of the Drosophila microbiota, Lactobacillus plantarum, is capable of stimulating the generation of reactive oxygen species (ROS) within cells, and inducing epithelial cell proliferation. Here, we show that microbial-induced ROS generation within Drosophila larval stem cell compartments exhibits a distinct spatial distribution. Lactobacilli-induced ROS is strictly excluded from defined midgut compartments that harbor adult midgut progenitor (AMP) cells, forming a functional 'ROS sheltered zone' (RSZ). The RSZ is undiscernible in germ-free larvae, but forms following monocolonization with L. plantarum. L. plantarum is a strong activator of the ROS-sensitive CncC/Nrf2 signaling pathway within enterocytes. Enterocyte-specific activation of CncC stimulated the proliferation of AMPs, which demonstrates that pro-proliferative signals are transduced from enterocytes to AMPs. Mechanistically, we show that the cytokine Upd2 is expressed in the gut following L. plantarum colonization in a CncC-dependent fashion, and may function in lactobacilli-induced AMP proliferation and intestinal tissue growth and development.

How commensal microbes shape the physiology of Drosophila melanogaster

“…L. plantarum triggers production of ROS in enterocytes, which then secrete the cytokine Unpaired2 (Upd2) that transduces the signal to the AMPs. The authors of this study did not provide detailed information about the impact of this mechanism on larval development, yet they show that upd2 knock-down in the larval enterocytes leads to reduced adult weight [26 ].…”

“…The mechanism of this buffering effect remains elusive, but it can be inhibited by the anti-oxidant N-Acetyl Cystein. Moreover, association with L. plantarum triggers ROS production in the gut, which leads to increased number of Adult Midgut Precursors (AMPs), the stem cells in the larval gut that give rise to the adult midgut during metamorphosis [26 ]. AMPs themselves are in a reducing micro-environment (the 'ROS-sheltered zone').…”

Germ‐free and microbiota‐associated mice yield small intestinal epithelial organoids with equivalent and robust transcriptome/proteome expression phenotypes

“…The microbiota can profoundly impact diverse aspects of epithelial physiology, including autophagy, mucus production and antimicrobial defence mechanisms (Benjamin, Sumpter, Levine, & Hooper, ; Chen et al, ; Jakobsson et al, ). Certain microbiota members even influence intestinal epithelial stem cell numbers and their proliferative capacity in vivo (Lee et al, ; Pan et al, ; Reedy, Luo, Neish, & Jones, ; Savage, Siegel, Snellen, & Whitt, ; Sommer & Bäckhed, ; Stecher et al, ). As a result, the non‐equal microbiota composition between separately kept mouse lines represents a major confounding factor in studies of how host genetics affect gut physiology and disease (Hausmann & Hardt, ; Mamantopoulos et al, ; Mamantopoulos, Ronchi, McCoy, & Wullaert, ; Robertson et al, ; Stappenbeck & Virgin, ).…”

JNK-dependent intestinal barrier failure disrupts host–microbe homeostasis during tumorigenesis

“…Due to the low diversity of its intestinal microbiota and powerful genetic tools, Drosophila has become an important model system to study host-microbe interactions. In Drosophila, the microbiota has been reported to be involved in host development (14)(15)(16)(17)(18)(19), influencing lifespan (20)(21)(22)(23) and affecting animal behavior and disease (24)(25)(26)(27)(28).…”