Innate Immune Homeostasis by the Homeobox Gene Caudal and Commensal-Gut Mutualism in Drosophila

Abstract

Although commensalism with gut microbiota exists in all metazoans, the host factors that maintain this homeostatic relationship remain largely unknown. We show that the intestinal homeobox gene Caudal regulates the commensal-gut mutualism by repressing nuclear factor kappa B-dependent antimicrobial peptide genes. Inhibition of Caudal expression in flies via RNA interference led to overexpression of antimicrobial peptides, which in turn altered the commensal population within the intestine. In particular, the dominance of one gut microbe, Gluconobacter sp. strain EW707, eventually led to gut cell apoptosis and host mortality. However, restoration of a healthy microbiota community and normal host survival in the Caudal-RNAi flies was achieved by reintroduction of the Caudal gene. These results reveal that a specific genetic deficiency within a host can profoundly influence the gut commensal microbial community and host physiology.

Integrating nutrition and immunology: A new frontier

“…Gut microbes also play a role in invertebrate biology (Dillon and Dillon, 2003) and digestive process [Brune, 2011 [Lundgren, 2010, and recently the composition of microbe gut populations has been described in a variety of insect species, including bees (Jeyaprakash et al, 2003;Mohr and Tebbe, 2006), beetles (Egert et al, 2005;Lehman et al, 2009;Nardi et al, 2006;Zhang and Jackson, 2008), flies (Cox and Gilmore, 2007;Ren et al, 2007;Ryu et al, 2008;Shin et al, 2011;Wong et al, 2011), lepidopterans (Pauchet et al, 2010;Xiang et al, 2006) and termites (Hongoh et al, 2003). In Drosophila, the microbiome regulates host metabolic homeostatic and developmental programs by modulating the insulin/insulin-like growth factor (Shin et al, 2011).…”

“…Alternatively, the gut microbiota can indirectly affect the development and persistence of parasites by inducing the host's immune system (Buchon et al, 2009;Douglas, 2010;Feldhaar and Gross, 2008;Kau et al, 2011;Lazzaro and Little, 2009;Ryu et al, 2010;Ryu et al, 2008;Wen et al, 2008). For instance, in mosquitoes, commensals can modulate Plasmodium infection (Cirimotich et al, 2011;Gonzalez-Ceron et al, 2003;Meister et al, 2009;Pumpuni et al, 1996).…”

“…Global transcription profiling of germ-free mosquitoes identified a subset of immune genes that were mostly down-regulated, including several anti-Plasmodium factors (Dong et al, 2009). In flies, gut microbiota modulate the immune system, and hence presumably susceptibility to invading parasites, by activating the Imd pathway transcription factor Relish (Ryu et al, 2008), which triggers the production of AMPs (Feldhaar and Gross, 2008;Ryu et al, 2008).…”

Friend, foe or food? Recognition and the role of antimicrobial peptides in gut immunity and Drosophila –microbe interactions

“…Comparisons between flies grown in the absence of gut microbiota (axenic) and conventionally reared flies have shown multiple contributions of bacteria to adult physiology, including lipid storage and glucose levels [58,70,71], gut stem cell activity [42,63], mating preference [72] and disease susceptibility [61,73]. Moreover, as discussed in greater detail below, as in other animals [1,2,7], the microbiota of D. melanogaster is also important for maturation of host immune and stress responses [3,13,14,21], and the gut epithelial immune response is considered an important regulator of microbiota composition and density [35,42,63,74].…”

“…The focus on the gut is extremely relevant, given that this is the most common interface by which Drosophila and other animals interact with microbes [12,13,34]. As such, there is growing recognition that gut immune responses are key components of host interactions with indigenous microbiota and dietary microbes [21,35,36]. This body of work has greatly expanded our understanding of the mechanisms of host-microbe interactions and has established D. melanogaster as an important tool to elucidate mechanisms of gut physiology and homeostasis.…”