Research Article

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

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Science  08 Feb 2008:
Vol. 319, Issue 5864, pp. 777-782
DOI: 10.1126/science.1149357


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.

The mucosal epithelia of all metazoans, such as those found in the gastrointestinal tract, are in intimate contact with a large number of commensal microbiota (1). As a consequence, commensal bacteria are known to influence many aspects of the host gut physiology, including innate immunity, development, and homeostasis (27). However, the lack of a genetically amenable animal model has limited in-depth analyses of gut-microbe interactions in vivo.

Recent studies have shown that the Drosophila gut activates host antimicrobial defense through the production of microbicidal reactive oxygen species (ROS) and antimicrobial peptides (AMPs) (811). During most gut-pathogen interactions, intestinal redox homeostasis, mediated via infection-induced ROS generation by the dual oxidase enzyme and subsequent ROS elimination by immune-regulated catalase, is critical for host survival (8, 9). The direct contact between gut epithelia and ingested pathogens also activates the immune deficiency (IMD) pathway and subsequent nuclear localization of the p105-like NF-κB, Relish, which in turn leads to de novo synthesis of diverse immune effectors: AMPs and immunosuppressive enzymes such as the peptidoglycan recognition proteins PGRP-SC and PGRP-LB (10, 1216). Although pathogen-initiated gut immunity is fairly well documented in Drosophila (810, 14, 16, 17), the molecular interaction between commensals and the Drosophila gut is poorly understood.

Role of gut commensal microbiota in the IMD-Relish pathway. To investigate the molecular mechanism for commensal-gut interactions, we first asked whether the commensal microbiota could elicit host gut immune responses. We produced germ-free wild-type (GFWT) and conventionally reared wild-type (CRWT) animals (fig. S1) to enable examination of the gut IMD-Relish pathway potential in the absence or presence of commensals. A large amount of the nuclear-translocated active form of Relish was detected in the intestine cells in the presence of commensals (CRWT flies) and was even more pronounced after gut infection with the Drosophila pathogen Erwinia carotovora carotovora-15 (Ecc15) (Fig. 1A).

Fig. 1.

Caudal acts as a gut-specific repressor for NF-κB–dependent AMP genes. (A) Nuclear-translocated active form of Relish (antibody to Relish, green) in posterior midgut (5- or 10-day-old flies). CRWT, conventionally reared wild-type flies; GFWT, germ-free wild-type flies; CRWT + Ab, antibiotics-treated CRWT flies as described in fig. S1; CRDredd, conventionally reared Dredd mutant flies; CRWT + Ecc15, natural gut infection with Ecc15. Nuclear staining was performed with 4′,6′-diamidino-2-phenylindole (DAPI). (B) Quantitative real-time PCR analysis of PGRP-SC, PGRP-LB, Diptericin (Dpt), and Cecropin (Cec) using dissected posterior midguts (without malpighian tubules) of 5-day-old flies. The target gene expression level in the tissues of GFWT flies was taken arbitrarily as 1. (C) CDREs are required for the repression of Cec expression (indicated by arrow) in the posterior midgut (upper panel) and the proventriculus (lower panel). A schematic diagram of the Cec promoter is also shown. (D) Quantitative real-time PCR analysis using posterior midguts or fat body. Genotypes of flies: CRCont (c729-GAL4/+) and CRCad-RNAi (c729-GAL4/+; UAS-Cad-RNAi/+). The target gene expression level in the gut or fat body of CRCont flies was taken arbitrarily as 1. Dpt, Diptericin; Cec, Cecropin; Drs, Drosomycin; Def, Defensin; Att, Attacin; Metch, Metchnikowin. (E) Quantitative real-time PCR analysis. Genotypes of flies (5-day-old GF or CR): Cont (c729-GAL4/+); Cad-RNAi (c729-GAL4/+; UAS-Cad-RNAi/+); Cad-RNAi + Dredd (DreddB118; c729-GAL4/+; UAS-Cad-RNAi/+); Cad-RNAi + TAK1 (TAK1; c729-GAL4/+; UAS-Cad-RNAi/+). The target gene expression level in the CRCont gut was taken arbitrarily as 1. (F) Overexpression of Cad can abolish infection-induced AMP expression. The target gene expression level in uninfected control gut was taken arbitrarily as 1. Natural gut infection for 6 hours with Ecc15 in (A), (D), and (F) was performed as described in (21); relative expression levels in (B), (D), (E), and (F) are expressed as means ± SD (P < 0.05) of three different experiments.

The well-characterized constitutive nuclear localization of Relish in the intestines of CRWT flies was almost completely abolished in the absence of commensals in GFWT or in antibiotics-treated CRWT flies. Similarly, it was not seen in flies carrying a mutation in the IMD-Relish pathway (CRDredd flies) (Fig. 1A). The expression levels of Relish-dependent immunosuppressive enzymes such as PGRP-SC and PGRP-LB (12, 13) were significantly higher in the guts of CRWT flies than in the guts of GFWT or CRDredd flies (Fig. 1B), which confirms that the IMD-Relish pathway was activated by commensals under normal gut conditions. However, the Relish-dependent immune effector molecules, such as AMP genes including Cecropin (Cec) and Diptericin (Dpt), were largely silenced in the CRWT gut despite chronic Relish activation. Similarly, no significant difference in AMP expression levels was observed between the GFWT and CRWT midguts (Fig. 1B). Taken together, these results indicate that although commensal organisms of the gut can chronically induce a high level of local IMD–NF-κB pathway activation, only a subset of target genes (notably excluding AMP genes) are activated.

Role of Caudal in gut AMP repression. We next investigated the potential mechanisms of repression of the gut AMP genes to determine how the selective silencing toward commensals might occur. Currently, the cis-regulatory elements controlling epithelial AMP gene expression are poorly understood. It is known, however, that the κB elements in the promoter regions responsible for nuclear factor kappa B (NF-κB)–Relish binding are essential for inducing epithelial AMP expression (1416), whereas the CDREs, responsive elements for the homeobox transcription factor Caudal (Cad) responsible for Cad binding, are found to be critical for constitutive AMP expression in certain types of epithelia, such as salivary glands and the ejaculatory duct (18). The homeobox transcription factor Cad was originally identified on the basis of its regulatory role in the anteroposterior body axis formation of the Drosophila embryo (19, 20). Because Cad expression in postembryonic life is known to be mostly restricted to the intestine (19) (fig. S2), we analyzed the contribution of CDREs to gut AMP gene expression in vivo. To accomplish this, we used green fluorescent protein (GFP) reporter–expressing transgenic flies carrying a Cec promoter in which the CDREs were mutated (CecCDRE-mut-GFP) and compared GFP expression with that of transgenic flies carrying the wild-type promoters fused to GFP (Cec-GFP) (Fig. 1C). We were unable to detect any Cec reporter activity in the midgut of Cec-GFP flies under normal conditions (Fig. 1C). Interestingly, however, CecCDRE-mut-GFP flies were found to exhibit high constitutive expression of Cec reporter activity in the posterior midgut and the proventriculus in the absence of oral infection (Fig. 1C).

To test whether Cad was involved in the negative regulation of Cec expression through CDREs, we generated transgenic flies that carried the UAS-Cad-RNAi construct to mimic the loss of function (fig. S3) via RNA interference (RNAi). A spontaneous activation of all tested AMPs was observed in the gut of CRCad-RNAi flies under conventional conditions without microbial infection, which was not the case in the control flies (Fig. 1D). Furthermore, similar AMP derepression was also observed in Cad-RNAi flies with different GAL4 drivers (fig. S4). The role of Cad as a repressor was further confirmed by a strong expression of Dpt reporter activity observed in the gut of CRCad-RNAi flies carrying the Dpt-LacZ reporter (fig. S5). Cad-dependent AMP repression is highly tissue-specific because no AMP derepression was observed in the fat body of CRCad-RNAi flies (Fig. 1D). Introduction of Cad-RNAi had no effect on the expression of PGRP-SC and PGRP-LB (Fig. 1D), which indicates that any repressive role of Cad is restricted to a distinct subset of NF-κB–dependent genes such as AMPs. When we examined Cad-RNAi–induced AMP derepression in the IMD-Relish pathway mutant genetic backgrounds (CRCad-RNAi + Dredd or CRCad-RNAi + TAK1 flies) or in the absence of commensals (GFCad-RNAi flies), the high level of AMP derepression was completely abolished (Fig. 1E).

These data show that Cad acts as a gut-specific transcriptional repressor exerting its antagonistic role in commensal-induced NF-κB–dependent AMP induction. Furthermore, the overexpression of Cad in the gut could abolish the infection-induced AMP expression (Fig. 1F). Thus, it is likely that a dynamic equilibrium between Cad and Relish is one of the major mechanistic aspects determining the selective deployment of gut IMD-AMP pathway potential (21) (Fig. 1 and fig. S6). Because AMPs have a microbicidal effect against a broad spectrum of microorganisms, Cad-mediated AMP repression is likely required for establishing an optimal environment for the commensal microbiota.

Role of Cad in gut homeostasis. Several recent lines of evidence suggest that deregulation of the intestinal NF-κB pathway may be relevant to the etiology and pathology of many important diseases, including inflammatory bowel diseases (IBDs) (2229). Given that IBDs typically involve apoptosis of intestinal cells, we examined whether cell death might be occurring in the gut of Cad-RNAi flies. Time-course analyses with adult flies showed that gut epithelial cell apoptosis was detected in Cad-RNAi flies at day 18, but not in control flies of the same age (Fig. 2A). Cell death was also observed in the intestines of CRCad-RNAi flies with different GAL4 drivers: c729-GAL4, Cad-GAL4, and Da-GAL4 (Fig. 2, A and B). Interestingly, gut epithelial cell apoptosis was abolished in the GFCad-RNAi gut (Fig. 2C), which suggests the involvement of commensal organisms in Cad-RNAi–mediated gut pathology. To determine whether the high apoptosis level seen in the Cad-RNAi gut was due to secondary effects of AMP hyperactivation, we overexpressed two AMP genes (Cec and Dpt) to mimic the Cad-RNAi genotype. AMP overexpression in CR flies (CRCec+Dpt) was sufficient to induce a high level of gut epithelial cell apoptosis (Fig. 2C). This was not the case in the absence of commensal microbiota (GFCec+Dpt) (Fig. 2C). When we overexpressed only a single AMP (Cec or Dpt) in CR flies (CRCec or CRDpt), similar gut epithelial cell apoptosis could be also observed (Fig. 2D). Overall, these in vivo results show that gut AMP overexpression in the presence but not in the absence of gut commensal microbes is sufficient to cause gut pathology.

Fig. 2.

Apoptosis assays reveal that AMP overexpression in the presence of commensal microbiota induces gut apoptosis. The posterior midguts of adult flies at different ages (A) and those of 18-day-old adult flies (B to D) were used. An apoptosis index was determined by dividing the number of apoptotic cells by the total number of cells and multiplying by 100. Values represent means ± SD (P < 0.05) of five independent experiments. The genotypes of Cad-RNAi flies with the c729-GAL4 driver in (A) and (C) were described in Fig. 1E. (A) Time course analyses of gut epithelial cell apoptosis in Cad-RNAi flies. (B) Apoptosis in Cad-RNAi flies with different GAL4 drivers: the intestine-specific Cad-GAL4 (Cad-GAL4/+; UAS-Cad-RNAi/+) and the strong ubiquitous Da-GAL4 (UAS-Cad-RNAi/Da-GAL4). Flies carrying only GAL4 driver were used as controls. (C) Apoptosis in CR and GF flies. The genotype of Cec + Dpt flies was c729-GAL4/UAS-Dpt; UAS-Cec/+. Left panel, apoptosis index; right panel, representative images of terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining. TUNEL-positive cells are labeled in green. (D) Apoptosis in flies overexpressing a single AMP. Fly genotypes: Cont (Da-GAL4/+); Cec (UAS-Cec/+; Da-GAL4/+); Dpt (UAS-Dpt/+; Da-GAL4/+). *ND, not detected.

Role of Cad in the gut commensal community structure. Because constitutive production of AMPs in the guts of Cad-RNAi flies likely affects the ecosystem of normal commensals, we next determined the dominant commensal species in the midgut of control (CRCont) and Cad-RNAi (CRCad-RNAi) flies. In wild-type flies, five commensal species dominate: Lactobacillus plantarum (LP), Lactobacillus brevis (LB), Acetobacter pomorum (AP), and two novel strains: Gluconobacter sp. strain EW707 (G707), and a bacterium in the family Acetobacteraceae, strain EW911 (A911) (21) (figs. S7 to S9 and table S1). All of these commensal bacteria, but not other bacteria such as Ecc15 and Escherichia coli, could persist in the gut, demonstrating their competences as commensal bacteria (Fig. 3A). Real-time polymerase chain reaction (PCR)–based quantitative analyses of each commensal (21) (figs. S9 to S11) clearly revealed that the commensal community structure of the Cad-RNAi flies differed from that of the control flies (Fig. 3B). Three bacteria—AP, LP, and LB—were commonly dominant in the gut of both control and Cad-RNAi flies (Fig. 3B). However, A911 [a dominant commensal member in controls, ∼1.4 × 105 colony-forming units (CFUs) per gut] was markedly diminished and maintained at a very low level in the Cad-RNAi gut (∼900 CFUs per gut), whereas G707 (a minor commensal member in the control gut, ∼800 CFUs per gut) emerged as a dominant commensal in the Cad-RNAi gut (∼1.7 × 104 CFUs per gut) (Fig. 3B). Time-course analyses with Cad-RNAi flies showed that loss of A911 was visible from as early as day 8, whereas dominance of G707 started at day 13 and reached the maximum level at day 18 (Fig. 3C). Given the high apoptosis levels in the gut epithelial cells of GFCont flies fed on the homogenates of the CRCad-RNAi gut, but not on homogenates of the CRCont gut (fig. S12), we reasoned that the dominant commensals in the Cad-RNAi gut, such as G707, may be involved in the gut pathology.

Fig. 3.

AMP overexpression in Cad-RNAi flies induces the commensal community modification and gut pathology. (A) Commensal microbes can persist in the gut. Colonization of GF animals with each of the isolated commensal microbes, as described in (21). Homogenates of dissected midguts (8-day-old adult flies) were plated. LP, Lactobacillus plantarum; LB, Lactobacillus brevis; AP, Acetobacter pomorum; G707, Gluconobacter sp. strain EW707; A911, Acetobacteraceae, strain EW911. Ecc15 and E. coli were also used as noncommensal microbes. (B and C) Real-time PCR-based analysis to quantify the number of each commensal microbe in the posterior midguts. Values represent means ± SD (P < 0.05) of three independent experiments. The genotypes of Cad-RNAi flies with the c729-GAL4 driver were described in Fig. 1E. Cad-RNAi flies with Cad-GAL4 or Da-GAL4 were described in Fig. 2B. The posterior midguts of 18-day-old adult flies (B) and those of adult flies at different ages (C) were used.

To validate this hypothesis, we introduced each of the isolated commensal bacteria into GFCont or GFCad-RNAi embryos and maintained these bacteria until the adult stage to generate monoassociated flies. High gut epithelial cell apoptosis was observed in all of the GF flies (GFCont or GFCad-RNAi) when the single organism was G707 (Fig. 4A), but not when the single organism was one of the other commensal organisms (LP, AP, or A911) (Fig. 4A). Additionally, G707 did not induce the apoptosis in the fat body (Fig. 4A), and G707 was pathogenic to the host when GF flies were subjected to gut infection with G707 (Fig. 4B). These results show that G707 is indeed pathogenic in a gut-specific manner when allowed to become the dominant gut microbe.

Fig. 4.

G707 is pathogenic to germ-free flies. (A) Gut epithelial cell apoptosis by G707. Colonization of GF animals was performed as described in Fig. 3A. The genotypes of Cad-RNAi flies with the c729-GAL4 driver were described in Fig. 1E. Apoptosis assay was performed at day 18 as described in Fig. 2. (B) Host mortality of GF animals by G707. Oral infection was performed as described in (21); w1118 and Oregon-R flies were used. (C) G707 dominance and A911 loss in the gut of AMP-overexpressing flies. Real-time PCR-based analysis was performed as described in Fig. 3. The genotypes of flies (18 days old) used in this experiment were described in Fig. 2, C and D. Flies carrying only GAL4 driver were used as controls. Values in (A) to (C) represent means ± SD (P < 0.05) of three or five independent experiments. *ND, not detected.

To further confirm that reorganization of the gut microbiota composition seen in the Cad-RNAi flies was due to the constitutive overexpression of microbicidal AMPs, we tested whether the artificial shift of gut microbiota composition could occur as a result of overexpression of AMPs. We found that overexpression of Cec and Dpt (CRCec+Dpt) was sufficient to induce the modification of commensal community (i.e., G707 dominance and a loss of A911), as in the case of the Cad-RNAi guts (Fig. 4C). Similar results could also be observed when we overexpressed only a single AMP (CRCec or CRDpt) (Fig. 4C). To confirm that the loss of A911 was due to the high sensitivity of this strain to AMP, we performed an in vitro antibacterial test with synthetic Cec A1 and determined the minimum inhibitory concentration (21). The result showed that A911 was highly susceptible to low concentrations of synthetic Cec A1, whereas all other commensals as well as G707 exhibited relatively high resistance to Cec A1 (Table 1). Thus, we conclude that gut AMP overexpression in Cad-RNAi flies acts as a distinct selection pressure on different commensal microbes, resulting in modification of the commensal community structure and pathogenic conditions in the gut.

Table 1.

In vitro antibacterial assay using synthetic Cec A1, performed as described in (21). The minimal Cec A1 concentration that prevented the growth of a given test organism was determined and was defined as the minimum inhibitory concentration (MIC).

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Role of the normal commensal community in gut homeostasis. Because G707 is normally present at a very low level in the wild-type commensal community, we investigated whether the normal wild-type commensal community structure could antagonize the dominance of G707. To accomplish this, we introduced G707 by oral feeding into the gut of either GFWT or CRWT flies and then examined its persistence. The results indicated that G707 bacteria could persist in the absence of other commensal organisms in GFWT flies but disappeared rapidly and were maintained at a low level in the presence of the normal commensal community in CRWT flies (Fig. 5A). Consistent with these results, we observed a high-level gut epithelial cell apoptosis in the G707-challenged GFWT flies, but not in the G707-challenged CRWT flies (Fig. 5A), which demonstrates the role of normal commensal community structure in gut homeostasis by maintaining G707 at a low level.

Fig. 5.

Cad is indispensable for immune homeostasis in preserving the indigenous commensal community and host health. (A) Normal commensal community structure is important to suppress G707 dominance in the gut. Germ-free wild-type flies (GFWT), wild-type flies carrying normal commensal microbiota (CRWT), and wild-type flies monoassociated with A911 (A911-GFWT) were used. G707 was introduced to these flies (3 days old) through oral feeding for 48 hours. Left panel: Real-time PCR-based analysis to quantify G707 in the gut was performed at 1, 5, and 10 days after G707 feeding. Right panel: Apoptosis assay was performed as described in Fig. 2. Values represent means ± SD (P < 0.05) of five independent experiments. (B to E) Restoration of basal AMP levels (B), normal commensal community structure (C), reduced apoptosis (D), and normal survival levels (E) could be achieved in the Cad-RNAi flies by genetic reintroduction of Cad. The posterior midguts of 18-day-old adult flies were used for analyses of commensal community structure and apoptosis. Apoptosis assay was performed as described in Fig. 2. Genotypes of CR flies: Cont (c729-GAL4/+); Cad-RNAi (c729-GAL4/+; UAS-Cad-RNAi/+); Cad-RNAi + Cad (c729-GAL4/UAS-Cad; UAS-Cad-RNAi/+). GFCont and GFCad-RNAi flies were also used. AP/A911/LP/LB-GFCad-RNAi flies carrying four major commensals (AP, A911, LP, and LB, excluding G707) were generated by colonizing GF embryos with commensals as described in (21). Values represent means ± SD (P < 0.05) of three independent experiments. *ND, not detected.

Given the numerical inferiority of A911 in G707-dominant gut environments, we investigated whether the presence of A911 was sufficient to suppress G707 dominance in the gut. To accomplish this, we generated monoassociated flies by introducing isolated A911 into GFWT embryos and maintaining this presence until the adult stage. When G707 was introduced into these monoassociated flies through oral feeding, the G707 bacteria rapidly decreased to a low level in the presence of A911, whereas a high initial G707 level was able to persist in the absence of A911 (in the case of GFWT flies) (Fig. 5A). After G707 introduction, a high apoptosis index was observed in the gut of the GFWT flies, but not in the gut of A911-monoassociated flies (Fig. 5A). This result shows that the presence of A911 is sufficient to prevent G707 dominance, and that the loss of A911 in the AMP-overexpressing genotype flies (such as Cad-RNAi flies or Cec-or Dpt-overexpressing flies) is likely to be responsible for G707 dominance.

Taken together, these results reveal that Cad acts as a critical host factor that maintains the immune homeostasis responsible for preservation of the normal commensal community structure. Failure of the balanced regulation of AMP, as in the case of Cad-RNAi flies, can act as a novel selection pressure leading to modification of the gut commensal structure. Because G707 is a highly pathogenic organism (Fig. 4, A and B), the G707-dominating host genotype acts as an initial cause of gut apoptosis, whereas the dominance of G707 acts as a direct cause of gut apoptosis.

Role of Cad in host physiology. The apoptosis of gut cells seen in Cad-RNAi flies with different GAL4 drivers was accompanied by elevated mortality (Fig. 5E and figs. S13 and S14). The high mortality of CRCad-RNAi flies was significantly ameliorated in the absence of commensal (GFCad-RNAi flies) (Fig. 5E) or in the presence of commensals under the IMD pathway mutant genetic backgrounds (CRCad-RNAi + Dredd) (fig. S14). The normal survival rate could be also observed in GFCad-RNAi flies stably associated with major commensal microbiota (AP, LP, LB, and A911) excluding G707, which implies the involvement of G707 in Cad-RNAi–mediated host mortality (Fig. 5E). Furthermore, the c-Jun N-terminal kinase pathway and interleukin-1β converting enzyme were shown to be involved in the microbiota-induced gut apoptosis and mortality process of the Cad-RNAi flies (fig. S15).

To demonstrate that the initial cause of death in the Cad-RNAi flies was the reduced expression of Cad, we attempted an in vivo rescue experiment. Restoration of the basal AMP level (Fig. 5B), healthy microbiota community structure (Fig. 5C), reduced apoptosis (Fig. 5D), and normal host survival levels (Fig. 5E) could be achieved in the Cad-RNAi flies by genetic reintroduction of Cad (CRCad-RNAi + Cad flies). Taken together, our results show that the intestinal homeobox Cad gene is responsible for the delicate immune homeostasis in the microbe-contacting gut tissue, which is essential for preservation of the normal microbiota community, gut homeostasis, and host survival.

Discussion. The gut epithelia of virtually all organisms have evolved to form a mutually beneficial strategic alliance with microorganisms (6). However, the role of the host factor in gut homeostasis has been largely overlooked, and little information regarding the molecular principles of gut homeostasis established by the interrelationship between the host immunity and commensal microbiota is available. In mammalian gut epithelia, deregulation of the NF-κBand AMP signaling pathways was found to be implicated in the pathogenesis of chronic IBDs (2229). However, the enormous diversity of the resident microbiota community of the mammalian gut (e.g., 500 to 1000 different species in the human gut) (30) and the genetic complexity of the host immune system make it difficult to clearly establish the molecular links that would clarify the relations among immune genotype, commensal microbiota structure, and disease phenotype at the organism level.

By using a genetically amenable model organism harboring an extremely simple gut commensal structure, we have shown that the commensal microbiota community structure links the defective immune genotype to the gut disease phenotype. Surprisingly, Drosophila gut epithelia have evolved an immune strategy by recruiting a developmental master control gene, Cad, to maintain appropriate AMP levels for preservation of the normal flora community structure. Defective regulation of the AMP level, as seen in the case of the Cad-RNAi genotype, promotes gut pathology by exerting a selection pressure that favors the dominance of a pathogenic commensal, G707, rather than by acting as a direct cause of the disease phenotype. The emergence of a disease-causing commensal organism under an immune-defective genotype indicates the involvement of a microorganism as an origin of chronic inflammation. Further elucidation of the link between the immune genotype–based commensal community structure and host physiology may provide important insights into the causative role of pathogenic commensal microbes in a variety of chronic inflammatory diseases of the commensal-contacting epithelia.

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