Commensal Gut Bacteria Buffer the Impact of Host Genetic Variants on Drosophila Developmental Traits under Nutritional Stress.

Eukaryotic genomes encode several buffering mechanisms that robustly maintain invariant phenotypic outcome despite fluctuating environmental conditions. Here we show that the Drosophila gut-associated commensals, represented by a single facultative symbiont, Lactobacillus plantarum (LpWJL), constitutes a so far unexpected buffer that masks the contribution of the host's cryptic genetic variation (CGV) to developmental traits while the host is under nutritional stress. During chronic under-nutrition, LpWJL consistently reduces variation in different host phenotypic traits and ensures robust organ patterning during development; LpWJL also decreases genotype-dependent expression variation, particularly for development-associated genes. We further provide evidence that LpWJL buffers via reactive oxygen species (ROS) signaling whose inhibition impairs microbiota-mediated phenotypic robustness. We thus identified a hitherto unappreciated contribution of the gut facultative symbionts to host fitness that, beyond supporting growth rates and maturation timing, confers developmental robustness and phenotypic homogeneity in times of nutritional stress.

Drosophila HNF4 Directs a Switch in Lipid Metabolism that Supports the Transition to Adulthood.

Animals must adjust their metabolism as they progress through development in order to meet the needs of each stage in the life cycle. Here, we show that the dHNF4 nuclear receptor acts at the onset of Drosophila adulthood to direct an essential switch in lipid metabolism. Lipid stores are consumed shortly after metamorphosis but contribute little to energy metabolism. Rather, dHNF4 directs their conversion to very long chain fatty acids and hydrocarbons, which waterproof the animal to preserve fluid homeostasis. Similarly, HNF4α is required in mouse hepatocytes for the expression of fatty acid elongases that contribute to a waterproof epidermis, suggesting that this pathway is conserved through evolution. This developmental switch in Drosophila lipid metabolism promotes lifespan and desiccation resistance in adults and suppresses hallmarks of diabetes, including elevated glucose levels and intolerance to dietary sugars. These studies establish dHNF4 as a regulator of the adult metabolic state.

Drosophila Perpetuates Nutritional Mutualism by Promoting the Fitness of Its Intestinal Symbiont Lactobacillus plantarum.

Facultative animal-bacteria symbioses, which are critical determinants of animal fitness, are largely assumed to be mutualistic. However, whether commensal bacteria benefit from the association has not been rigorously assessed. Using a simple and tractable gnotobiotic model- Drosophila mono-associated with one of its dominant commensals, Lactobacillus plantarum-we reveal that in addition to benefiting animal growth, this facultative symbiosis has a positive impact on commensal bacteria fitness. We find that bacteria encounter a strong cost during gut transit, yet larvae-derived maintenance factors override this cost and increase bacterial population fitness, thus perpetuating symbiosis. In addition, we demonstrate that the maintenance of the association is required for achieving maximum animal growth benefits upon chronic undernutrition. Taken together, our study establishes a prototypical case of facultative nutritional mutualism, whereby a farming mechanism perpetuates animal-bacteria symbiosis, which bolsters fitness gains for both partners upon poor nutritional conditions.

Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition.

In most animal species, juvenile growth is marked by an exponential gain in body weight and size. Here we show that the microbiota of infant mice sustains both weight gain and longitudinal growth when mice are fed a standard laboratory mouse diet or a nutritionally depleted diet. We found that the intestinal microbiota interacts with the somatotropic hormone axis to drive systemic growth. Using monocolonized mouse models, we showed that selected lactobacilli promoted juvenile growth in a strain-dependent manner that recapitulated the microbiota's effect on growth and the somatotropic axis. These findings show that the host's microbiota supports juvenile growth. Moreover, we discovered that lactobacilli strains buffered the adverse effects of chronic undernutrition on the postnatal growth of germ-free mice.

Pathogen Virulence Impedes Mutualist-Mediated Enhancement of Host Juvenile Growth via Inhibition of Protein Digestion.

The microbial environment impacts many aspects of metazoan physiology through largely undefined molecular mechanisms. The commensal strain Lactobacillus plantarum(WJL) (Lp(WJL)) sustains Drosophila hormonal signals that coordinate systemic growth and maturation of the fly. Here we examine the underlying mechanisms driving these processes and show that Lp(WJL) promotes intestinal peptidase expression, leading to increased intestinal proteolytic activity, enhanced dietary protein digestion, and increased host amino acid levels. Lp(WJL)-mediated peptidase upregulation is partly driven by the peptidoglycan recognition and signaling cascade PGRP-LE/Imd/Relish. Additionally, this mutualist-mediated physiological benefit is antagonized upon pathogen infection. Pathogen virulence selectively impedes Lp(WJL)-mediated intestinal peptidase activity enhancement and juvenile growth promotion but does not alter growth of germ-free animals. Our study reveals the adaptability of host physiology to the microbial environment, whereby upon acute infection the host switches to pathogen-mediated host immune defense at the expense of mutualist-mediated growth promotion.

Studying host-microbiota mutualism in Drosophila: Harnessing the power of gnotobiotic flies.

The complex interaction between the metazoan host and its commensal gut microbiota is one of the essential features of symbiosis in the animal kingdom. As there is a burgeoning interest to decipher the molecular dialog that shapes host-microbiota mutualism, the use of gnotobiotic model organism becomes an imperative approach to unambiguously parse the specific contributions to such interaction from the microbiome. In this review, we focus on several remarkable gnotobiotic studies in Drosophila that functionally depicted how the gut microbes can alter host physiology and behavior through transcriptomic regulation, hormonal control, and diet modification. These results in concert illustrate that the gnotobiotic flies mono- or poly-associated with members of its gut microbiota deliver a versatile and powerful model that is amenable to different types of studies ranging from classic genetics to large-scale systems approaches.

Metformin, microbes, and aging.

The mechanisms underlying the biological activity of metformin, a widely prescribed drug to treat type 2 diabetes, remain elusive. In a recent issue of Cell, Cabreiro et al. report that in C. elegans, metformin indirectly impacts lifespan by altering the methionine metabolism of its microbial partner E. coli (Cabreiro et al., 2013).

Host-intestinal microbiota mutualism: "learning on the fly".

Given the complexity of the mammalian microbiota, there is a need for simple models to decipher the effector and regulatory mechanisms underlying host/microbiota mutualism. Approaches using Drosophila and its simple microbiota carry the potential to unravel the evolutionarily conserved mechanisms engaged in this association. Here, we review recent work carried out in this model, providing insights and exciting perspectives.

Lactobacillus plantarum promotes Drosophila systemic growth by modulating hormonal signals through TOR-dependent nutrient sensing.

There is growing evidence that intestinal bacteria are important beneficial partners of their metazoan hosts. Recent observations suggest a strong link between commensal bacteria, host energy metabolism, and metabolic diseases such as diabetes and obesity. As a consequence, the gut microbiota is now considered a "host" factor that influences energy uptake. However, the impact of intestinal bacteria on other systemic physiological parameters still remains unclear. Here, we demonstrate that Drosophila microbiota promotes larval growth upon nutrient scarcity. We reveal that Lactobacillus plantarum, a commensal bacterium of the Drosophila intestine, is sufficient on its own to recapitulate the natural microbiota growth-promoting effect. L. plantarum exerts its benefit by acting genetically upstream of the TOR-dependent host nutrient sensing system controlling hormonal growth signaling. Our results indicate that the intestinal microbiota should also be envisaged as a factor that influences the systemic growth of its host.