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Key Points Toll-like receptors (TLRs) are type-I transmembrane proteins with extracellular leucine-rich repeat (LRR) motifs and an intracellular Toll/interleukin-1R (TIR) domain. TLR genes are restricted to eumetazoans and probably originated at the dawn of animal evolution more than 700 million years ago. With rare exceptions, both TLR and nuclear factor-kappaB (NF-κB) genes are found in sequenced animal genomes, pointing to the ancient origin of the TLR–NF-κB signalling module. Early diversification of TLR structures resulted in two forms of the protein: multiple cysteine cluster TLRs found mostly in protostomes and single cysteine cluster TLRs found mostly in deuterostomes. Three distinct functions of TLRs have been identified: TLRs are essential during host immune responses through NF-κB signalling in insects and vertebrates; they contribute to normal patterning and organogenesis during development through NF-κB signalling in insects; and they contribute to cell adhesion during embryonic development, apparently independently of NF-κB activation in both insects and nematodes. The lack of functional information on TLRs in several lineages such as lophotrocozoans and cnidarians precludes the drawing of a robust evolutionary scenario for the emergence of TLR-mediated immunity or the ancestral function of TLRs. However, two hypotheses can explain the observed similarities and differences in TLR-mediated immunity in vertebrates and insects: an ancient origin of TLR-mediated immunity in the bilaterian ancestor followed by a substantial diversification along the lineages; or a convergent evolution based on the independent recruitment of TLRs to mediate immunity in deuterostomes and insects. The recurrent use of similar protein modules (the TIR domain and LRR motifs) and signalling pathways (NF-κB) in the immune response is observed in phylogenetically distant lineages. Future challenges include analysing TLR function in invertebrate deuterostomes, lophochotrozoan and cnidarian model organisms, and further dissection of the NF-κB-independent role of TLRs during development. Toll-like receptors have important functions in immunity and development across the animal kingdom. An evolutionary analysis suggests that the analogous immune functions have arisen independently in vertebrates and invertebrates. The Toll receptor was initially identified in Drosophila melanogaster for its role in embryonic development. Subsequently, D. melanogaster Toll and mammalian Toll-like receptors (TLRs) have been recognized as key regulators of immune responses. After ten years of intense research on TLRs and the recent accumulation of genomic and functional data in diverse organisms, we review the distribution and functions of TLRs in the animal kingdom. We provide an evolutionary perspective on TLRs, which sheds light on their origin at the dawn of animal evolution and suggests that different TLRs might have been co-opted independently during animal evolution to mediate analogous immune functions.

In the animal kingdom, nutritional mutualism is a perpetual and intimate dialogue carried out between the host and its associated gut community members. This dialogue affects many aspects of the host's development and physiology. Some constituents of the animal gut microbiota can stably reside within the host for years, and such long-term persistence might be a prerequisite for these microbes to assert their beneficial impact. How long-term persistence is established and maintained is an interesting question, and several classic model organisms associated with cultivable resident strains are used to address this question. However, in Drosophila, this model has long eluded fly geneticists. In this issue of PLOS Biology, Pais and colleagues present the most rigorous and comprehensive demonstration to date that persistence and gut residency do take place in the digestive tract of Drosophila melanogaster. This natural gut isolate of Acetobacter thailandicus stably colonizes the adult fly foregut, accelerates larval maturation, and boosts host fecundity and fertility as efficiently as the known laboratory strains. The discovery of such stable association will be a boon for the Drosophila community interested in host-microbiota interaction, as it not only provides a novel model to unravel the molecular underpinnings of persistence but also opens a new arena for using Drosophila to study the implications of gut persistence in evolution and ecology.

Abstract Lactobacillus species are found in nutrient-rich habitats associated with food, feed, plants, animals and humans. Due to their economic importance, the metabolism, genetics and phylogeny of lactobacilli have been extensively studied. However, past research primarily examined lactobacilli in experimental settings abstracted from any natural history, and the ecological context in which these bacteria exist and evolve has received less attention. In this review, we synthesize phylogenetic, genomic and metabolic metadata of the Lactobacillus genus with findings from fine-scale phylogenetic and functional analyses of representative species to elucidate the evolution and natural history of its members. The available evidence indicates a high level of niche conservatism within the well-supported phylogenetic groups within the genus, with lifestyles ranging from free-living to strictly symbiotic. The findings are consistent with a model in which host-adapted Lactobacillus lineages evolved from free-living ancestors, with present-day species displaying substantial variations in terms of the reliance on environmental niches and the degree of host specificity. This model can provide a framework for the elucidation of the natural and evolutionary history of Lactobacillus species and valuable information to improve the use of this important genus in industrial and therapeutic applications. This review synthesizes phylogenetic, genomic and metabolic metadata with findings from ecological and population genetic studies to elucidate the natural history of species within the Lactobacillus genus. Based on this analysis, a model for the evolution of distinct lifestyles was proposed: lifestyles of lactobacilli range from free living to strictly host adapted, with substantial variation among species in terms of the reliance on environmental niches and the degree of host specificity.

The interplay between nutrition and the microbial communities colonizing the gastrointestinal tract (i.e., gut microbiota) determines juvenile growth trajectory. Nutritional deficiencies trigger developmental delays, and an immature gut microbiota is a hallmark of pathologies related to childhood undernutrition. However, how host-associated bacteria modulate the impact of nutrition on juvenile growth remains elusive. Here, using gnotobiotic Drosophila melanogaster larvae independently associated with Acetobacter pomorum WJL (Ap WJL) and Lactobacillus plantarum NC8 (Lp NC8), 2 model Drosophila-associated bacteria, we performed a large-scale, systematic nutritional screen based on larval growth in 40 different and precisely controlled nutritional environments. We combined these results with genome-based metabolic network reconstruction to define the biosynthetic capacities of Drosophila germ-free (GF) larvae and its 2 bacterial partners. We first established that Ap WJL and Lp NC8 differentially fulfill the nutritional requirements of the ex-GF larvae and parsed such difference down to individual amino acids, vitamins, other micronutrients, and trace metals. We found that Drosophila-associated bacteria not only fortify the host's diet with essential nutrients but, in specific instances, functionally compensate for host auxotrophies by either providing a metabolic intermediate or nutrient derivative to the host or by uptaking, concentrating, and delivering contaminant traces of micronutrients. Our systematic work reveals that beyond the molecular dialogue engaged between the host and its bacterial partners, Drosophila and its associated bacteria establish an integrated nutritional network relying on nutrient provision and utilization.

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.

Dysregulation of energy metabolism, including hyperglycemia, insulin resistance and fatty liver have been reported in a substantial proportion of lean children. However, non-obese murine models recapitulating these features are lacking to study the mechanisms underlying the development of metabolic dysregulations in lean children. Here, we develop a model of diet-induced metabolic dysfunction without obesity in juvenile mice by feeding male and female mice a diet reflecting Western nutritional intake combined with protein restriction (mWD) during 5 weeks after weaning. mWD-fed mice (35% fat, 8% protein) do not exhibit significant weight gain and have moderate increase in adiposity compared to control mice (16% fat, 20% protein). After 3 weeks of mWD, juvenile mice have impaired glucose metabolism including hyperglycemia, insulin resistance and glucose intolerance. mWD also triggers hepatic metabolism alterations, as shown by the development of simple liver steatosis. Both male and female mice fed with mWD displayed metabolic dysregulation, which a probiotic treatment with Lactiplantibacillus plantarum WJL failed to improve. Overall, mWD-fed mice appear to be a good preclinical model to study the development of diet-induced metabolic dysfunction without obesity in juveniles.

Metazoans establish mutually beneficial interactions with their resident microorganisms. However, our understanding of the microbial cues contributing to host physiology remains elusive. Previously, we identified a bacterial machinery encoded by the dlt operon involved in Drosophila melanogaster ’s juvenile growth promotion by Lactiplantibacillus plantarum . Here, using crystallography combined with biochemical and cellular approaches, we investigate the physiological role of an uncharacterized protein (DltE) encoded by this operon. We show that lipoteichoic acids (LTAs) but not wall teichoic acids are D-alanylated in Lactiplantibacillus plantarum NC8 cell envelope and demonstrate that DltE is a D-Ala carboxyesterase removing D-Ala from LTA. Using the mutualistic association of L. plantarum NC8 and Drosophila melanogaster as a symbiosis model, we establish that D-alanylated LTAs (D-Ala-LTAs) are direct cues supporting intestinal peptidase expression and juvenile growth in Drosophila . Our results pave the way to probing the contribution of D-Ala-LTAs to host physiology in other symbiotic models.

Like every metazoan species hosting a gut flora, drosophila tolerate commensal microbiota yet remain able to mount an efficient immune response to food-borne pathogens. New findings explain how the quantity of reactive oxygen species in the gut is 'tuned' to microbial burden and how intestinal immune homeostasis is thereby maintained.

Aeromonas bacteria living in the gut of zebrafish produce a specific molecule to pacify the immune system of their host.Aeromonas bacteria living in the gut of zebrafish produce a specific molecule to pacify the immune system of their host.

BackgroundChronic undernutrition leads to growth hormone resistance and poor growth in children, which has been shown to be modulated by microbiota. We studied whether Lactobacillus fermentum CECT5716 (LfCECT5716), isolated from mother’s breast milk, could promote juvenile growth through the modulation of lipid absorption in a model of starvation.MethodsGerm-free (GF) Drosophila melanogaster larvae were inoculated with LfCECT5716 in conditions of undernutrition with and without infant formula. The impact of LfCECT5716 on larval growth was assessed 7 days after egg laying (AED) by measuring the larval size and on maturation by measuring the emergence of pupae during 21 days AED. For lipid absorption test, Caco2/TC7 intestinal cells were incubated with LfCECT5716 and challenged with mixed lipid micelles.ResultsThe mono-associated larvae with LfCECT5716 were significantly longer than GF larvae (3.7 vs 2.5 mm; p < 0.0001). The effect was maintained when LfCECT5716 was added to the infant formula. The maturation time of larvae was accelerated by LfCECT5716 (12 vs 13.2 days; p = 0.01). LfCECT5716 did not have significant impact on lipid absorption in Caco2/TC7 cells.ConclusionsLfCECT5716 is a growth-promoting strain upon undernutrition in Drosophila, with a maintained effect when added to an infant formula but without effect on lipid absorption in vitro.