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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.

Despite the identification of numerous key players of the cell death machinery, little is known about their physiological role. Using RNA interference (RNAi) in vivo , we have studied the requirement of all Drosophila caspases and caspase-adaptors in different paradigms of apoptosis. Of the seven caspases, Dronc, drICE, Strica and Decay are rate limiting for apoptosis. Surprisingly, Hid-mediated apoptosis requires a broader range of caspases than apoptosis initiated by loss of the caspase inhibitor DIAP1, suggesting that Hid causes apoptosis not only by antagonizing DIAP1 but also by activating DIAP1-independent caspase cascades. While Hid killing requires Strica, Decay, Dronc/Dark and drICE, apoptosis triggered by DIAP1 depletion merely relied upon Dronc/Dark and drICE. Furthermore, we found that overexpression of DIAP2 can rescue diap1 -RNAi-mediated apoptosis, suggesting that DIAP2 regulates caspases directly. Consistently, we show that DIAP2 binds active drICE. Since DIAP2 associates with Hid, we propose a model whereby Hid co-ordinately targets both DIAP1 and DIAP2 to unleash drICE.

The Drosophila immune system discriminates between different classes of infectious microbes and responds with pathogen-specific defense reactions through selective activation of the Toll and the immune deficiency (Imd) signaling pathways. The Toll pathway mediates most defenses against Gram-positive bacteria and fungi, whereas the Imd pathway is required to resist infection by Gram-negative bacteria. The bacterial components recognized by these pathways remain to be defined. Here we report that Gram-negative diaminopimelic acid–type peptidoglycan is the most potent inducer of the Imd pathway and that the Toll pathway is predominantly activated by Gram-positive lysine-type peptidoglycan. Thus, the ability of Drosophila to discriminate between Gram-positive and Gram-negative bacteria relies on the recognition of specific forms of peptidoglycan.

The Drosophila innate immune system discriminates between pathogens and responds by inducing the expression of specific antimicrobial peptide‐encoding genes through distinct signaling cascades. Fungal infection activates NF‐κB‐like transcription factors via the Toll pathway, which also regulates innate immune responses in mammals. The pathways that mediate antibacterial defenses, however, are less defined. We have isolated loss‐of‐function mutations in the caspase encoding gene dredd , which block the expression of all genes that code for peptides with antibacterial activity. These mutations also render flies highly susceptible to infection by Gram‐negative bacteria. Our results demonstrate that Dredd regulates antibacterial peptide gene expression, and we propose that Dredd, Immune Deficiency and the P105‐like rel protein Relish define a pathway that is required to resist Gram‐negative bacterial infections.

Background Chronic undernutrition, a condition currently affecting more than 17 millions of children under five years of age, has severe long-term consequences including stunting. Epidemiologic studies have emphasized that undernutrition cannot be ascribed to food insecurity alone and gut microbiota has been shown to play an active role in disease aetiology. In mammals, post-natal growth is controlled by the activity of the somatotropic axis. Undernutrition leads to a decrease of the Insulin like Growth Factor 1 (IGF-1) and a state of Growth Hormon (GH) resistance. Aims Previously we have shown the capacity of selected Lactobacillus plantarum strain to maintain growth in infant mono-colonized mice during chronic undernutrition. Here we show that L. plantarum retains its growth promoting capabilities also in a conventional mouse model. Methods C57BL6 male mice were weaned at 21 days and bred on a standard or an experimental (isocaloric, hypoprotidic and hypolipidic) diet until young adulthood. One group of mice on experimental diet received an LpWJL oral supplementation (2*10^8 CFU/day; 5 days per week) and the other group received placebo. Length and weight were measured weekly. Mice were sacrificed at day 56 to study the impact of the LpWJL oral supplementation on IGF-1 levels and organ growth. Somatotropic axis activity was tested at Day 28 by injecting the mice with GH and measured by the STAT5 phosphorylation level. Results At D56, mice fed with the experimental diet were smaller than the standard diet group (7.7 vs 8.9 cm; p< 0.01). Undernourished mice had a lower hepatic level of IGF-1 (113 ± 39 vs 174 ± 35 pg/mg tissues; p<0.01) and a lower plasmatic level of IGF-1 (150 ± 50 vs 388 ± 103 ng/mL; p< 0.01) compared with the standard diet group. Body length of mice fed experimental diet was longer in LpWJL –supplemented group compared to the placebo supplementation (8.02 ± 0.19 vs 7.73 ± 0.16 cm; p<0.0001). LpWJL-treated mice showed 23% increase in daily growth gain compared to placebo without the change in the mean daily food intake. In the LpWJL group, mice had a higher hepatic IGF-1 level (108 ± 12.5 vs 59.8 ± 18.5 pg/mg tissues; p< 0.0001) and a higher plasmatic IGF-1 level (209 ± 51 vs 148 ± 32 ng/mL; p< 0.001) compared to the placebo group. At day 28, mice exposed to LpWJL during starvation process showed an increase of the sensibility of the hepatic GH receptor to GH according to the STAT5 phosphorylation level. Conclusions Oral supplementation by LpWJL alleviates the GH resistance and improves juvenile growth of conventional infant mice upon undernutrition. Funding Agencies None

Human immunodeficiency virus 1 (HIV‐1) expresses several accessory proteins that manipulate various host‐cell processes to achieve optimum replicative efficiency. One of them, viral protein U (Vpu), has been shown to interfere with the cellular degradation machinery through interaction with SCF β‐TrCP complexes. To learn more about Vpu function in vivo , we used the genetically tractable fruit fly, Drosophila melanogaster . Our results show that the directed expression of Vpu, but not the non‐phosphorylated form, Vpu2/6, in fat‐body cells affects Drosophila antimicrobial responses. In flies, the Toll and Imd pathways regulate antimicrobial‐peptide gene expression. We show that Vpu specifically affects Toll pathway activation by inhibiting Cactus degradation. Given the conservation of the Toll/nuclear factor‐κB (NF‐κB) signalling pathways between flies and mammals, our results suggest a function for Vpu in the inhibition of host NF‐κB‐mediated innate immune defences and provide a powerful genetic approach for studying Vpu inhibition of NF‐κB signalling in vivo .

Animal survival in fluctuating environments depend on the ability to modulate their developmental pace in response to nutrient availability, a phenomenon known as developmental plasticity. In Drosophila larvae, we uncover a critical endocrine mechanism that coordinates this process under conditions of amino acid restriction. We identify the peptide hormone Limostatin as an enterokine, produced by a small population of midgut enteroendocrine cells, that acts systemically to inhibit the expression and release of dILP2, the major insulin-like peptide controlling developmental progression. Limostatin expression in enteroendocrine cells is triggered by reduced amino acid availability through an inter-organ relay involving the fat body and neuroendocrine insulin-producing cells in the brain. Limostatin participates in a feedback control loop that slows down developmental progression once systemic nutrient shortage is sensed. This gut-brain axis enables larvae to preserve viability under nutritional stress. Our findings define the larval gut as a nutrient-sensitive endocrine organ and position Limostatin as a key regulator of developmental plasticity. Our work expands the concept of decretins to include developmental pace control, suggesting that enterokines that regulate IGF signalling, rather than insulin release per se, may represent an evolutionarily conserved or convergent strategy in regulating developmental plasticity.

Khush et al comment on studies by Choe et al and Michel et al that identify two peptidoglycan recognition proteins (PGRPs) in the fruit fly that are probable pattern recognition receptors for the insect innate immune response. The growing appreciation of the conservation of some immune responses in insects and mammals has produced an exchange of ideas and results that has invigorated the field of innate immunity.