Definition of a Dietary Pattern Expressing the Intake of Vegetables and Fruits and Its Association with Intestinal Microbiota.

Daily dietary habits directly or indirectly influence the intestinal microbiota, and the resulting changes in its composition and metabolic activity alter the health conditions of the host. Although many studies have analyzed the association between individual nutrients/food items and intestinal microbiota, the assessment of the diet and intestinal microbiota from a macroscopic perspective has not yet been performed in Japan. Therefore, we focused on vegetables and fruits and aimed to identify dietary patterns of high intake of these foods and to examine their relationship with the intestinal microbiota. This cross-sectional study included 1019 healthy individuals aged ≥20 years in a rural area in northern Japan. Six dietary patterns were detected by factor analysis using the brief-type self-administered diet history questionnaire (BDHQ) data to identify the "vege pattern", which was the dietary pattern rich in vegetables and fruits. Permutational multivariate analysis of variance revealed changes in ß-diversity according to dietary patterns. In multivariable-adjusted models, the adherence to the vege pattern was positively correlated with α-diversity. This is the first study to reveal a correlation between intestinal microbiota and dietary habits rich in vegetables and fruits in a rural area of Japan.

Recognition of commensal bacterial peptidoglycans defines Drosophila gut homeostasis and lifespan.

Commensal microbes in animals have a profound impact on tissue homeostasis, stress resistance, and ageing. We previously showed in Drosophila melanogaster that Acetobacter persici is a member of the gut microbiota that promotes ageing and shortens fly lifespan. However, the molecular mechanism by which this specific bacterial species changes lifespan and physiology remains unclear. The difficulty in studying longevity using gnotobiotic flies is the high risk of contamination during ageing. To overcome this technical challenge, we used a bacteria-conditioned diet enriched with bacterial products and cell wall components. Here, we demonstrate that an A. persici-conditioned diet shortens lifespan and increases intestinal stem cell (ISC) proliferation. Feeding adult flies a diet conditioned with A. persici, but not with Lactiplantibacillus plantarum, can decrease lifespan but increase resistance to paraquat or oral infection of Pseudomonas entomophila, indicating that the bacterium alters the trade-off between lifespan and host defence. A transcriptomic analysis using fly intestine revealed that A. persici preferably induces antimicrobial peptides (AMPs), while L. plantarum upregulates amidase peptidoglycan recognition proteins (PGRPs). The specific induction of these Imd target genes by peptidoglycans from two bacterial species is due to the stimulation of the receptor PGRP-LC in the anterior midgut for AMPs or PGRP-LE from the posterior midgut for amidase PGRPs. Heat-killed A. persici also shortens lifespan and increases ISC proliferation via PGRP-LC, but it is not sufficient to alter the stress resistance. Our study emphasizes the significance of peptidoglycan specificity in determining the gut bacterial impact on healthspan. It also unveils the postbiotic effect of specific gut bacterial species, which turns flies into a "live fast, die young" lifestyle.

Activation of innate immunity during development induces unresolved dysbiotic inflammatory gut and shortens lifespan.

An early-life inflammatory response is associated with risks of age-related pathologies. How transient immune signalling activity during animal development influences life-long fitness is not well understood. Using Drosophila as a model, we find that activation of innate immune pathway Immune deficiency (Imd) signalling in the developing larvae increases adult starvation resistance, decreases food intake and shortens organismal lifespan. Interestingly, lifespan is shortened by Imd activation in the larval gut and fat body, whereas starvation resistance and food intake are altered by that in neurons. The adult flies that developed with Imd activation show sustained Imd activity in the gut, despite complete tissue renewal during metamorphosis. The larval Imd activation increases an immunostimulative bacterial species, Gluconobacter sp., in the gut microbiome, and this dysbiosis is persistent to adulthood. Removal of gut microbiota by antibiotics in the adult fly mitigates intestinal immune activation and rescues the shortened lifespan. This study demonstrates that early-life immune activation triggers long-term physiological changes, highlighted as an irreversible alteration in gut microbiota, prolonged inflammatory intestine and concomitant shortening of the organismal lifespan.

Gut Bacterial Species Distinctively Impact Host Purine Metabolites during Aging in Drosophila.

Gut microbiota impacts the host metabolome and affects its health span. How bacterial species in the gut influence age-dependent metabolic alteration has not been elucidated. Here we show in Drosophila melanogaster that allantoin, an end product of purine metabolism, is increased during aging in a microbiota-dependent manner. Allantoin levels are low in young flies but are commonly elevated upon lifespan-shortening dietary manipulations such as high-purine, high-sugar, or high-yeast feeding. Removing Acetobacter persici in the Drosophila microbiome attenuated age-dependent allantoin increase. Mono-association with A. persici, but not with Lactobacillus plantarum, increased allantoin in aged flies. A. persici increased allantoin via activation of innate immune signaling IMD pathway in the renal tubules. On the other hand, analysis of bacteria-conditioned diets revealed that L. plantarum can decrease allantoin by reducing purines in the diet. These data together demonstrate species-specific regulations of host purine levels by the gut microbiome.

Local Necrotic Cells Trigger Systemic Immune Activation via Gut Microbiome Dysbiosis in Drosophila.

Necrotic cells elicit an inflammatory response through their endogenous factors with damage-associated molecular patterns. Blocking apoptosis in Drosophila wings leads to the necrosis-driven systemic immune response by unknown mechanisms. Here, we demonstrate that immune activation in response to necrotic cells is mediated by commensal gut microbiota. Removing the microbiome attenuates hyperactivation of the innate immune signaling IMD pathway in necrosis-induced flies. Necrotic cells in wings trigger Gluconobacter expansion in the gut. An isolated Gluconobacter sp. strain is sufficient for pathological IMD activation in necrosis-induced flies, while it is not inflammatory for control animals. In addition, bacterial colonization shifts the host metabolome and shortens the lifespan of necrosis-induced flies. This study shows that local necrosis triggers a pathological systemic inflammatory response through interaction between the host and the dysbiotic gut microbiome.