A novel fasting regimen revealed protein reservation and complement C3 down-regulation after 14-day's continual dietary deprivation.

Objectives: The aim is to evaluate the effect of a novel 14-day fasting regimen on the balance between skeletal muscle and adipose tissue composition which might associate with inflammatory factors. Our analysis includes basic physical examinations, clinical laboratory analysis, bioelectrical impedance and biochemical analytic assessments of healthy volunteers. Methods: Eight healthy subjects were randomly selected from a pool of volunteers to undergo a continual dietary deprivation (CDD) regimen. Individuals were assigned to take Flexible Abrosia (FA, prebiotic combination) plus appropriate mineral supplement of potassium and magnesium at 3 mealtime every day to prevent potential injury from starved intestinal flora and avoid spasms of smooth muscle due to hunger. Physical and medical examinations were conducted and blood samples were collected at following timepoints: before CDD as self-control (0D), day 7 and day 14 during fasting, and 7-21days and/or 2~3mo after refeeding. Results: The combination of FA and mineral supplements significantly decreased self-reported physical response of starvation, with tolerable hunger-mediated sensations experienced during CDD. Bioelectrical and biochemical results indicated significant reduction in both muscle lean and fat mass on day 7. Meanwhile, markers related to fat composition consistently decreased during and after CDD. In addition, most biochemical marker levels, including serum proteins, reached their inflection points at the 7th day of CDD as compared to the control measurements. Levels of these factors started to show a relative plateau, or reversed direction upon the 14th day of CDD. The exceptions of above factors were myostatin and complement protein C3, which remained at lower concentrations in the blood throughout CDD, and were unable to fully recover toward baseline levels even after 3 months' refeeding. Conclusion: Our results indicated that human subjects undergoing prolonged dietary restriction were well protected by FA and mineral ions from gut injury or physical discomfort of starvation. Most factors showed a relative plateau response at the end of 14D-CDD. The muscle tissues were well preserved during prolonged fasting, and an improved protein/lipid ratio was observed. Upon refeeding, constant lower levels of myostatin and complement C3 were maintained after CDD implies a long-term beneficial effect in dealing with anti-aging and inflammation.

Whole Transcriptome Analysis of Hypothalamus in Mice during Short-Term Starvation.

Molecular profiling of the hypothalamus in response to metabolic shifts is a critical cue to better understand the principle of the central control of whole-body energy metabolism. The transcriptional responses of the rodent hypothalamus to short-term calorie restriction have been documented. However, studies on the identification of hypothalamic secretory factors that potentially contribute to the control of appetite are lacking. In this study, we analyzed the differential expression of hypothalamic genes and compared the selected secretory factors from the fasted mice with those of fed control mice using bulk RNA-sequencing. We verified seven secretory genes that were significantly altered in the hypothalamus of fasted mice. In addition, we determined the response of secretory genes in cultured hypothalamic cells to treatment with ghrelin and leptin. The current study provides further insights into the neuronal response to food restriction at the molecular level and may be useful for understanding the hypothalamic control of appetite.

Early-life starvation alters lipid metabolism in adults to cause developmental pathology in Caenorhabditis elegans.

Early-life malnutrition increases adult disease risk in humans, but the causal changes in gene regulation, signaling, and metabolism are unclear. In the roundworm Caenorhabditis elegans, early-life starvation causes well-fed larvae to develop germline tumors and other gonad abnormalities as adults. Furthermore, reduced insulin/IGF signaling during larval development suppresses these starvation-induced abnormalities. How early-life starvation and insulin/IGF signaling affect adult pathology is unknown. We show that early-life starvation has pervasive effects on adult gene expression which are largely reversed by reduced insulin/IGF signaling following recovery from starvation. Early-life starvation increases adult fatty-acid synthetase fasn-1 expression in daf-2 insulin/IGF signaling receptor-dependent fashion, and fasn-1/FASN promotes starvation-induced abnormalities. Lipidomic analysis reveals increased levels of phosphatidylcholine in adults subjected to early-life starvation, and supplementation with unsaturated phosphatidylcholine during development suppresses starvation-induced abnormalities. Genetic analysis of fatty-acid desaturases reveals positive and negative effects of desaturation on development of starvation-induced abnormalities. In particular, the ω3 fatty-acid desaturase fat-1 and the Δ5 fatty-acid desaturase fat-4 inhibit and promote development of abnormalities, respectively. fat-4 is epistatic to fat-1, suggesting that arachidonic acid-containing lipids promote development of starvation-induced abnormalities, and supplementation with ARA enhanced development of abnormalities. This work shows that early-life starvation and insulin/IGF signaling converge on regulation of adult lipid metabolism, affecting stem-cell proliferation and tumor formation.

Ancient Europeans farmed dairy-but couldn't digest milk.

Giant study of ancient pottery and DNA challenges common evolutionary explanation for lactase persistence.

Boosting nutrient starvation-dominated cancer therapy through curcumin-augmented mitochondrial Ca2+ overload and obatoclax-mediated autophagy inhibition as supported by a novel nano-modulator GO-Alg@CaP/CO.

BACKGROUND: By hindering energy supply pathway for cancer cells, an alternative therapeutic strategy modality is put forward: tumor starvation therapy. And yet only in this blockade of glucose supply which is far from enough to result in sheer apoptosis of cancer cells. RESULTS: In an effort to boost nutrient starvation-dominated cancer therapy, here a novel mitochondrial Ca2+ modulator Alg@CaP were tailor-made for the immobilization of Glucose oxidase for depriving the intra-tumoral glucose, followed by the loading of Curcumin to augment mitochondrial Ca2+ overload to maximize the therapeutic efficiency of cancer starvation therapy via mitochondrial dysfunctions. Also, autophagy inhibitors Obatoclax were synchronously incorporated in this nano-modulator to highlight autophagy inhibition. CONCLUSION: Here, a promising complementary modality for the trebling additive efficacy of starvation therapy was described for cutting off the existing energy sources in starvation therapy through Curcumin-augmented mitochondrial Ca2+ overload and Obatoclax-mediated autophagy inhibition.

Effects of an electric field on sleep quality and life span mediated by ultraviolet (UV)-A/blue light photoreceptor CRYPTOCHROME in Drosophila.

Although electric fields (EF) exert beneficial effects on animal wound healing, differentiation, cancers and rheumatoid arthritis, the molecular mechanisms of these effects have remained unclear about a half century. Therefore, we aimed to elucidate the molecular mechanisms underlying EF effects in Drosophila melanogaster as a genetic animal model. Here we show that the sleep quality of wild type (WT) flies was improved by exposure to a 50-Hz (35 kV/m) constant electric field during the day time, but not during the night time. The effect was undetectable in cryptochrome mutant (cryb) flies. Exposure to a 50-Hz electric field under low nutrient conditions elongated the lifespan of male and female WT flies by ~ 18%, but not of several cry mutants and cry RNAi strains. Metabolome analysis indicated that the adenosine triphosphate (ATP) content was higher in intact WT than cry gene mutant strains exposed to an electric field. A putative magnetoreceptor protein and UV-A/blue light photoreceptor, CRYPTOCHROME (CRY) is involved in electric field (EF) receptors in animals. The present findings constitute hitherto unknown genetic evidence of a CRY-based system that is electric field sensitive in animals.

Elucidating the Multi-Targeted Role of Nutraceuticals: A Complementary Therapy to Starve Neurodegenerative Diseases.

The mechanisms underlying multifactorial diseases are always complex and challenging. Neurodegenerative disorders (NDs) are common around the globe, posing a critical healthcare issue and financial burden to the country. However, integrative evidence implies some common shared mechanisms and pathways in NDs, which include mitochondrial dysfunction, neuroinflammation, oxidative stress, intracellular calcium overload, protein aggregates, oxidative stress (OS), and neuronal destruction in specific regions of the brain, owing to multifaceted pathologies. The co-existence of these multiple pathways often limits the advantages of available therapies. The nutraceutical-based approach has opened the doors to target these common multifaceted pathways in a slow and more physiological manner to starve the NDs. Peer-reviewed articles were searched via MEDLINE and PubMed published to date for in-depth research and database collection. Considered to be complementary therapy with current clinical management and common drug therapy, the intake of nutraceuticals is considered safe to target multiple mechanisms of action in NDs. The current review summarizes the popular nutraceuticals showing different effects (anti-inflammatory, antioxidant, neuro-protectant, mitochondrial homeostasis, neurogenesis promotion, and autophagy regulation) on vital molecular mechanisms involved in NDs, which can be considered as complementary therapy to first-line treatment. Moreover, owing to its natural source, lower toxicity, therapeutic interventions, biocompatibility, potential nutritional effects, and presence of various anti-oxidative and neuroprotective constituents, the nutraceuticals serve as an attractive option to tackle NDs.

Palmitate reduces starvation-induced ER stress by inhibiting ER-phagy in hypothalamic cells.

Palmitate is a saturated fatty acid that is well known to induce endoplasmic reticulum (ER) stress and autophagy. A high-fat diet increases the palmitate level in the hypothalamus, the main region of the brain regulating energy metabolism. Interestingly, hypothalamic palmitate level is also increased under starvation, urging the study to distinguish the effects of elevated hypothalamic palmitate level under different nutrient conditions. Herein, we show that ER-phagy (ER-targeted selective autophagy) is required for progress of ER stress and that palmitate decreases ER stress by inhibiting ER-phagy in hypothalamic cells under starvation. Palmitate inhibited starvation-induced ER-phagy by increasing the level of B-cell lymphoma 2 (Bcl-2) protein, which inhibits autophagy initiation. These findings suggest that, unlike the induction of ER stress under nutrient-rich conditions, palmitate protects hypothalamic cells from starvation-induced stress by inhibiting ER-phagy.

HLH-30-dependent rewiring of metabolism during starvation in C. elegans.

One of the most fundamental challenges for all living organisms is to sense and respond to alternating nutritional conditions in order to adapt their metabolism and physiology to promote survival and achieve balanced growth. Here, we applied metabolomics and lipidomics to examine temporal regulation of metabolism during starvation in wild-type Caenorhabditis elegans and in animals lacking the transcription factor HLH-30. Our findings show for the first time that starvation alters the abundance of hundreds of metabolites and lipid species in a temporal- and HLH-30-dependent manner. We demonstrate that premature death of hlh-30 animals under starvation can be prevented by supplementation of exogenous fatty acids, and that HLH-30 is required for complete oxidation of long-chain fatty acids. We further show that RNAi-mediated knockdown of the gene encoding carnitine palmitoyl transferase I (cpt-1) only impairs survival of wild-type animals and not of hlh-30 animals. Strikingly, we also find that compromised generation of peroxisomes by prx-5 knockdown renders hlh-30 animals hypersensitive to starvation, which cannot be rescued by supplementation of exogenous fatty acids. Collectively, our observations show that mitochondrial functions are compromised in hlh-30 animals and that hlh-30 animals rewire their metabolism to largely depend on functional peroxisomes during starvation, underlining the importance of metabolic plasticity to maintain survival.

[Starvation ketoacidosis during prolonged fasting of 26 days]. / Hypercétose dans un contexte de jeûne prolongé de 26 jours.

Ketosis is a metabolic situation involving an increase in blood and urine concentrations of ketones that, when prolonged, leads to acidosis. Moderate ketosis usually appears after a fast of a few hours, but its prolongation exposes to hyperketosis. Observation: A 25-year-old woman presented to the emergency department for cohercitive vomiting. She was fasting for a long time in a spiritual setting and had a restricted diet limited to water and vitamin supplements. Clinical and biological assessment was in favour of fasting ketoacidosis. Evolution was favorable with intravenous hydration, poly-ionic and micronutrient supplementation and a gradual resumption of oral feeding. Conclusion: We report the case of a patient with fasting ketoacidosis. Besides consequences of this ketoacidosis, the challenge was also in resuming oral feeding in order to avoid a potentially fatal inappropriate renutrition syndrome.

Starvation-induced autophagy via calcium-dependent TFEB dephosphorylation is suppressed by Shigyakusan.

Kampo, a system of traditional Japanese therapy utilizing mixtures of herbal medicine, is widely accepted in the Japanese medical system. Kampo originated from traditional Chinese medicine, and was gradually adopted into a Japanese style. Although its effects on a variety of diseases are appreciated, the underlying mechanisms remain mostly unclear. Using a quantitative tf-LC3 system, we conducted a high-throughput screen of 128 kinds of Kampo to evaluate the effects on autophagy. The results revealed a suppressive effect of Shigyakusan/TJ-35 on autophagic activity. TJ-35 specifically suppressed dephosphorylation of ULK1 and TFEB, among several TORC1 substrates, in response to nutrient deprivation. TFEB was dephosphorylated by calcineurin in a Ca2+ dependent manner. Cytosolic Ca2+ concentration was increased in response to nutrient starvation, and TJ-35 suppressed this increase. Thus, TJ-35 prevents the starvation-induced Ca2+ increase, thereby suppressing induction of autophagy.

Transcriptomic Analysis Reveals the Molecular Adaptation of Three Major Secondary Metabolic Pathways to Multiple Macronutrient Starvation in Tea (Camellia sinensis).

Tea (Camellia sinensis (L.) O. Kuntze) is a widely consumed beverage. Lack of macronutrients is a major cause of tea yield and quality losses. Though the effects of macronutrient starvation on tea metabolism have been studied, little is known about their molecular mechanisms. Hence, we investigated changes in the gene expression of tea plants under nitrogen (N), phosphate (P), and potassium (K) deficient conditions by RNA-sequencing. A total of 9103 differentially expressed genes (DEG) were identified. Function enrichment analysis showed that many biological processes and pathways were common to N, P, and K starvation. In particular, cis-element analysis of promoter of genes uncovered that members of the WRKY, MYB, bHLH, NF-Y, NAC, Trihelix, and GATA families were more likely to regulate genes involved in catechins, L-theanine, and caffeine biosynthetic pathways. Our results provide a comprehensive insight into the mechanisms of responses to N, P, and K starvation, and a global basis for the improvement of tea quality and molecular breeding.

Glucose Oxidase-Instructed Traceable Self-Oxygenation/Hyperthermia Dually Enhanced Cancer Starvation Therapy.

Cancer theranostics based on glucose oxidase (GOx)-induced starvation therapy has got more and more attention in cancer management. Herein, GOx armed manganese dioxide nanosheets (denoted as MNS-GOx) were developed as cancer nanotheranostic agent for magnetic resonance (MR)/photoacoustic (PA) dual-modal imaging guided self-oxygenation/hyperthermia dually enhanced starvation cancer therapy. The manganese dioxide nanomaterials with different morphologies (such as nanoflowers, nanosheets and nanowires) were synthesized by a biomimetic approach using melanin as a biotemplate. Afterwards, the manganese dioxide nanosheets (MNS) with two sides and large surface area were selected as the vehicle to carry and deliver GOx. The as-prepared MNS-GOx can perform the circular reaction of glucose oxidation and H2O2 decomposition for enhanced starvation therapy. Moreover, the catalytic activity of GOx could be further improved by the hyperthermia of MNS-GOx upon near-infrared laser irradiation. Most intriguingly, MNS-GOx could achieve "turn-on" MR imaging and "turn-off" PA imaging simultaneously. The theranostic capability of MNS-GOx was evaluated on A375 tumor-bearing mice with all tumor elimination. Our findings integrated molecular imaging and starvation-based synergistic cancer therapy, which provided a new platform for cancer nanotheranostics.

Severe food restriction activates the central renin angiotensin system.

We previously showed that 2 weeks of a severe food restricted (sFR) diet (40% of the caloric intake of the control (CT) diet) up-regulated the circulating renin angiotensin (Ang) system (RAS) in female Fischer rats, most likely as a result of the fall in plasma volume. In this study, we investigated the role of the central RAS in the mean arterial pressure (MAP) and heart rate (HR) dysregulation associated with sFR. Although sFR reduced basal mean MAP and HR, the magnitude of the pressor response to intracerebroventricular (icv) microinjection of Ang-[1-8] was not affected; however, HR was 57 ± 13 bpm lower 26 min after Ang-[1-8] microinjection in the sFR rats and a similar response was observed after losartan was microinjected. The major catabolic pathway of Ang-[1-8] in the hypothalamus was via Ang-[1-7]; however, no differences were detected in the rate of Ang-[1-8] synthesis or degradation between CT and sFR animals. While sFR had no effect on the AT1 R binding in the subfornical organ (SFO), the organum vasculosum laminae terminalis (OVLT) and median preoptic nucleus (MnPO) of the paraventricular anteroventral third ventricle, ligand binding increased 1.4-fold in the paraventricular nucleus (PVN) of the hypothalamus. These findings suggest that sFR stimulates the central RAS by increasing AT1 R expression in the PVN as a compensatory response to the reduction in basal MAP and HR. These findings have implications for people experiencing a period of sFR since an activated central RAS could increase their risk of disorders involving over activation of the RAS including renal and cardiovascular diseases.

Adjustment of fuel loads in stingless bees (Melipona subnitida).

Eusocial bee foragers leave their nest with nectar as flight fuel, therewith reducing the risk of starvation during a foraging trip. Yet, the extra mass results in an increase of energetic expenditure for flight. Thus, bees should tune their fuel loads to the respective foraging situation. In the present study, we investigated the fuel adjustment in the Brazilian stingless bee Melipona subnitida (Apidae, Meliponini). Specifically, we examined whether foragers of this species increase their fuel loads when they have low expectation for nectar collection during a foraging trip. Crop load measurements revealed that nectar foragers carried significantly less fuel on departing the nest than foragers collecting either pollen, clay, or resin. Surprisingly, 75% of nectar foragers left the nest without any detectable amount of nectar, which suggests that the majority of bees collected at nearby nectar sources and avoided an increase in foraging costs. Moreover, foragers increased their fuel loading when repeatedly experiencing empty food sources that had previously been rewarding. These results support our hypothesis and demonstrate that the capability of fuel adjustment is not restricted to honey bees.

Identification of hypothalamic genes in associating with food intake during incubation behavior in domestic chicken.

The molecular mechanism underlying in the onset and maintenance of incubation behavior are not fully understood, and it is still unknown the reason why White Leghorn, a layer strain, hens never display incubation behavior. Therefore, to explore specific hypothalamic genes regulating incubation behavior, cap analysis of gene expression (CAGE) were applied to comparison between incubating Silkie and laying White Leghorn hens. In addition, mRNA expression of some differentially expressed genes (DEGs) and melanocortinergic appetite genes including agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) was also analyzed on Silkie hens under natural anorexia and starvation. The CAGE identified 217 hypothalamic DEGs in incubating Silkie hens, and that of two, transthyretin (TTR) and prolactin-releasing peptide (PrRP), suggested as appetite gene, were markedly up- and down-regulated in incubating hens, respectively. In addition, AgRP and POMC expression also increased in incubating bird. mRNA expression of TTR, PrRP, and appetite genes were not differed significantly by starvation, although TTR mRNA expression was relatively high in fasting hens. Consequently, transcriptome by CAGE identified a number of hypothalamic genes differentially expressed by incubation behavior in Silkie hens. Of these, it is suggested that TTR and PrRP may, at least in part, be related to adaptation to natural anorexia in incubating Silkie chickens.

Relationship between polyunsaturated fatty acid and eating disorders: Systematic review and meta-analysis.

OBJECTIVES: Eating disorders result in poor nutrition, poor physical conditions and even suicidality and mortality. Although polyunsaturated fatty acids (PUFAs) have attracted attention in the emerging field of nutritional psychiatry, their role in eating disorders remains unknown. This meta-analysis investigates the differences of PUFA levels between patients with eating disorders and healthy controls, and the potentially beneficial effects of PUFAs in such patients. METHODS: We conducted a systematic literature search and meta-analysis under the random effects model. RESULT: Eleven studies were included in the current meta-analysis. Compared with controls, 379 patients with eating disorders had significantly higher plasma levels of alpha-linolenic acid, eicosapentaenoic acid, stearidonic acid, osbond acid, palmitoleic acid, oleic acid, and total omega-3 fatty acids; and lower levels of total omega-6 fatty acids and omega-6/omega-3 ratio. Eating disorders were associated with significantly higher red blood cell membrane levels of palmitoleic acid and oleic acid and lower levels of adrenic acid, arachidonic acid, and total omega-6 fatty acids. In addition, PUFA supplements were associated with a benefit to body weight outcomes but not disease severity and mood symptoms in interventional trials. DISCUSSION: This meta-analysis indicates abnormal levels of PUFAs in peripheral blood tissues in patients with eating disorders. The relationship between PUFAs and eating disorders should be interpreted cautiously considering the specific lipid metabolism under starvation state. To investigate the role of PUFAs on psychopathological and therapeutic effects in eating disorders, further larger clinical studies are warranted.

Death and Survival of Patients with Hansen's Disease in Colonial Korea / 의사학

The purpose of this research is to describe how Hansen's disease patients experienced the modern system of control of Hansen's disease introduced by Japan, and the inimical attitude of society against them in colonial Korea. The study also seeks to reveal the development of the system to eliminate Hansen's disease patients from their home and community to larger society and leprosarium in this era. Sorokdo Charity hospital (SCH), a hospital for Hansen's disease patients, was built in 1916, and vagrant Hansen's disease patients began to be isolated in this hospital beginning in 1917 by the Japanese Government-General of Korea (JGGK). Once the police detained and sent vagrant Hansen's disease patients to SCH, stigma and discrimination against them strengthened in Korean society. Because of strong stigma and discrimination in Korean society, Hansen's disease patients suffered from daily threats of death. First, their family members were not only afraid of the contagiousness of Hansen's disease but also the stigma and discrimination against themselves by community members. If a family had a Hansen's disease patient, the rest of community members would discriminate against the entire family. Furthermore, because Hansen's disease patients were excluded from any economic livelihood such as getting a job, the existence of the patients was a big burden for their families. Therefore, many patients left their homes and began their vagrancy. The patients who could not leave their homes committed suicide or were killed by their family members. The victims of such deaths were usually women, who were at the lower position in the family hierarchy. In the strong Confucian society in Korea, more female patients were killed by themselves than male patients. Moreover, all of patients victims in the murder were women. This shows that the stigma and discrimination against Hansen's disease patients within their families were stronger against women than men. Strong stigma and discrimination made the patients rely on superstition such as cannibalism. Patients believed that there were not any effective medicine. There were a few reports of patients who were cured, and many were treated with chaulmoogra oil in the modern Hansen's disease hospitals. Eating human flesh was known as a folk remedy for Hansen's disease. As such, patients began to kill healthy people, usually children, to eat their flesh. Increased stigma led to increased victims. Hansen's disease patients who left their homes faced many threats during their vagrancy. For survival, they established their own organizations in the late 1920's. The patients who were rejected to be hospitalized in the Western Hansen's disease hospital at Busan, Daegu, and Yeosu organized self-help organizations. The purpose of these organizations was first to secure the medicine supply of chaulmoogra oil. However, as stigma and discrimination strengthened, these organizations formed by Hansen's disease patients demanded the Japanese Government-General of Korea to send and segregate them on Sorok island. They did not know the situation of the inside of this island because news media described it as a haven for patients, and very few patients were discharged from this island to tell the truth. On this island, several hundreds of patients were killed by compulsory heavy labor, starvation, and violence. They were not treated as patients, but as something to be eliminated. Under strong suppression on this island, the patients resisted first by escaping this island. However, in 1937, some patients tried to kill a Korean staff but failed. Attempted murderers were all put in the jail, also located on this island. In 1941, a patient murdered another patient who had harassed other patients, and in 1942, Chunsang Lee, a patient, killed the director of Sorok island. These instances show that there was a system to eliminate Hansen's disease patients in colonial Korea.

Calretinin Neurons in the Midline Thalamus Modulate Starvation-Induced Arousal.

Orchestration of sleep and feeding behavior is essential for organismal health and survival. Although sleep deprivation promotes feeding and starvation suppresses sleep, the underlying neural mechanisms remain largely unknown. Here, we showed that starvation in mice potently promoted arousal and activated calretinin neurons (CR+) in the paraventricular thalamus (PVT). Direct activation of PVTCR+ neurons promoted arousal, and their activity was necessary for starvation-induced sleep suppression. Specifically, the PVTCR+-bed nucleus of the stria terminalis (BNST) circuit rapidly initiated arousal. Selective inhibition of BNST-projecting PVT neurons opposed arousal during starvation. Taken together, our results define a cell-type-specific neural circuitry modulating starvation-induced arousal and coordinating the conflict between sleeping and feeding.

Bacterial Methionine Metabolism Genes Influence Drosophila melanogaster Starvation Resistance.

Animal-associated microorganisms (microbiota) dramatically influence the nutritional and physiological traits of their hosts. To expand our understanding of such influences, we predicted bacterial genes that influence a quantitative animal trait by a comparative genomic approach, and we extended these predictions via mutant analysis. We focused on Drosophila melanogaster starvation resistance (SR). We first confirmed that D. melanogaster SR responds to the microbiota by demonstrating that bacterium-free flies have greater SR than flies bearing a standard 5-species microbial community, and we extended this analysis by revealing the species-specific influences of 38 genome-sequenced bacterial species on D. melanogaster SR. A subsequent metagenome-wide association analysis predicted bacterial genes with potential influence on D. melanogaster SR, among which were significant enrichments in bacterial genes for the metabolism of sulfur-containing amino acids and B vitamins. Dietary supplementation experiments established that the addition of methionine, but not B vitamins, to the diets significantly lowered D. melanogaster SR in a way that was additive, but not interactive, with the microbiota. A direct role for bacterial methionine metabolism genes in D. melanogaster SR was subsequently confirmed by analysis of flies that were reared individually with distinct methionine cycle Escherichia coli mutants. The correlated responses of D. melanogaster SR to bacterial methionine metabolism mutants and dietary modification are consistent with the established finding that bacteria can influence fly phenotypes through dietary modification, although we do not provide explicit evidence of this conclusion. Taken together, this work reveals that D. melanogaster SR is a microbiota-responsive trait, and specific bacterial genes underlie these influences.IMPORTANCE Extending descriptive studies of animal-associated microorganisms (microbiota) to define causal mechanistic bases for their influence on animal traits is an emerging imperative. In this study, we reveal that D. melanogaster starvation resistance (SR), a model quantitative trait in animal genetics, responds to the presence and identity of the microbiota. Using a predictive analysis, we reveal that the amino acid methionine has a key influence on D. melanogaster SR and show that bacterial methionine metabolism mutants alter normal patterns of SR in flies bearing the bacteria. Our data further suggest that these effects are additive, and we propose the untested hypothesis that, similar to bacterial effects on fruit fly triacylglyceride deposition, the bacterial influence may be through dietary modification. Together, these findings expand our understanding of the bacterial genetic basis for influence on a nutritionally relevant trait of a model animal host.