Aim/ Kidney transplant recipients (KTR) require lifelong immunosuppression with tacrolimus (TAC), a narrow therapeutic index drug with high intra- and inter-patient pharmacokinetic (PK) variability. Evidence suggests the gut microbiome modulates TAC dose requirements. Given the frequent use of antibiotics in KTR, this study investigates their impact on TAC PK to clarify the microbiome’s role in TAC PK variability. Methods/ REFLECT is a retrospective study analysing TAC PK evolution during antibiotherapy in KTR. Routinely collected data were obtained at 4 study occasions: baseline, infection diagnosis, during antibiotherapy (ATB), and 1-month post-ATB stop. Mixed-effects modelling accounted for hierarchical data. Results/ 107 antibiotherapies (760 TAC trough concentrations Ctrough) were analysed. Three PK endpoints were modelled: TAC dose and weight-adjusted Ctrough (Ctrough/(dose kg-1)), TAC Ctrough and TAC dose kg-1. Antibiotic intake influenced all PK endpoints, alongside age, CYP3A5 genotype, haematocrit, creatinine, C-reactive protein, post-transplant period and trimethoprim/sulfamethoxazole prophylaxis. During ATB, mean TAC Ctrough/(dose kg-1) increased by 15.3% (p=0.004) and Ctrough by 16.4% (p<0.001) compared to baseline values, while TAC dosing remained unchanged. At the post-ATB occasion, TAC dose kg-1 decreased by 13.4% (p<0.0001), restoring Ctrough to baseline values. Antibiotics linked to greater Clostridioides difficile infection (CDI) risk and dysbiosis were associated with a larger Ctrough increase (+19.8%, p<0.001). Conclusion/ Antibiotherapy significantly increases TAC exposure without dose adjustment. The greater effect observed with antibiotics associated with an increased risk of CDI supports the hypothesis that gut microbiome contributes to TAC PK variability. These findings underscore the need for close TAC monitoring during and after antibiotherapy.

Abstract Introduction Acute myeloid leukemia (AML) is a hematological malignancy associated with muscle wasting. As the relative abundance of Lachnospira eligens was reduced in patients with AML compared to healthy individuals and correlated positively with muscle strength, we hypothesized that L. eligens positively impacts the muscle through the production of small metabolites reaching the systemic circulation. Methods L. eligens levels were analyzed in two additional independent cohorts. Six L. eligens isolates were characterized through whole-genome sequencing to select clinically relevant strains. The composition of their culture supernatant was analyzed by metabolomics. The impact of L. eligens supernatant on dexamethasone- and interleukin-6-atrophied murine myotubes was assessed. Bioactive metabolites and their production mechanism were identified using among others bioactivity-guided fractionation. The underlying mechanism was also explored on the host side through myotubes’ transcriptome analysis and metabolic flux analysis. The relevance of bioactive metabolites and their production mechanism was evaluated through clinical data and samples analyses and in a mouse model of leukemia. Results The levels of L. eligens are reduced in independent cohorts of patients with AML and its supernatant counteracts myotube atrophy. This anti-atrophic effect, conserved between strains of the same species, depends on the occurrence of mixed acid fermentation (MAF) in anoxic culture conditions and the presence of its acid end-products acetate, formate and D-lactate. Consistent with those results, blood levels of acetate are decreased and the relative abundance of fecal bacteria capable of performing aerobic respiration is increased in patients with AML. However, bacterial supernatant failed to prevent muscle atrophy and weakness in leukemic mice, likely due to insufficient sustained elevation of acid end-products in the blood. Conclusion This work reveals the anti-atrophic effect of MAF end-products on myotubes and suggests the importance of considering gut electron acceptor levels (e.g. O 2 ) in disorders affecting muscle health. Graphical abstract Mixed acid fermentation products from Lachnospira eligens counteract myotube atrophy. Our study suggests that gut anaerobiosis is disrupted in treatment-naïve patients with acute myeloid leukemia (AML), leading to decreased circulating acetate levels and a reduced relative abundance of L. eligens , which significantly correlated with muscle strength. In line with this framework, in vitro experiments demonstrate that the culture supernatant of L. eligens , which contains mixed acid fermentation (MAF) end-products such as acetate, effectively counteracts C2C12 myotube atrophy in the presence of pro-atrophying stimuli. Further mechanistic experiments indicate a causal role for MAF end-products in this anti-atrophying effect. Created with BioRender.com. Legend: solid frames: experimental results; dashed frames: hypothetical conclusions derived from results; black solid arrow: established correlation; black dashed arrows: hypothetical causation.

Cachexia is a wasting disorder associated with high morbidity and mortality in patients with cancer. Tumour–host interaction and maladaptive metabolic reprogramming are substantial, yet poorly understood, contributors to cachexia. Here we present a comprehensive overview of the spatio-temporal metabolic reprogramming during cachexia, using integrated metabolomics, RNA sequencing and 13C-glucose tracing data from multiple tissues and tumours of C26 tumour-bearing male mice at different disease stages. We identified one-carbon metabolism as a tissue-overarching pathway characteristic for metabolic wasting in mice and patients and linked to inflammation, glucose hypermetabolism and atrophy in muscle. The same metabolic rewiring also occurred in five additional mouse models, namely Panc02, 8025, ApcMin, LLC and KPP, and a humanised cachexia mouse model. Together, our study provides a molecular framework for understanding metabolic reprogramming and the multi-tissue metabolite-coordinated response during cancer cachexia progression, with one-carbon metabolism as a tissue-overarching mechanism linked to wasting. Multi-omics profiling of diverse cancer cachexia models uncovers a multi-tissue metabolite-coordinated response associated with disease progression and links multi-tissue one-carbon metabolism to wasting.

Cachexia is a metabolic wasting syndrome affecting many patients with cancer, with poor survival outcomes. Disturbed lipid metabolism is a hallmark of cachexia, and our previous work has identified increased levels of circulating ceramides, which are bioactive lipids with adverse effects in metabolic diseases, as biomarkers for cachexia in mouse models and patients. Here, we investigated the role of ceramides on cachexia development using the well-established C26 colon carcinoma model. We demonstrated that elevated ceramides in cachexia arose from increased liver synthesis. We showed that ceramides directly contributed to impaired mitochondrial function and energy homeostasis in cachexia target tissues. Targeting ceramide synthesis using miRNA interference, or myriocin, an approved compound targeting the key synthesis enzyme serine palmitoyltransferase (SPT), improved markers of muscle atrophy in cachectic male mice. Importantly, we demonstrated that key enzymes involved in ceramide production were also elevated in livers, but not in other organs, of patients with cancer cachexia, correlating with disease severity. Our data place ceramides as contributors to metabolic dysfunction in cachexia and highlight the suitability of the ceramide synthesis pathway for therapeutic targeting.

Background & Aims Eating disorders are serious pathologies with a strong negative impact on patients’ quality of life and mortality. The gut microbiota was recently proposed as one of the potential factors involved in eating disorders. To gain a better understanding of the potential role of the gut microbiota in these diseases, we explored its composition in patients with all typical forms of eating disorders. Methods We used 16S rRNA sequencing to compare the composition of the faecal microbiota of patients with anorexia nervosa, bulimia nervosa or binge-eating disorder, with that of healthy individuals. Results Our results demonstrate that each type of eating disorder is associated with a specific gut bacterial signature. We observed, for example, a decrease in the relative abundances of Agathobacter and Romboutsia genera and an increase in Pseudomonas in patients diagnosed with anorexia, while patients diagnosed with binge-eating disorder exhibit a decrease in the relative abundances of Akkermansia and Intestinimonas genera and an increase in Streptococcus, Eggerthella and Proteus. We also highlight a heterogeneity in gut microbiota composition in different subcategories of eating disorders. By focusing on the comorbidities reported by patients, we finally identified several bacterial taxa, such as Acidaminococcus and Eggerthella genera, whose level correlates with the occurrence of anxiety or depressive-like symptoms. Conclusion Together, our work demonstrates that eating disorders are associated with specific changes in gut microbiota composition and highlight the necessity to finely stratify patients to identify robust microbial signatures. In addition, we identified bacterial taxa correlating with comorbidities and decreased quality of life reported by patients. Our results now pave the way for determining the predictive value of the abundance of these taxa on the duration of the pathology or on the likelihood of relapse. They also constitute a valuable resource to further demonstrate the causal role of the gut microbiota in the onset or chronicisation of eating disorders.

The Farnesoid X Receptor (FXR), a nuclear bile acid (BA) receptor highly expressed in the liver and intestine, is a potential pharmacological target for Metabolic dysfunction-Associated SteatoHepatitis (MASH). While intestinal FXR inhibition reduces high-fat diet (HFD)-induced hepatic steatosis, its role in MASH progression remains unclear. This study investigates the impact of intestinal FXR-deficiency on MASH development in a diet-induced murine model. Intestinal FXR-deficient (intFXR KO) and control mice were fed a high-fat, sucrose, and cholesterol-enriched diet (HFSC) for 24 weeks. Intestinal immune phenotyping, microarray, 16 S rRNA sequencing, bile acid quantification and liver assessments (histology, biochemistry and single-cell RNA sequencing (scRNA-seq)) were performed. intFXR KO mice were protected against HFSC diet-induced obesity and hepatic steatosis but exhibited altered expression of intestinal barrier-associated genes, with increased cytotoxic CD8+ T-lymphocytes. Microbiota composition and bile acid profiles were altered, including reduced Lachnospiraceae species correlating negatively with liver hyocholic acid levels. Despite a protection against hepatic steatosis, liver inflammation and fibrosis were unchanged in intFXR KO mice. Transcriptomic and Immune cell scRNA-seq analysis revealed alteration in immune-related pathways with an increased neutrophil proportion and higher cDC1:cDC2 and CD4:CD8 T cell ratios. Thus, intestinal FXR-deficiency limits steatosis but promote a distinct hepatic immune-inflammatory response and does not prevent progression to MASH.

BACKGROUND & AIMS:Gut bacteria produce a wide variety of metabolites that are playing important roles in human health. Dietary fibres (DF) are beneficial nutrients that have been shown to modulate key intestinal functions when fermented by gut bacteria. Since most bacteria-derived metabolites are volatile, their presence in exhaled breath allows to propose new non-invasive methods to study DF-microbiome interactions in humans. We aimed to identify potential novel biomarkers of gut microbiota activity released in exhaled breath following the consumption of DF at breakfast, upon untargeted analysis in healthy volunteers. METHODS:14 volunteers (7 women/7 men, 21 ± 2 years old) participated to two test days at a one-month interval, where they received either a low-(2.6 g) or high-(16.1 g) fibre breakfast. Before each test days, stools were collected to evaluate the microbiota composition using Illumina sequencing (V5-V6 region of 16S rRNA gene). Throughout the test days, breath samples were analysed using selected-ion flow-tube mass spectrometry (SIFT-MS). A sparse partial least squares-discriminant analysis (sPLS-DA) identified 30 signals that best discriminated between test days, corresponding to 173 candidate breath compounds. RESULTS:The gut microbiota of the volunteers remained stable one month apart. The composition of exhaled breath shifted starting from 5 h after the high-fibre breakfast ingestion. Ninety compounds were identified as potential metabolites of gut microbes, with 81 showing increased concentrations after the high-fibre breakfast. These included acrylic acid (positively correlated with Faecalibacterium/Ruminococcaceae/Bacillota and negatively correlated with Bifidobacterium/Bifidobacteriaceae/Actinomycetota). The high-fibre breakfast also led to increases in limonene, ethylbenzene/xylene, p-cymene, and methionol that were positively correlated with the genus Faecalibacterium. Moreover, positive correlations were observed between cyclooctane/ethylcyclohexane, methanol and the phylum Bacillota. Dimethyl disulfide was strongly negatively correlated with the genus Bacteroides and its family Bacteroidaceae. CONCLUSION:This study shows that DF consumption at breakfast stimulates the production of exhaled bacteria-derived metabolites reflecting profound changes in the metabolic activity of the gut microbiota. We also identified new potential biomarkers of DF intake, that are not directly linked to DF fermentation. Specific bacteria known to play a role in gut barrier, immunity and host metabolism were associated with those new metabolites.

Ultra-processed foods and drinks (UPFD) have been acknowledged to promote metabolic disturbances and inflammation. Knowing that both events can be associated with gut microbiota alterations, this observational longitudinal analysis aimed to explore the link between UPFD intake, faecal microbiota composition and activity, and inflammatory biomarkers. MICROBOOST-1 study included 20 adults for 3 study visits spaced at least 7 days apart. Dietary intakes were collected using three non-consecutive 24 h recalls, including a weekend day, and performed the week preceding each study visit. Foods and drinks were categorized in a double-blind manner as ultra-processed following the NOVA classification. Mean energy-adjusted UPFD consumption was then divided into quartiles. Stool samples were collected at most four days before each study visit. Faecal microbiota composition was analysed using 16S-rDNA Illumina sequencing, and exhaled breath hydrogen – reflecting gut microbial fermentation – was measured. Inflammatory cytokines were quantified in saliva. Mixed models were applied accounting for multiple time points per participant. Overall UPFD, “meat, fish, and cheese” (MFC) and “sugar-sweetened beverages” (SSB) categories were investigated. In comparison with the lowest consumption quartile of UPFD categories, the highest quartile showed no change in α- and β-diversity, but a lower relative abundance of Faecalibacterium, Desulfovibrio, Veillonella and a higher relative abundance of Hominimerdicola and Phocaeicola for all UPFD (q-value < 0.05). A decrease in Agathobacter and Coprococcus and an increase in Actinomyces relative abundances characterized the MFC category, whereas higher Actinomyces and lower Flintibacter relative abundances were observed for SSB category (q-value < 0.05). SSB intake was also related to lower exhaled hydrogen and to higher salivary level of IL-6 (p-value < 0.05). Total UPFD intake was linked to increased salivary IL-1β (p-value < 0.05). This cytokine was positively associated with Flintibacter and negatively associated with Faecalibacterium. In addition, Phocaeicola, Desulfovibrio, Veillonella, Actinomyces and Coprococcus were positively associated with IL-6, while Desulfovibrio and Veillonella were positively and Actinomyces and Agathobacter negatively related to IL-8 (p-value < 0.05). In our study, using non-invasive tools, we observed associations between the level of UPFD intake and components of the gut microbiota and inflammation. The protocol is recorded at «clinicaltrials.gov» (NCT05949411).

Introduction In kidney transplantation, immunosuppressive therapy is essential to control alloimmune reactions, prevent graft rejection and improve patient survival rates. However, commonly used drugs like tacrolimus (TAC) and mycophenolate mofetil (MMF) have a narrow therapeutic window and exhibit significant inter- and intra-individual variability in pharmacokinetics (PK) and dose-response relationships. Recent pilot studies suggest that the gut microbiome may influence this variability.Methods and analysis ElucidatiNg Immunosuppressant pharmacokinetic variabilities by investigating Gut Microbiome modulations After kidney transplantation (ENIGMA) is a prospective, low-interventional, naturalistic longitudinal trial designed to identify biomarkers of TAC and MMF PK variability by examining gut microbiome changes and modulations after kidney transplantation and their link with TAC and MMF PK. Biological samples from 50 patients will be collected at nine specific timepoints pre- and post-transplantation using a rich PK and biological sampling strategy. This approach will enable the derivation of PK parameters for the investigated drugs and the creation of a biobank for future hypothesis testing.Ethics and dissemination The ENIGMA trial has received ethical approval from the European Medicines Agency (EMA). The reference number of our project is R&D/1325226 and is registered on the Clinical Trial Information System (CTIS) platform with European Union Clinical Trial number 2023–5 08 335-31-00. Results of the trial will be published in scientific journals and presented at different (inter)national conferences.Trial registration number 2023–5 08 335-31-00 EMA.

BACKGROUND:Cachexia is a debilitating syndrome associated with involuntary weight loss, often occurring in cancer patients. In both humans and animal models, alterations in endocannabinoid (eCB) signaling occur in association with both metabolic disorders and several types of tumors. The wider signaling system, including the two eCBs, anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), their congeners and other long chain fatty acid amides, as well as their metabolic enzymes and receptors, is known as endocannabinoidome (eCBome). The eCBome is involved, among others, in the control of energy balance and cancer and interacts with the gut microbiome. METHODS:Using mass spectrometry-based targeted lipidomics, we measured the hepatic and intestinal concentrations of eCBome mediators in mice injected with colon carcinoma 26 (C26) cells, a model of cancer cachexia characterized, among others, by weight loss, hepatic dyslipidemia, and gut microbiome dysbiosis. RESULTS:We report that, 10 days after C26 cell injection, concomitant with >10% weight loss, eCBome lipids levels, namely 2-AG, AEA, and some of its N-acyl-ethanolamine congeners, as well as N-oleoyl-glycine, N-acyl-serotonins, and N-acyl-taurines (NATs), are altered in intestinal sections and the liver of C26 mice (e.g., hepatic 2-AG -30%, jejunal 2-AG + 30%, jejunal AEA -55%, hepatic N-oleoyl-ethanolamine (OEA) + 223%, hepatic NATs +144%, +141%, +216%). Gut dysbiosis was evident in these mice (PERMANOVA at the family level: R² = 69%, p < 0.001), with altered levels in 3 phyla (mainly the Proteobacteria, +1484%), 12 families, and 12 genera (all with adjusted p < 0.05). Additionally, 2-AG, AEA, OEA, N-arachidonoyl-serotonin, and NAT levels in the liver positively correlated with hepatic total lipids, triglycerides, and cholesterol, whereas N-docosahexaenoyl-ethanolamine and N-docosahexaenoyl-serotonin showed negative correlations. Jejunal AEA negatively, and hepatic OEA and NATs positively, correlated with weight loss. Intestinal eCBome mediators correlated with several cecal microbial taxa, including genera known to include strains beneficial in metabolic disorders, such as Bacteroides, Parabacteroides, Dysosmobacter, and Prevotella. CONCLUSIONS:These observations pinpoint eCBome mediators as new multi-functional players in the hepatic complications and gut dysbiosis accompanying cancer cachexia.

Background and aims: Alcohol Use Disorder (AUD) is a psychiatric disorder characterized notably by gut microbial dysbiosis and insufficient dietary fiber (DF) intake. This study aims to investigate the effect of DF placebo-controlled intervention in patients suffering from AUD during a three-week period of alcohol withdrawal, in order to discover microbial-derived metabolites that could be involved in metabolic and behavioral status. Methods: A randomized, double-blind, placebo-controlled study was performed with 50 AUD patients supplemented with inulin (prebiotic DF) or maltodextrin (placebo) during 17 days. Fecal microbiota composition, plasma and fecal metabolomics (liquid chromatography coupled to mass spectrometry), blood markers of inflammation and hepatic alterations, and psychological assessment (questionnaires) were analyzed before and after the intervention. Results: Fecal metabolomics revealed 14 metabolites significantly modified by inulin versus placebo treatment (increased N8-acetylspermidine and decreased indole-3-butyric acid, 5-amino valeric acid betaine (5-AVAB) and bile acids). Thirteen plasma metabolites differentiated both treatments (higher levels of long-chain fatty acids, medium-chain acylcarnitines and sphingomyelin species, and reduced 3methylhistidine by inulin versus placebo). Fecal Lachnoclostridium correlated with 6 of the identified fecal metabolites, whereas plasma lipidic moieties positively correlated with fecal Ruminococcus torques group and Flavonifractor. Interestingly, parameters reflecting liver alterations inversely correlated with sphingomyelin (SM 36:2). Conclusions: Three weeks of inulin supplementation during alcohol withdrawal leads to specific and different changes in the plasma and fecal metabolome of AUD patients, some of these gut microbiotarelated metabolites being correlated with liver function.

Obesity is associated with alterations in the gut microbiome that may contribute to metabolic and mental health disturbances. Fecal microbiota transplantation (FMT) from humans to mice is a model proposed to study human microbiota-associated disorders. In this study, we investigated whether gut microbiota from human donors with obesity could affect behavior and metabolomic profiles of mice. Stools from donors with obesity and from lean donors were inoculated to antibiotic-pretreated mice fed a standard low-fat diet throughout the experiment. Obese-recipient mice exhibited a lower bacterial alpha-diversity and limited changes in specific taxa (e.g., an increase in Eubacterium) but were similar to lean-recipient mice in terms of dietary intake, body weight, fat mass, anxiety/depression-like behavior and glucose homeostasis. Non-targeted LC-MS metabolomic analysis revealed no change in the portal and cava serum samples. However, 1-methylnicotinamide, indole-3-acetic acid (I3A) and methyllysine were increased in the cecal content of obese-recipient compared to lean-recipient mice. Microbial metabolites derived from amino acids were positively correlated with Eubacterium. These results indicate that FMT from donors with obesity to mice fed chow diet (low in lipids) leads to minor but persistent change in intestinal microbial-derived metabolites, without recapitulating the metabolic and behavioral alterations of obesity.

Alterations in bile acid profile and pathways contribute to hepatic inflammation in cancer cachexia, a syndrome worsening the prognosis of cancer patients. As the gut microbiota impinges on host metabolism through bile acids, the current study aimed to explore the functional contribution of gut microbial dysbiosis to bile acid dysmetabolism and associated disorders in cancer cachexia. Using three mouse models of cancer cachexia (the C26, MC38 and HCT116 models), we evidenced a reduction in the hepatic levels of several secondary bile acids, mainly taurodeoxycholic (TDCA). This reduction in hepatic TDCA occurred before the appearance of cachexia. Longitudinal analysis of the gut microbiota pinpointed an ASV, identified as Xylanibacter rodentium, as a bacterium potentially involved in the reduced production of TDCA. Coherently, stable isotope-based experiments highlighted a robust decrease in the microbial 7α-dehydroxylation (7α-DH) activity with no changes in the bile salt hydrolase (BSH) activity in cachectic mice. This approach also highlighted a reduced microbial 7α-hydroxysteroid dehydrogenase (7α-HSDH) and 12α-hydroxysteroid dehydrogenase (12α-HSDH) activities in these mice. The contribution of the lower production of TDCA to cancer cachexia was explored in vitro and in vivo. In vitro, TDCA prevented myotube atrophy, whereas in vivo hepatic whole transcriptome analysis revealed that TDCA administration to cachectic mice improved the unfolded protein response and cholesterol homeostasis pathways. Coherently, TDCA administration reversed hepatic cholesterol accumulation in these mice. Altogether, this work highlights the contribution of the gut microbiota to bile acid dysmetabolism and the therapeutic interest of the secondary bile acid TDCA for hepatic cholesterol homeostasis in the context of cancer cachexia. Such discovery may prove instrumental in the understanding of other metabolic diseases characterized by microbial dysbiosis. More broadly, our work demonstrates the interest and relevance of microbial activity measurements using stable isotopes, an approach currently underused in the microbiome field.

The sequence of events associated with cancer cachexia induction needs to be further characterized. Using the C26 mouse model, we found that prior to cachexia, cancer progression was associated with increased levels of IL-6 and growth differentiation factor 15 (GDF15), highly induced production of positive acute phase proteins (APPs) and reduced levels of most amino acids in the systemic circulation, while signal transducer and activator of transcription 3 (STAT3) signaling was induced (1) in the growing spleen, alongside activation of ribosomal protein S6 (rpS6) and alpha subunit of eukaryotic translation initiation factor-2 (eIF2α) signalings, and (2) in the liver, alongside increased positive-APP expression, decreased albumin expression, and upregulation of autophagy. At the onset of cachexia, rpS6 and eIF2α signalings were concomitantly activated in the liver, with increased expression of activating transcription factor 4 (ATF4) target genes involved in amino acid synthesis and transport, as well as autophagy. Data show that pre-cachectic (pre-Cx) alterations in protein/aa homeostasis are followed by activation of eIF2α signaling in the liver, an adaptive mechanism likely regulating protein/amino acid metabolism upon progression to cachexia.

Inulin-type fructans (ITF) are fermentable dietary fibres (DF) that can confer beneficial metabolic health effects through changes in the gut microbiota. Many papers suggest that complex food rich in DF could be more relevant than purified DF in terms of health effect. We compared the prebiotic effect of natural source of inulin (scorzonera) versus native inulin extracted from chicory root in a model of obesity. Mice were fed during 6 weeks a low-fat (LF), high-fat (HF) or high-fat diet enriched with either purified inulin from chicory root (Inu) or lyophilized scorzonera (Sco), with the same amount of ITF intake (10

This editorial piece co-authored by the Senior Editors at Microbiome aims to highlight current challenges in the field of environmental and host-associated microbiome research. We also take the opportunity to clarify our expectations for the articles submitted to the journal. At Microbiome, we are seeking studies that provide either new mechanistic insights into the role of microbiomes in health and environmental systems or substantial conceptual or technical advances. Manuscripts need to meet high standards of language accuracy, quality of microbiome analyses, and data and protocol availability, including detailed reporting of wet-lab and in silico protocols, all of which can critically enhance transparency and reproducibility. We think that such efforts are essential to push the boundaries of our knowledge on microbiomes in a concerted, international effort.

SUMMARYThe gut microbiota is a major factor contributing to the regulation of energy homeostasis and has been linked to both excessive body weight and accumulation of fat mass (i.e., overweight, obesity) or body weight loss, weakness, muscle atrophy, and fat depletion (i.e., cachexia). These syndromes are characterized by multiple metabolic dysfunctions including abnormal regulation of food reward and intake, energy storage, and low-grade inflammation. Given the increasing worldwide prevalence of obesity, cachexia, and associated metabolic disorders, novel therapeutic strategies are needed. Among the different mechanisms explaining how the gut microbiota is capable of influencing host metabolism and energy balance, numerous studies have investigated the complex interactions existing between nutrition, gut microbes, and their metabolites. In this review, we discuss how gut microbes and different microbiota-derived metabolites regulate host metabolism. We describe the role of the gut barrier function in the onset of inflammation in this context. We explore the importance of the gut-to-brain axis in the regulation of energy homeostasis and glucose metabolism but also the key role played by the liver. Finally, we present specific key examples of how using targeted approaches such as prebiotics and probiotics might affect specific metabolites, their signaling pathways, and their interactions with the host and reflect on the challenges to move from bench to bedside.

The gut microbiota makes critical contributions to host homeostasis, and its role in the treatment of acute myeloid leukemia (AML) has attracted attention. We investigated whether the gut microbiome is affected by AML, and whether such changes are associated with hallmarks of cachexia. Biological samples and clinical data were collected from 30 antibiotic- free AML patients at diagnosis and matched volunteers (1:1) in a multicenter, cross-sectional, prospective study. The composition and functional potential of the fecal microbiota were analyzed using shotgun metagenomics. Fecal, blood, and urinary metabolomics analyses were performed. AML patients displayed muscle weakness, anorexia, signs of altered gut function, and glycemic disorders. The composition of the fecal microbiota differed between patients with AML and control subjects, with an increase in oral bacteria. Alterations in bacterial functions and fecal metabolome support an altered redox status in the gut microbiota, which may contribute to the altered redox status observed in patients with AML. Eubacterium eligens, reduced 3-fold in AML patients, was strongly correlated with muscle strength and citrulline, a marker of enterocyte mass and function. Blautia and Parabacteroides, increased in patients with AML, were correlated with anorexia. Several bacterial taxa and metabolites (e.g., Blautia, Prevotella, phenylacetate, and hippurate) previously associated with glycemic disorders were altered. Our work revealed important perturbations in the gut microbiome of AML patients at diagnosis, which are associated with muscle strength, altered redox status, and anorexia. These findings pave the way for future mechanistic work to explore the function and therapeutic potential of the bacteria identified in this study.

Cancer cachexia is an involuntary loss of body weight, mostly of skeletal muscle. Previous research favors the existence of a microbiota-muscle crosstalk, so the aim of the study was to evaluate the impact of microbiota alterations induced by antibiotics on skeletal muscle proteins expression. Skeletal muscle proteome changes were investigated in control (CT) or C26 cachectic mice (C26) with or without antibiotic treatment (CT-ATB or C26-ATB, n = 8 per group). Muscle protein extracts were divided into a sarcoplasmic and myofibrillar fraction and then underwent label-free liquid chromatography separation, mass spectrometry analysis, Mascot protein identification, and METASCAPE platform data analysis. In C26 mice, the atrogen mafbx expression was 353% higher than CT mice and 42.3% higher than C26-ATB mice. No effect on the muscle protein synthesis was observed. Proteomic analyses revealed a strong effect of antibiotics on skeletal muscle proteome outside of cachexia, with adaptative processes involved in protein folding, growth, energy metabolism, and muscle contraction. In C26-ATB mice, proteome adaptations observed in CT-ATB mice were blunted. Differentially expressed proteins were involved in other processes like glucose metabolism, oxidative stress response, and proteolysis. This study confirms the existence of a microbiota-muscle axis, with a muscle response after antibiotics that varies depending on whether cachexia is present.