RESUMEN
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.
Asunto(s)
Antibacterianos , Caquexia , Músculo Esquelético , Proteoma , Caquexia/metabolismo , Caquexia/microbiología , Animales , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/efectos adversos , Proteoma/metabolismo , Proteoma/análisis , Ratones , Neoplasias/metabolismo , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Proteínas Musculares/metabolismo , Masculino , Proteómica/métodos , Microbiota/efectos de los fármacos , Metabolismo Energético/efectos de los fármacosRESUMEN
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.
RESUMEN
OBJECTIVE: Tumour progression drives profound alterations in host metabolism, such as adipose tissue depletion, an early event of cancer cachexia. As fatty acid consumption by cancer cells increases upon acidosis of the tumour microenvironment, we reasoned that fatty acids derived from distant adipose lipolysis may sustain tumour fatty acid craving, leading to the adipose tissue loss observed in cancer cachexia. METHODS: To evaluate the pro-lipolytic capacities of acid-exposed cancer cells, primary mouse adipocytes from subcutaneous and visceral adipose tissue were exposed to pH-matched conditioned medium from human and murine acid-exposed cancer cells (pH 6.5), compared to naive cancer cells (pH 7.4). To further address the role of tumoral acidosis on adipose tissue loss, a pH-low insertion peptide was injected into tumour-bearing mice, and tumoral acidosis was neutralised with a sodium bicarbonate buffer. Prolipolytic mediators were identified by transcriptomic approaches and validated on murine and human adipocytes. RESULTS: Here, we reveal that acid-exposed cancer cells promote lipolysis from subcutaneous and visceral adipocytes and that dampening acidosis in vivo inhibits adipose tissue depletion. We further found a set of well-known prolipolytic factors enhanced upon acidosis adaptation and unravelled a role for ß-glucuronidase (GUSB) as a promising new actor in adipocyte lipolysis. CONCLUSIONS: Tumoral acidosis promotes the mobilization of fatty acids derived from adipocytes via the release of soluble factors by cancer cells. Our work paves the way for therapeutic approaches aimed at tackling cachexia by targeting the tumour acidic compartment.
Asunto(s)
Acidosis , Adipocitos , Tejido Adiposo , Caquexia , Lipólisis , Animales , Ratones , Acidosis/metabolismo , Adipocitos/metabolismo , Humanos , Tejido Adiposo/metabolismo , Caquexia/metabolismo , Masculino , Microambiente Tumoral , Línea Celular Tumoral , Ratones Endogámicos C57BL , Ácidos Grasos/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Femenino , Glucuronidasa/metabolismo , Concentración de Iones de HidrógenoRESUMEN
BACKGROUND: Cancer cachexia is a life-threatening, inflammation-driven wasting syndrome that remains untreatable. Adiponectin, the most abundant adipokine, plays an important role in several metabolic processes as well as in inflammation modulation. Our aim was to test whether administration of AdipoRon (AR), a synthetic agonist of the adiponectin receptors, prevents the development of cancer cachexia and its related muscle atrophy. METHODS: The effect of AR on cancer cachexia was investigated in two distinct murine models of colorectal cancer. First, 7-week-old CD2F1 male mice were subcutaneously injected with colon-26 carcinoma cells (C26) or vehicle (CT). Six days after injection, mice were treated for 5 days with AdipoRon (50 mg/kg/day; C26 + AR) or the corresponding vehicle (CT and C26). Additionally, a genetic model, the ApcMin/+ mouse, that develops spontaneously numerous intestinal polyps, was used. Eight-week-old male ApcMin/+ mice were treated with AdipoRon (50 mg/kg/day; Apc + AR) or the corresponding vehicle (Apc) over a period of 12 weeks, with C57BL/6J wild-type mice used as controls. In both models, several parameters were assessed in vivo: body weight, grip strength and serum parameters, as well as ex vivo: molecular changes in muscle, fat and liver. RESULTS: The protective effect of AR on cachexia development was observed in both cachectic C26 and ApcMin/+ mice. In these mice, AR administration led to a significant alleviation of body weight loss and muscle wasting, together with rescued muscle strength (P < 0.05 for all). In both models, AR had a strong anti-inflammatory effect, reflected by lower systemic interleukin-6 levels (-55% vs. C26, P < 0.001 and -80% vs. Apc mice, P < 0.05), reduced muscular inflammation as indicated by lower levels of Socs3, phospho-STAT3 and Serpina3n, an acute phase reactant (P < 0.05 for all). In addition, AR blunted circulating levels of corticosterone (-46% vs. C26 mice, P < 0.001 and -60% vs. Apc mice, P < 0.05), the predominant murine glucocorticoid known to induce muscle atrophy. Accordingly, key glucocorticoid-responsive factors implicated in atrophy programmes were-or tended to be-significantly blunted in skeletal muscle by AR. Finally, AR protected against lipid metabolism alterations observed in ApcMin/+ mice, as it mitigated the increase in circulating triglyceride levels (-38%, P < 0.05) by attenuating hepatic triglyceride synthesis and fatty acid uptake by the liver. CONCLUSIONS: Altogether, these results show that AdipoRon rescued the cachectic phenotype by alleviating body weight loss and muscle atrophy, along with restraining inflammation and hypercorticism in preclinical murine models. Therefore, AdipoRon could represent an innovative therapeutic strategy to counteract cancer cachexia.
Asunto(s)
Caquexia , Inflamación , Receptores de Adiponectina , Animales , Caquexia/etiología , Caquexia/tratamiento farmacológico , Caquexia/metabolismo , Ratones , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/metabolismo , Masculino , Inflamación/tratamiento farmacológico , Modelos Animales de Enfermedad , Línea Celular Tumoral , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , PiperidinasRESUMEN
The gut microbiota makes critical contributions to host homeostasis, and its role in the treatment of acute myeloid leukaemia (AML) has attracted attention. We investigated whether the gut microbiome is affected by AML, and whether such changes are associated with cachectic hallmarks. 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 faecal microbiota were analyzed using shotgun metagenomics. Faecal, blood, and urine metabolomics analyses were performed. AML patients displayed muscle weakness, anorexia, signs of altered gut function, and glycaemic disorders. The composition of the faecal microbiota differed between patients with AML and control subjects, with an increase in oral bacteria. Alterations in bacterial functions and faecal 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 glycaemic 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.
RESUMEN
OBJECTIVE: Malnutrition is one of the most threatening conditions in geriatric populations. The gut microbiota has an important role in the host's metabolic and muscular health: however, its interplay with disease-related malnutrition is not well understood. We aimed to identify the association of malnutrition with the gut microbiota and predict clinical outcomes in hospitalized acutely ill older adults. METHODS: We performed a secondary longitudinal analysis in 108 geriatric patients from a prospective cohort evaluated at admission and 72 h of hospitalization. We collected clinical, demographic, nutritional, and 16S rRNA gene-sequenced gut microbiota data. Microbiota diversity, overall composition, and differential abundance were calculated and compared between patients with and without malnutrition. Microbiota features associated with malnutrition were used to predict clinical outcomes. RESULTS: Patients with malnutrition (51%) had a different microbiota composition compared to those who were well-nourished during hospitalization (ANOSIM R = 0.079, P = 0.003). Patients with severe malnutrition showed poorer α-diversity at admission (Shannon P = 0.012, Simpson P = 0.018) and follow-up (Shannon P = 0.023, Chao1 P = 0.008). Differential abundance of Lachnospiraceae NK4A136 group, Subdoligranulum, and Faecalibacterium prausnitzii were significantly lower and inversely associated with malnutrition, while Corynebacterium, Ruminococcaceae Incertae Sedis, and Fusobacterium were significantly increased and positively associated with malnutrition. Corynebacterium, Ruminococcaceae Incertae Sedis, and the overall composition were important predictors of critical care in patients with malnutrition during hospitalization. CONCLUSION: Older adults with malnutrition, especially in a severe stage, may be subject to substantial gut microbial disturbances during hospitalization. The gut microbiota profile of patients with malnutrition might help us to predict worse clinical outcomes.
Asunto(s)
Microbioma Gastrointestinal , Desnutrición , Desnutrición Proteico-Calórica , Humanos , Anciano , Microbioma Gastrointestinal/genética , Estudios Prospectivos , ARN Ribosómico 16S/genética , Desnutrición/complicacionesRESUMEN
BACKGROUND AND AIMS: Subcutaneous adipose tissue (SAT) dysfunction contributes to NAFLD pathogenesis and may be influenced by the gut microbiota. Whether transcript profiles of SAT are associated with liver fibrosis and are influenced by synbiotic treatment (that changes the gut microbiome) is unknown. We investigated: (a) whether the presence of clinically significant, ≥F2 liver fibrosis associated with adipose tissue (AT) dysfunction, differential gene expression in SAT, and/or a marker of tissue fibrosis (Composite collagen gene expression (CCGE)); and (b) whether synbiotic treatment modified markers of AT dysfunction and the SAT transcriptome. METHODS: Sixty-two patients with NAFLD (60 % men) were studied before and after 12 months of treatment with synbiotic or placebo and provided SAT samples. Vibration-controlled transient elastography (VCTE)-validated thresholds were used to assess liver fibrosis. RNA-sequencing and histological analysis of SAT were performed to determine differential gene expression, CCGE and the presence of collagen fibres. Regression modelling and receiver operator characteristic curve analysis were used to test associations with, and risk prediction for, ≥F2 liver fibrosis. RESULTS: Patients with ≥F2 liver fibrosis (n = 24) had altered markers of AT dysfunction and a SAT gene expression signature characterised by enrichment of inflammatory and extracellular matrix-associated genes, compared to those with Asunto(s)
Enfermedad del Hígado Graso no Alcohólico
, Simbióticos
, Masculino
, Humanos
, Femenino
, Enfermedad del Hígado Graso no Alcohólico/genética
, Enfermedad del Hígado Graso no Alcohólico/terapia
, Enfermedad del Hígado Graso no Alcohólico/complicaciones
, Biomarcadores
, Cirrosis Hepática/genética
, Cirrosis Hepática/terapia
, Cirrosis Hepática/complicaciones
, Fibrosis
, Tejido Adiposo/patología
, Colágeno/genética
, Hígado/patología