The presence of
(Akk) in the human gut is associated with good health, leanness and fitness. Mouse experimentation has demonstrated positive effects for Akk, which counteracts aging, mediates ...antiobesity and antidiabetic effects, dampens inflammation and improves anticancer immunosurveillance. Clinical trials have confirmed antidiabetic effects for Akk. Here, we investigated the time-dependent effects of oral administration of Akk (which was live or pasteurized) and other bacteria to mice on the metabolome of the ileum, colon, liver and blood plasma. Metabolomics was performed by a combination of chromatographic and mass spectrometric methods, yielding a total of 1.637.227 measurements. Akk had major effects on metabolism, causing an increase in spermidine and other polyamines in the gut and in the liver. Pasteurized Akk (Akk-past) was more efficient than live Akk in elevating the intestinal concentrations of polyamines, short-chain fatty acids, 2-hydroxybutyrate, as well multiple bile acids, which also increased in the circulation. All these metabolites have previously been associated with human health, providing a biochemical basis for the beneficial effects of Akk.
Chronic alcohol consumption is an important cause of liver-related deaths. Specific intestinal microbiota profiles are associated with susceptibility or resistance to alcoholic liver disease in both ...mice and humans. We aimed to identify the mechanisms by which targeting intestinal microbiota can improve alcohol-induced liver lesions.
We used human associated mice, a mouse model of alcoholic liver disease transplanted with the intestinal microbiota of alcoholic patients and used the prebiotic, pectin, to modulate the intestinal microbiota. Based on metabolomic analyses, we focused on microbiota tryptophan metabolites, which are ligands of the aryl hydrocarbon receptor (AhR). Involvement of the AhR pathway was assessed using both a pharmacological approach and AhR-deficient mice.
Pectin treatment modified the microbiome and metabolome in human microbiota-associated alcohol-fed mice, leading to a specific faecal signature. High production of bacterial tryptophan metabolites was associated with an improvement of liver injury. The AhR agonist Ficz (6-formylindolo (3,2-b) carbazole) reduced liver lesions, similarly to prebiotic treatment. Conversely, inactivation of the
gene in alcohol-fed AhR
mice abrogated the beneficial effects of the prebiotic. Importantly, patients with severe alcoholic hepatitis have low levels of bacterial tryptophan derivatives that are AhR agonists.
Improvement of alcoholic liver disease by targeting the intestinal microbiota involves the AhR pathway, which should be considered as a new therapeutic target.
The gut microbiome is emerging as a key regulator of several metabolic, immune and neuroendocrine pathways
. Gut microbiome deregulation has been implicated in major conditions such as obesity, type ...2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease and cancer
, but its precise role in aging remains to be elucidated. Here, we find that two different mouse models of progeria are characterized by intestinal dysbiosis with alterations that include an increase in the abundance of Proteobacteria and Cyanobacteria, and a decrease in the abundance of Verrucomicrobia. Consistent with these findings, we found that human progeria patients also display intestinal dysbiosis and that long-lived humans (that is, centenarians) exhibit a substantial increase in Verrucomicrobia and a reduction in Proteobacteria. Fecal microbiota transplantation from wild-type mice enhanced healthspan and lifespan in both progeroid mouse models, and transplantation with the verrucomicrobia Akkermansia muciniphila was sufficient to exert beneficial effects. Moreover, metabolomic analysis of ileal content points to the restoration of secondary bile acids as a possible mechanism for the beneficial effects of reestablishing a healthy microbiome. Our results demonstrate that correction of the accelerated aging-associated intestinal dysbiosis is beneficial, suggesting the existence of a link between aging and the gut microbiota that provides a rationale for microbiome-based interventions against age-related diseases.
The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics ...was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.
Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we ...report an unexpected function of the endoplasmic reticulum stress transducer IRE1α as a structural determinant of MAMs that controls mitochondrial calcium uptake. IRE1α deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions. IRE1α determined the distribution of inositol-1,4,5-trisphosphate receptors at MAMs by operating as a scaffold. Using mutagenesis analysis, we separated the housekeeping activity of IRE1α at MAMs from its canonical role in the unfolded protein response. These observations were validated in vivo in the liver of IRE1α conditional knockout mice, revealing broad implications for cellular metabolism. Our results support an alternative function of IRE1α in orchestrating the communication between the endoplasmic reticulum and mitochondria to sustain bioenergetics.
Cisplatin is the most widely used chemotherapeutic agent, and resistance of neoplastic cells against this cytoxicant poses a major problem in clinical oncology. Here, we explored potential metabolic ...vulnerabilities of cisplatin‐resistant non‐small human cell lung cancer and ovarian cancer cell lines. Cisplatin‐resistant clones were more sensitive to killing by nutrient deprivation in vitro and in vivo than their parental cisplatin‐sensitive controls. The susceptibility of cisplatin‐resistant cells to starvation could be explained by a particularly strong dependence on glutamine. Glutamine depletion was sufficient to restore cisplatin responses of initially cisplatin‐resistant clones, and glutamine supplementation rescued cisplatin‐resistant clones from starvation‐induced death. Mass spectrometric metabolomics and specific interventions on glutamine metabolism revealed that, in cisplatin‐resistant cells, glutamine is mostly required for nucleotide biosynthesis rather than for anaplerotic, bioenergetic or redox reactions. As a result, cisplatin‐resistant cancers became exquisitely sensitive to treatment with antimetabolites that target nucleoside metabolism.
Synopsis
Cisplatin‐resistant cancers acquire a vulnerability to nutrient depletion depending on glutamine‐fueled nucleotide biosynthesis, suggesting new opportunities for combination therapies.
Cisplatin‐resistant cancer cells are sensitive to starvation in vitro and in vivo.
Glutamine suppresses starvation‐induced cell death.
Glutamine rescues cisplatin‐resistant cells from starvation‐induced death by elevating the intracellular concentrations of nucleosides.
Cisplatin‐resistant cells become exclusively sensitive to antimetabolites targeting nucleotide biosynthesis.
Cisplatin‐resistant cancers are exquisitely sensitive to starvation due to strong dependence on glutamine and nucleotide metabolism.
Retinal ganglion cells (RGCs) are the sole projecting neurons of the retina and their axons form the optic nerve. Here, we show that embryogenesis‐associated mouse RGC differentiation depends on ...mitophagy, the programmed autophagic clearance of mitochondria. The elimination of mitochondria during RGC differentiation was coupled to a metabolic shift with increased lactate production and elevated expression of glycolytic enzymes at the mRNA level. Pharmacological and genetic inhibition of either mitophagy or glycolysis consistently inhibited RGC differentiation. Local hypoxia triggered expression of the mitophagy regulator BCL2/adenovirus E1B 19‐kDa‐interacting protein 3‐like (BNIP3L, best known as NIX) at peak RGC differentiation. Retinas from NIX‐deficient mice displayed increased mitochondrial mass, reduced expression of glycolytic enzymes and decreased neuronal differentiation. Similarly, we provide evidence that NIX‐dependent mitophagy contributes to mitochondrial elimination during macrophage polarization towards the proinflammatory and more glycolytic M1 phenotype, but not to M2 macrophage differentiation, which primarily relies on oxidative phosphorylation. In summary, developmentally controlled mitophagy promotes a metabolic switch towards glycolysis, which in turn contributes to cellular differentiation in several distinct developmental contexts.
Synopsis
Retinal ganglion cell differentiation and M1 macrophage polarization depend on metabolic reprogramming towards glycolysis, which is triggered by hypoxia‐induced autophagic degradation of mitochondria (mitophagy).
Programmed mitophagy eliminates mitochondria during mouse retinal development.
Hypoxia‐induces NIX‐dependent mitophagy.
Mitophagy allows for a glycolytic shift required for retinal ganglion cell differentiation.
Mitophagy also regulates metabolic reprogramming during M1 macrophage polarization.
Retinal ganglion cell differentiation and M1 macrophage polarization depend on metabolic reprogramming towards glycolysis, which is triggered by hypoxia‐induced autophagic degradation of mitochondria (mitophagy).
Several approaches to manipulate the gut microbiome for improving the activity of cancer immune-checkpoint inhibitors (ICI) are currently under evaluation. Here, we show that oral supplementation ...with the polyphenol-rich berry camu-camu (CC; Myrciaria dubia) in mice shifted gut microbial composition, which translated into antitumor activity and a stronger anti-PD-1 response. We identified castalagin, an ellagitannin, as the active compound in CC. Oral administration of castalagin enriched for bacteria associated with efficient immunotherapeutic responses (Ruminococcaceae and Alistipes) and improved the CD8+/FOXP3+CD4+ ratio within the tumor microenvironment. Moreover, castalagin induced metabolic changes, resulting in an increase in taurine-conjugated bile acids. Oral supplementation of castalagin following fecal microbiota transplantation from ICI-refractory patients into mice supported anti-PD-1 activity. Finally, we found that castalagin binds to Ruminococcus bromii and promoted an anticancer response. Altogether, our results identify castalagin as a polyphenol that acts as a prebiotic to circumvent anti-PD-1 resistance.
The polyphenol castalagin isolated from a berry has an antitumor effect through direct interactions with commensal bacteria, thus reprogramming the tumor microenvironment. In addition, in preclinical ICI-resistant models, castalagin reestablishes the efficacy of anti-PD-1. Together, these results provide a strong biological rationale to test castalagin as part of a clinical trial. This article is highlighted in the In This Issue feature, p. 873.
Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological ...interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4'-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.
Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus-host interactions during cancer therapies remain elusive. When ...comparing nasopharyngeal swabs from cancer and noncancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Cancer patients with a prolonged SARS-CoV-2 RNA detection exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of nonconventional monocytes, and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T-helper cells, and non-naive Granzyme B
FasL
, Eomes
TCF-1
, PD-1
CD8
Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity, and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long-term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.
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