Biology subjects

Ramirez de Molina, A.

Publications and source records attributed to Ramirez de Molina, A..

7 recordsLinked to original sources

bioRxiv2025

Gut microbial ecosystems differ across metabolic and obesity phenotypes

Obesity is a heterogeneous condition comprising a continuum of phenotypes with various metabolic and inflammatory profiles. Metabolically healthy obesity (MHO) identifies individuals with obesity but a relatively preserved metabolic state. However, the criteria defining MHO remain inconsistent, and little is known about the gut microbiome (GM) features underlying this intermediate phenotype. Here, we aim to describe microbial structures contributing to metabolic health and disease. To do so, we analyzed the GM of 959 individuals classified as metabolically healthy non-obese (MHNO), MHO, metabolically unhealthy non-obese (MUNO), and metabolically unhealthy obese (MUO), using stool shotgun metagenomics. MHO subjects display intermediate anthropometric and biochemical profiles, with a GM composition and diversity in an in-between state among MHNO and MUO individuals. Network science analyses reveal that metabolic health, rather than obesity, drives microbial connectivity: MHNO and MHO individuals harbor more robust and functionally cohesive microbial networks, whose most influential nodes are focused toward SCFA production. In contrast, MUO and MUNO communities exhibit a dysbiotic state with reduced connectivity and increased influence of low-abundance, ectopic and potentially pro-inflammatory species resulting in a damaged, unstable microbial community network. These findings suggest that metabolic disorders disrupt microbial ecology beyond compositional shifts, emphasizing the need for systems-level approaches. Our findings show differences in microbial connectivity and association patterns across metabolic and obesity phenotypes, shedding light on how distinct microbial structures may contribute to metabolic health and disease.

bioinformatics↗

bioRxiv2023

Non-responsive Celiac disease symptoms associated with microbiome network structure and function

Non-responsive celiac disease (NRCD) poses a challenge for clinicians due to the persistence of symptoms despite maintaining a gluten-free diet (GFD). This study investigated the gut microbiome, mucosal integrity, and metabolomic profiles of 39 NRCD patients to gain insights into the underlying mechanisms contributing to symptom persistence. Two distinct clusters of patients were identified based on clinical and demographic variables not influenced by gluten consumption. Cluster 1, labelled "Low-grade symptoms," displayed milder symptoms and lower inflammatory markers. In contrast, Cluster 2, named "High-grade symptoms," exhibited more severe gastrointestinal and extraintestinal symptoms, along with elevated inflammatory markers and increased intestinal permeability. Despite similar mucosal damage in both clusters, network analysis of the gut microbiome revealed specific microbial taxa with potential functional implications. Cluster 1 displayed a microbiome associated with immune homeostasis and gut barrier integrity, potentially lowering inflammation and symptom severity. In contrast, Cluster 2 had a distinct microbiome linked to lactate production, Th17 activation, possibly contributing to heightened inflammation and gastrointestinal symptoms. Metabolomic analysis revealed differential metabolites between clusters, particularly in amino acid metabolism pathways. Metabolites associated with specific symptoms were identified, implicating their potential role in symptom manifestation. Notably, vitamin D deficiency was observed in both clusters, suggesting its relevance in the context of NRCD. The study highlights the importance of the gut microbiome, mucosal integrity, and metabolic pathways in symptom persistence among NRCD patients. The associations between microbial-derived metabolites and symptom severity provide valuable insights into potential therapeutic targets. Further research is needed to validate these findings and develop targeted interventions for improving clinical outcomes in NRCD patients.

microbiology↗

bioRxiv2023

EPIGENOMIC VARIABILITY AND TRANSCRIPTOMICS AS A NOVEL MULTIOMIC COMPLEMENTARY APPROACH FOR PERSONALIZED NUTRITION IN COLORECTAL CANCER PATIENTS

Food natural compounds are of interest as modulators of cancer progression and prognosis, as they participate in cellular processes such as growth and differentiation, DNA repair, programmed cell death and oxidative stress. Here we select dietary biocompounds for specific subgroups of 285 colorectal adenocarcinoma (COAD) samples by finding bioactives with opposite transcriptomic profiles to the subgroup-specific tumoral transcriptomes, hypothesizing they may counteract the cancer gene-expression profiles. To establish a CRC classification based on epigenetic variability, we selected 2,189 CpGs based on their differentially variable methylation between tumor and normal samples by a combination of linear and Bartlett tests. Samples were meta-clustered by 1) classifying each sample by 8 different methods (including k-means and hierarchical clustering), 2) building a network and 3) meta-clustering it by the edge-betweenness method. We extracted 6 main subgroups, 2 of them with immune-affected transcriptomes. We compared the transcriptomes of the 6 subgroups with the ones of 56 in vitro bioactive studies from GEO by Gene Set Enrichment Analysis (GSEA), resulting in a potential positive effect of resveratrol, japonicone A and vitamin D. In summary, we present a promising in silico strategy to suggest specific bioactives as co-adjuvants in cancer treatment.

bioinformatics↗

bioRxiv2022

Bioinformatic methods for stratification of obese patients and identification of cancer susceptibility biomarkers based on the analysis of the gut microbiome

Obesity has an impact on health by increasing the risk of various diseases. However, these risks might also depend on the metabolic health status, as it seems that metabolically healthy obese subjects are under a reduced risk of suffering comorbidities such as colorectal cancer. The gut microbiome has an effect on obesity and metabolic disorders through several integration pathways, making it a potential therapeutic target for these diseases. In this study, we characterized the gut microbiota of 356 obese and non-obese European individuals with different comorbidities associated with obesity. Using approaches based on supervised machine learning and network biology, we found a set of biomarkers of interest for differentiating metabolically healthy from unhealthy subjects. Then, we performed a linear discriminant analysis of effect size on a population of 1593 colorectal cancer, adenoma and control subjects assembled by the COST Action ML4Microbiome to investigate their role in colorectal cancer risk. Four of our biomarkers appeared in both approaches, suggesting their possible role in colorectal cancer development, prognosis and follow up: Clostridium leptum, Gordonibacter pamelaeae, Eggerthella lenta and Collinsella intestinalis. Further research via longitudinal studies or experimental validation of these microbial species would be necessary to confirm this association.

bioinformatics↗

bioRxiv2021

Metataxonomic review to elucidate the role of the microbiome in Celiac disease across the gastrointestinal tract

BackgroundDysbiosis of the microbiome has been related to the Celiac disease (CeD) progress, an autoimmune disease characterised by gluten intolerance developed in genetically susceptible individuals under certain environmental factors. The microbiome contributes to CeD pathophysiology modulating the immune response by the action of short-chain fatty acids (SCFA), affecting gut barrier integrity allowing the entrance of gluten derived proteins, and degrading immunogenic peptides of gluten through endoprolyl peptidase enzymes. We reviewed state of the art in taxonomic composition for CeD and compiled the larger dataset of 16S prokaryotic ribosomal RNA (rRNA) gene high-throughput sequencing for consensus profiling. We present for the first time an integrative analysis of metataxonomic data from CeD patients, including samples from different body sites (saliva, pharynx, duodenum, and stool). We found the presence of coordinated changes through the gastrointestinal tract characterised by an increase in Actinobacteria species in the upper tract (pharynx and duodenum), and an increase in Proteobacteria in the lower tract (duodenum and stool), as well as site- specific changes evidencing a dysbiosis in CeD patients microbiota. Moreover, we described the effect of adherence to a gluten-free diet (GFD) evidenced by an increase in beneficial bacteria and a decrease in some Betaproteobacteriales but not fully restoring CeD-related dysbiosis. We illustrate that the gut microbiota acts as an enhancer of immune response in CeD through the production of lipopolysaccharides and other bacterial components that activate the immune response and by decrease SCFA producers bacteria. Furthermore, microbial changes observed through the gastrointestinal tract of CeD patients may help manage the disease and follow-up GFD treatment.

microbiology↗

bioRxiv2019

TAT-Cx43266-283 impairs metabolic plasticity in glioma stem cells in vitro and in vivo

Glioblastoma is the most aggressive primary brain cancer, with a median survival of 1 to 2 years1. These tumours contain glioma stem cells (GSCs), which are highly tumorigenic, resistant to conventional therapies2, 3, and exhibit metabolic plasticity to adapt to challenging environments4, 5. GSCs can be specifically targeted by a short cell-penetrating peptide based on connexin43 (Cx43) (TAT-Cx43266-283) that reduces tumour growth and increases survival in preclinical models6 via c-Src inhibition7. Because several reports revealed poor clinical efficacy of various antitumoral drugs due to metabolic rewiring in cancer cells8-10, we investigated the effect of TAT-Cx43266-283 on GSC metabolism and metabolic plasticity. Here we show that TAT-Cx43266-283 decreases GSC glucose uptake and oxidative phosphorylation without a compensatory increase in glycolysis, with no effect on neuron or astrocyte metabolism. GSC changes were mediated by decreased hexokinase (HK) activity and aberrant mitochondrial localization, ultrastructure and function. Moreover, TAT-Cx43266-283 reduced GSC growth and survival under different nutrient availability conditions by impairing the metabolic plasticity needed to exploit glucose as an energy source in the absence of other nutrients. Finally, GSCs intracranially implanted into mice together with TAT-Cx43266-283 showed decreased levels of important targets for cancer therapy, such as HK-211, 12 and glucose transporter 3 (GLUT-3)13, evidencing the reduced ability of treated GSCs to survive in challenging environments. Our results confirm the value of TAT-Cx43266-283 for glioma therapy alone or in combination with therapies whose resistance relies on metabolic adaptation. More importantly, these results allow us to conclude that the advantageous metabolic plasticity of GSCs is a targetable vulnerability in malignant gliomas.

cancer biology↗

bioRxiv2018

A more physiological approach to lipid metabolism alterations in cancer: CRC-like organoids assessment

Precision medicine might be the response to the recent questioning of the use of metformin as an anticancer drug in colorectal cancer (CRC). Thus, in order to establish properly its benefits, its application need to be assayed on the different progression stages of CRC. In this way, organoids imply a more physiological tool, representing a new therapeutic opportunity for CRC personalized treatment to assay tumor stage-dependent drugs effects. Since the lipid metabolism-related axis, ACSL/SCD, stimulates colon cancer progression and Metformin is able to rescuing the invasive and migratory phenotype conferred to cancer cells upon this axis overexpression; we checked ACSL/SCD status, its regulatory miRNAs and the effect of Metformin treatment in organoids as a model for specific and personalized treatment. Despite ACSL4 expression is upregulated in CRC-like organoids, Metformin is able to downregulate it, especially in the first stages. Besides, organoids are clearly more sensitive in this first stage (Apc mutated) to Metformin than current chemotherapeutic drugs such as fluorouracil (5-FU). Metformin performs an independent \"Warburg effect\" blockade to cancer progression and is able to reduce crypt stem cell markers expression such as Lgr5+. These results suggest a putative increased efficiency of the use of Metformin in the first stages of CRC than in advanced disease.

cancer biology↗