Biology subjects

Rodriguez-Blanco, G.

Publications and source records attributed to Rodriguez-Blanco, G..

5 recordsLinked to original sources

bioRxiv2026

Early-life vancomycin and meropenem treatment exert distinct effects on microbiota-gut-brain axis signalling in zebrafish larvae

The microbiota-gut-brain axis is a bidirectional communication pathway between the gastrointestinal tract, gut microbiota and the central nervous system, that influences host neurobiology, metabolism and behaviour. Although germ-free and antibiotic-treated animals demonstrate a role for microbial signalling in mood and behaviour, mechanisms linking microbiome disruption to altered neural signalling during early development remain incompletely understood. Here, we investigated the impact of antibiotic-induced perturbations of the gut microbiota on behaviour, neurotransmitter levels as well as central and peripheral metabolism in 5 dpf zebrafish larvae, an established neurodevelopmental model. Larvae were exposed to the broad-spectrum antibiotic meropenem, the Gram-positive-directed antibiotic vancomycin, or their combination, and assessed gut microbiota composition, behaviour, neurotransmitter levels and metabolite profiles. All treatments altered microbial community composition, although the extent differed markedly, with pronounced restructuring after meropenem and combination treatment and more subtle changes after vancomycin. Behavioural analysis using the light-dark transition assay revealed reduced centre locomotion during the dark phase in all treated groups, without a general reduction in swimming activity, consistent with anxiety-like behaviour. These behavioural changes were accompanied by reduced expression of serotonergic genes and widespread central and peripheral metabolic disruptions in all antibiotic-treated groups. Treatment- and tissue-specific effects included suppression of the arginine-polyamine pathway in the brain following vancomycin treatment and increased peripheral glutamate, GABA and L-DOPA levels after meropenem exposure. Together, these findings demonstrate that early-life microbiome perturbation reshapes behaviour, neurotransmitter levels, and host metabolism in zebrafish larvae. In addition, we identified candidate metabolic pathways through which the microbiome may influence neurodevelopment.

neuroscience↗

bioRxiv2024

Impact of high fat diet and exercise on bone and bile acid metabolism in rats

BackgroundBile acids help facilitate the intestinal lipids absorption, and have endocrine activity in glucose, lipid and bone metabolism. Obesity and exercise influence bile acid metabolism and have opposite effects in bone. This given study investigates if regular exercise helps mitigate the adverse effects of obesity on bone, potentially by reversing alterations in bile acid metabolism. MethodsFour-month-old female Sprague Dawley rats either received high fat diet (HFD) or chow-based standard diet (lean controls). During the 10-month study period, half of the animals performed 30 min of running at moderate speed on five consecutive days followed by two days of rest. The other half was kept inactive (inactive controls). At study end, bone quality was assessed by micro computed tomography and biomechanical testing. Bile acids were measured in serum and stool. ResultsHFD feeding was related to reduced trabecular (-33%, p=1.14x10-7) and cortical (-21%, p=2.9x10-8) bone mass, and lowered femoral stiffness (12-41%, p=0.005). Furthermore, HFD decreased total bile acids in serum (-37%, p=1.0x10-6), but increased bile acids in stool (+2-fold, p=7.3x10-9). These quantitative effects were accompanied by changes in the relative abundance of individual bile acids. The concentration of serum bile acids correlated positively with all cortical bone parameters (r=0.593 - 0.708), whilst stool levels showed inverse correlations at cortical (r=-0.651 - -0.805) and trabecular level (r=-0.656 - -0.750). Exercise improved some trabecular and cortical bone quality parameters (+11-31%, p=0.043 to 0.001) in lean controls, but failed to revert the bone loss related to HFD. Similarly, changes in bile acid metabolism were not mitigated by exercise. ConclusionProlonged HFD consumption induced quantitative and qualitative alterations in bile acid metabolism, accompanied by bone loss. Tight correlations between bile acids and structural indices of bone quality support further functional analyses on the potential role of bile acids in bone metabolism. Regular moderate exercise improved trabecular and cortical bone quality in lean controls but failed mitigating the effects related to HFD in bone and bile acid metabolism.

molecular biology↗

bioRxiv2023

Paracrine secretion of MUFAs prevents ferroptosis in triple-negative breast cancer and reveals selenocysteine synthesis dependency for lung metastasis

The limited availability of therapeutic options for patients with triple-negative breast cancer (TNBC) contributes to the high rate of metastatic recurrence and poor prognosis. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation and counteracted by the antioxidant activity of the selenoprotein GPX4. Here, we show that TNBC cells secrete an anti-ferroptotic factor in the extracellular environment when cultured at high cell densities but are primed to ferroptosis when forming colonies at low density. We found that secretion of the anti-ferroptotic factors, identified as monounsaturated fatty acid (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depends on the low expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of Sec-tRNAsec biosynthesis, an essential step for selenoprotein production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells that are no longer protected by the MUFA-rich environment of the primary tumour.

cancer biology↗

bioRxiv2023

Cancer-associated fibroblasts produce matrix-bound vesicles that influence endothelial cell function

Intercellular communication between different cell types in solid tumors contributes to tumor growth and metastatic dissemination. The secretome of cancer-associated fibroblasts (CAFs) plays major roles in these processes. Using human mammary CAFs, we unveil a mechanism of cell-cell communication between CAFs with myofibroblast phenotype and endothelial cells (ECs) based on intercellular protein transfer through extracellular vesicles (EVs). CAFs transfer proteins to ECs, including plasma membrane receptors, which we have identified by using mass spectrometry- based proteomics. Using THY1 as an example of transferred plasma membrane-bound protein, we show that CAF-derived proteins can influence how ECs interact with other cell types. Here, we show that CAFs produce high amounts of matrix-bound EVs that have a key role in protein transfer. Hence, our work paves the way for further studies to understand how CAF-derived matrix-bound EVs influence tumor pathology by regulating functions of neighboring cancer, stromal and immune cells. One sentence summaryCAFs with a myofibroblastic-like phenotype transfer proteins to ECs, including plasma membrane receptors, through matrix-bound EVs

cancer biology↗

bioRxiv2020

Microbiome-derived metabolites reproduce the mitochondrial dysfunction and decreased insulin sensitivity observed in type 2 diabetes

Diabetes is a global health problem that was estimated to be the 7th leading cause of death worldwide in 2016. Type 2 diabetes mellitus (T2DM) is classically associated with genetic and environmental factors, however recent studies have demonstrated that the gut microbiome, which is altered in T2DM patients, is also likely to play a significant role in disease development. Despite this, the identity of microbiome-derived metabolites that influence T2DM onset and/or progression remain elusive. Here we demonstrate that a serum biomarker for T2DM, previously of unknown structure and origin, is actually two microbiome-derived metabolites, 3-methyl-4-(trimethylammonio)butanoate (3M-4-TMAB) and 4-(trimethylammonio)pentanoate (4-TMAP). These metabolites are produced by the Lachnospiraceae family of bacteria, which are highly prevalent in the gut microbiome of T2DM patients and are associated with high dietary fat intake. Treatment of human liver cells with 3M-4-TMAB and 4-TMAP results in a distinct change in the acylcarnitine profile in these cells and significantly reduced their insulin sensitivity; both indicators of T2DM. These results provide evidence of a mechanistic link between gut microbiome derived metabolites and T2DM.

microbiology↗