Dulcenombre Gómez-Garre

The human gut microbiota, a dynamic and highly complex ecosystem comprising bacteria, archaea, fungi, viruses, and their collective genetic material, has emerged over the past two decades as one of the most intensively studied determinants of human health and disease

Background: Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) has been implicated in vascular inflammation beyond its action on LDL-C degradation. We investigated whether PCSK9 may exacerbate proinflammatory signaling of M1 macrophages and if its neutralization with alirocumab could attenuate this effect and plaque progression by LDL-C independent mechanisms. Methods: ApoE⁻/⁻ mice were treated with alirocumab for 13 weeks, and aortic arches were isolated for atherosclerotic plaque characterization based on lesion size and lipid and macrophage infiltration. Plasma and splenic monocytes/macrophages were also assessed by flow cytometry, and PCSK9, the lipid profile, and inflammatory cytokines were measured by qPCR or Western blot. Cultured THP-1-derived M1 macrophages were stimulated with PCSK9 and evaluated for TLR4-NFκB-NLRP3 activation and cytokine production. In addition, soluble PCSK9, LDL-C, and proinflammatory factors were analyzed in 1190 patients with acute coronary syndrome (ACS). Results: Alirocumab reduced plaque lesion (0.42-fold; p < 0.05) and lipid (0.63-fold; p < 0.01) and macrophage (0.61-fold; p < 0.05) infiltration, mainly the M1 subtype (0.37-fold; p < 0.01), as well as TLR4, NLRP3 and caspase-1 expressions (0.49-fold, 0.51-fold and 0.51-fold, respectively; p < 0.05), without altering LDL-C. Also, it decreased proinflammatory cytokines but enhanced anti-inflammatory factors and M2 markers at the descending aorta. Alirocumab enriched circulating Ly6C^low monocytes (1.51-fold; p < 0.05) and splenic M2 macrophages (1.32-fold; p < 0.01), while reducing M1 (0.62-fold; p < 0.05). In cultured M1 macrophages, PCSK9 overexpressed proinflammatory cytokines (i.e., CXCL9, CXCL10, TNF-α, IL-1β, and IL-6), downregulated anti-inflammatory mediators (i.e., CCL17, TGM2, TGF-β1, and IL-10), and promoted NFκB-p65 nuclear translocation and NLRP3 and gasdermin-D activation. However, TLR4 inhibition or silencing blunted these effects. In patients with AC, there was a positive association between PCSK9 and hsCRP and FGF-23 plasma levels, independently of LDL-C. Conclusions: PCSK9 may be released in parallel to proinflammatory factors such as hsCRP and FGF-23 in patients with ACS, independently of LDL-C levels. PCSK9 may directly promote macrophage-driven inflammatory responses through the TLR4-NFκB-NLRP3 signaling, but its neutralization with alirocumab attenuated this inflammatory axis and limited atherosclerotic progression, supporting an anti-inflammatory benefit secondary to PCSK9 inhibition.

Background/Objectives: Hypertension control remains a global challenge. Evidence on the association between adherence to the Dietary Approaches to Stop Hypertension (DASH) diet and blood pressure (BP) control in older Mediterranean populations is limited. We aimed to assess this association in Spanish older adults. Methods: This cross-sectional analysis included 371 participants (69 ± 9 years). Dietary intake was assessed using a validated 146-item food frequency questionnaire (FFQ), and DASH diet adherence was categorized as low, medium, or high. Multivariable logistic regression models were used to examine associations with BP control. Results: Among participants with hypertension (n = 218), 52.8% achieved adequate BP control and consumed significantly more low-fat dairy products (+56%) and less sodium (−11%) than those with uncontrolled BP. The low adherence group had lower proportion of participants with controlled BP (21%) than the medium and high adherence groups (36% and 39%, respectively) (p < 0.05). Across increasing DASH diet adherence categories, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 4–5 mmHg and 3–4 mmHg lower, respectively. Medium adherence to the DASH diet was independently associated with substantially lower odds of uncontrolled BP (OR = 0.37; 95% CI: 0.16–0.82; p = 0.015). High adherence showed a similar magnitude of association but did not reach statistical significance. Conclusions: In this cohort of older Spanish adults, moderate adherence to the DASH diet was associated with meaningful improvements in BP control, suggesting that achievable, intermediate levels of DASH diet adherence may be sufficient to improve hypertension management in real-world settings. Longitudinal studies are needed to confirm causality and long-term cardiovascular benefits.

Background: Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) may directly promote vascular inflammation beyond its action on LDL-C degradation. We investigated whether PCSK9 may exacerbate proinflammatory signalling of M1 macrophages and if alirocumab could attenuate this effect and plaque progression by LDL-C independent mechanisms. Methods: ApoE⁻/⁻ mice were treated with alirocumab for 13 weeks and aortic arches were isolated for atherosclerotic plaques characterization based on lesion size and lipid and macrophage infiltration. Also, plasma and splenic monocytes/macrophages were assessed by flow cytometry, and PCSK9, the lipid profile, inflammatory cytokines were measured by qPCR or western blot. Cultured THP-1-derived M1 macrophages were stimulated with PCSK9 and evaluated for TLR4-NFκB-NLRP3 activation and cytokine production. PCSK9 and proinflammatory factors were analysed in 1190 patients with acute coronary syndrome (ACS). Results: Alirocumab reduced plaque lesion (0.42-fold; p< 0.05) and lipid (0.63-fold; p< 0.01) and macrophage (0.61-fold; plow monocytes (1.51-fold; p<0.05) and splenic M2 macrophages (1.32-fold; p<0.01), while reducing M1 (0.62-fold; p<0.05). In cultured M1 macrophages, PCSK9 overexpressed proinflammatory cytokines (i.e., CXCL9, CXCL10, TNF-α, IL-1β, IL-6) and downregulated anti-inflammatory mediators (i.e., CCL17, TGM2, TGF-β1, IL-10), promoted NFκB-p65 nuclear translocation, and NLRP3 and gasdermin-D activation. However, TLR4 inhibition or silencing blunted these effects. In addition, there was a positive association between PCSK9 with hsCRP and FGF-23 plasma levels in ACS patients. Conclusions: PCSK9 may be released in parallel to proinflammatory factors such as hsCRP and FGF-23 in ACS patients. However, alirocumab could exert lipid-independent anti-inflammatory effects through activation of the TLR4-NFκB-NLRP3 signaling in M1 macrophages, promotion of M2, and reducing plaque inflammation.

Purpose: The microbiota is recognized as an important contributor to the efficacy of immunotherapies. The aim of this study is to analyze the role of gut microbiota and related metabolites in the response of chimeric antigen receptor (CAR) T cells for non-Hodgkin lymphoma. Experimental Design: Stool, serum, and clinical data were collected from 84 patients with non-Hodgkin lymphoma from four hospitals before CD19 CAR T-cell treatment. The microbiota was characterized through 16S rRNA gene sequencing, and serum short-chain fatty acids (SCFA) were measured using mass spectrometry. CAR T cells were exposed to butyrate; their in vitro cytotoxicity was determined, and molecular mechanisms were characterized by flow cytometry and RNA sequencing and then assessed in an in vivo model. Results: As we confirmed the negative impact of antibiotics on the response, we delved into the mechanisms involved. We showed that they reduce microbiota diversity and that their composition correlates with the response. We identified SCFA-producing bacterial groups, including Prevotella, Ruminococcus, and Butyricicoccus, as having a relatively higher abundance in the microbiota of patients who responded to CAR T cells. Analysis of butyrate levels revealed a positive correlation with survival, potentially representing a novel biomarker of response. Finally, we found that stimulation of CAR T cells with butyrate induced phenotypic and transcriptomic changes associated with enhanced antitumor efficacy. Conclusions: Our results support the relationship between microbiota and CAR T-cell therapy major outcomes. Analysis of microbiota led to the identification of SCFAs, especially butyrate, as a prognostic factor, and also provides the basis for considering them as chemical modifiers of CAR T cells to improve their efficacy.

The colonic epithelium renews rapidly and must balance proliferation with apoptosis to preserve barrier integrity. We investigated whether grape antioxidant dietary fiber (GADF), a grape pomace-derived dietary fiber matrix naturally rich in high molecular weight non-extractable polyphenols, modulates barrier integrity, through proliferation/cell cycle and apoptosis. To gain mechanistic insight, we examined the role of heat-shock proteins (Hsps), and AMP-activated protein kinase (AMPK)–mTOR–lipid-metabolism signaling in healthy proximal colon. Male Wistar rats received either a cellulose-based control diet or an isoenergetic diet where cellulose was replaced with 5% GADF for four weeks. Morphometric analysis, immunohistochemistry, Western blotting, TUNEL, and caspase activity assays quantified cell cycle, apoptotic, Hsps, and metabolic pathways. GADF strengthened the epithelial barrier, increasing goblet cells, occludin, and ZO-1, while reducing crypt depth. Proliferation was suppressed, as indicated by reduced PCNA, cyclins E and D1, and higher p-p53^Ser392, p21^Cip1/Waf1, and p27^Kip1 levels, consistent with G1 arrest. Apoptosis was attenuated, with increased mitochondrial Bcl-2/Bax and Bcl-xL/Bax ratios, lower cytosolic cytochrome c and apoptosis-inducing factor (AIF), and reduced caspase-9 and caspase-3 activities. Hsp27, but not Hsp70, was selectively induced. GADF activated AMPK and p-Raptor, enhanced ACC1 phosphorylation and CPT1, and supported a shift toward fatty acid β-oxidation. Correlation analysis revealed a strong association between Hsp27 and p-p53^Ser392, suggesting potential links between barrier proteins and metabolic pathways. In conclusion, GADF preserves barrier integrity and redirects metabolism via AMPK–Hsp27 signaling, thereby promoting colonic homeostasis. These findings highlight grape pomace as a sustainable source of functional ingredients for nutritional strategies to reinforce epithelial defenses and reduce disease risk.

Background/Objective: Milk and fermented dairy products are widely consumed functional foods and beverages, offering not only essential nutrients but also bioactive compounds with potential to modulate host immunity, metabolism, and the gut microbiome. This narrative review aims to synthesize current knowledge on the relationship between dairy consumption, gut microbiome, immune modulation, adverse reactions to food, physical performance and cardiometabolic health. Methods: An extensive literature analysis was conducted to explore how milk and fermented dairy products modulate the gut microbiome and influence the immune and cardiometabolic health. This study synthesis focused on key dairy bioactive compounds, such as probiotics, miRNAs, milk-derived peptides and exosomes and on evaluating their proposed mechanisms of action in inflammation and metabolic regulation, and their possible influence on physical performance through gut–microbiome interactions. Additionally, advances in metagenomic and metabolomic technologies were reviewed for their potential to uncover host–microbiota interactions relevant to precision nutrition strategies. Results: Fermented dairy products have shown potential in promoting beneficial bacteria growth such as Lactobacillus and Bifidobacterium, short-chain fatty acid synthesis and reduction in proinflammatory biomarkers. Specific dairy-derived peptides and exosomal components may further support gut barrier integrity, immune regulation and improve physical performance and reduce cardiometabolic risk factors. Additionally, emerging evidence links individual gut microbiota profiles to specific metabolic responses, including tolerance to lactose and bovine milk proteins. Conclusions: Integrating microbiome science with traditional nutritional paradigms enhances our understanding of how dairy influences immune and cardiometabolic health. Overall, current evidence suggests that investigating dairy-microbiome interactions, alongside lifestyle factors such as physical activity, may inform future personalized nutrition strategies aimed at supporting metabolic and immune health.

According to the World Health Organization (WHO), indoor air quality (IAQ) is becoming a serious global concern due to its significant impact on human health. However, not all relevant health parameters are currently regulated. For example, particle number concentration (PNC) and its associated carbonaceous species, such as black carbon (BC), which are classified as carcinogenic by the International Agency for Research on Cancer (IARC), are not currently regulated. Compared with IAQ studies in other types of buildings, studies focusing on IAQ in hospitals or other healthcare facilities are scarce. Therefore, this study aims to evaluate the impact of these outdoor pollutants, among others, on the indoor environment of a hospital under different atmospheric conditions. To identify the seasonal influence, two different periods of two consecutive seasons (summer 2020 and winter 2021) were selected for the measurements. Regulated pollutants (NO, NO2, O3, PM10, and PM2.5) and nonregulated pollutants (PM1, PNC, and equivalent BC (eBC)) in outdoor air were simultaneously measured indoor and outdoor. This study also investigated the impact of indoor activities on indoor air quality. In the absence of indoor activities, outdoor sources significantly contribute to indoor traffic-related pollutants. Indoor and outdoor (I-O) measurements showed similar behavior, but indoor concentrations were lower, with peak levels delayed by up to two hours. Seasonal variations in indoor/outdoor (I/O) ratios were lower for particles than for associated gaseous pollutants. Particle infiltration depended on particle size, with it being higher the smaller the particle size. Indoor activities also significantly affected indoor pollutants. PMx (especially PM10 and PM2.5) concentrations were mainly modulated by walking-induced particle resuspension. Vertical eBC profiles indicated a relatively well-mixed environment. Ventilation through open windows rapidly altered indoor air quality. Outdoor-dominant pollutants (PNC, eBC, and NOX) had I/O ratios ≥ 1. Staying in the room with an open window had a synergistic effect, increasing the I/O ratios for all pollutants. Higher I/O ratios were associated with turbulent outdoor conditions in both unoccupied and occupied conditions. Statistically significant differences were observed between stable (TKE ≤ 1 m2 s−2) and unstable (TKE > 1 m2 s−2) conditions, except for NO2 in summer. This finding was particularly significant when the wind direction was westerly or easterly during unstable conditions. The results of this study highlight the importance of understanding the behavior of indoor particulate matter and related pollutants. These pollutants are highly variable, and knowledge about them is crucial for determining their health effects, particularly in public buildings such as hospitals, where information on IAQ is often limited. More measurement data is particularly important for further research into I-O transport mechanisms, which are essential for developing preventive measures and improving IAQ.

Tetraselmis chuii is a microalga commercialized because of its richness in health-beneficial molecules. Previous studies have profusely demonstrated the biological properties of compounds isolated from T. chuii, but data are not yet available on the impact that gastrointestinal digestion could exert. This article describes the passage of T. chuii through the gastrointestinal tract, combining the INFOGEST procedure and in vitro colonic fermentation to examine potential effects on the human colonic microflora composition and its metabolic activity. Microbial plate counting was conducted to determine the different groups of microorganisms. Amplification of the 16S ribosomal RNA gene was performed via polymerase chain reaction to examine in detail the main genera of bacteria, and its metabolic activity was evaluated by measuring of short-chain fatty acids (SCFAs) by gas chromatography. The presence of T. chuii modified the fecal microbiota. Although the evolution of lactic acid bacteria and Enterococcus spp. content during 72 h showed that the use of T. chuii, compared to fructopolysaccharides such as inulin, would not provide nutritional advantages, the microalgae extract contributed to a significant decrease in Clostridium, Staphylococcus, and Enterobacteriaceae. Furthermore, T. chuii increased the relative abundance of Akkermansia and Butyricimonas, genera considered highly beneficial. In correlation with the presence of these microorganisms, the results show that the presence of T. chuii favored the release of SCFA, such as acetic (20 mM), propionic (>5 mM), isovaleric (0.3 mM), isobutyric (0.15 mM), and, mainly, butyric (>2 mM), after 72 h colonic fermentation, being indicators of gut health. These findings suggest that T. chuii has potential as a functional ingredient for promoting health through its modulatory effects on the intestinal microbiota.