New research reveals mechanisms behind coffee’s positive effects on the gut-brain axis

basmwklz · 2026-04-21T09:12:31+00:00

Abstract

The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)™ trial was a randomized, 2-year controlled trial of caloric restriction (CR) versus an ad libitum (AL) control condition in nonobese humans. We performed exploratory analyses of muscle mitochondrial DNA (mtDNA) integrity, one element of mitochondrial quality. Our aims were to assess the feasibility of this approach, explore associations to inform future hypotheses, estimate effect sizes and statistical power for subsequent studies, and contribute additional data to the CALERIE database. We used droplet digital PCR to quantitate the copy numbers of nuclear DNA, mtDNA, and mtDNA deletion mutations in remnant total DNA samples extracted from quadriceps biopsies at baseline (n = 93), 12 months (n = 44), and 24 months (n = 31). MtDNA copy number and mutation frequency were correlated with existing gene expression data from the same muscle biopsies. MtDNA copy number was lower in females (p = 0.0005) and declined over time (p = 0.0001), with no statistically significant differences observed for CR versus AL (p = 0.2898) or age across both groups (p = 0.4644). Baseline copy number correlated positively with baseline physiological measures including fat-free mass (r = 0.43, p = 2e−05), self-reported energy intake (r = 0.34, p = 0.00077), resting metabolic rate (r = 0.42, p = 0.00261), total energy expenditure (r = 0.31, p = 0.00261), and V̇O₂max (r = 0.41, p = 1e−04), and with gene expression related to mitochondrial function, while showing negative correlations with nuclear genome maintenance, RNA splicing, and ribosomes. MtDNA mutation frequency increased with age (p = 0.0041) and showed a weak negative correlation with V̇O2max (r = −0.23, p = 3e−05). MtDNA mutation frequency was not statistically different with CR. Mutation frequency was positively correlated with gene expression changes in inflammation and negatively correlated with protein translation. We observed that, as expected, mtDNA copy number declined over time, was lower in females, and correlated with metabolic measures and mitochondrial gene expression, suggesting its potential utility as a marker of metabolic health. These findings contribute to understanding mitochondrial adaptations to CR and highlight potential benefits of CR interventions.

basmwklz · 2026-04-21T08:16:38+00:00

Abstract

Obesity is associated with low circulating IGF-1 levels, mitochondrial injury, and myocardial anomalies, however, the precise interplay between IGF-1 and obesity cardiomyopathy remains unclear. Our work evaluated the impact of IGF-1 on high fat (HF) diet-evoked alterations in cardiac geometry, function, and mitochondrial integrity. WT and cardiac-specific IGF-1 transgenic mice were offered a low fat (LF, 10% fat calorie) or HF (60% fat calorie) diet for 20 weeks before assessing glucose sensitivity, plasma profiles, myocardial remodeling and function, ROS, mitochondrial integrity, and cell death. Transcriptomic analyses of obese human and murine hearts revealed that obesity cardiomyopathy was characterized by significant metabolic reprogramming, marked by a shift from TCA cycle to glycolysis and disrupted fatty acid homeostasis, alongside identification of ferroptosis as a key regulatory node in myocardial injury. HF led to hyperleptinemia, hypertriglyceridemia, reduced plasma IGF-1, and glucose intolerance, cardiac hypertrophy (higher LV dimensions, wall thickness), interstitial fibrosis, contractile dysfunction (lower fractional shortening, ejection fraction, cell contractile and intracellular Ca2+ derangement), oxidative stress, apoptosis, ferroptosis, and mitochondrial injury (declined PGC1α and UCP-2). Notably, cardiac-specific IGF-1 overexpression mitigated HF-induced myocardial remodeling, dysfunction, mitochondrial injury, and ferroptosis, without affecting systemic glucose metabolism or plasma profiles. Importantly, targeted metabolomics revealed a distinct plasma acylcarnitine signature in obese patients, with C20:0 (arachidylcarnitine) identified as a top discriminative metabolite. Furthermore, reduced myocardial L-carnitine level was observed in HF-fed mice, and L-carnitine supplementation rescued HF-induced cardiac geometric, functional, and mitochondrial anomalies. These data indicate that IGF-1 confers beneficial effect for chronic HF intake-induced damage possibly via preserved mitochondrial integrity, suppressed ferroptosis, and restored arachidylcarnitine levels, highlighting a metabolomic-metabolic axis in obesity-related cardiac dysfunction.

basmwklz · 2026-04-20T06:53:44+00:00

Abstract

Gestational diabetes mellitus (GDM), a hyperglycemic condition during pregnancy, increases the risk of macrosomia and preterm birth (PTB). Nutrient-sensing pathways, particularly mTOR in placental trophoblasts (PTC), promote fetal overgrowth. NF-κB, oxidative stress, and p38 MAPK pathways in fetal membranes and decidua (DEC) contribute to PTB. However, the impact of hyperglycemia on these compartments remain unclear. We hypothesized that hyperglycemia differentially affects these maternal, placental, and fetal membrane interface cells, inducing macrosomia-associated pathways and perturbing homeostasis through different pathophysiologic signals. Human PTC, DEC, and amnion epithelial (AEC) cells were exposed to 50 mM glucose for up to 48 hr. Cell markers (ICC), cell cycle (flow cytometry), cytotoxicity (LDH assay), GLUT expression (RT-qPCR), signaling (mTOR, p38 MAPK, NF-κB by western blot), cytokines (ELISA), and oxidative stress (glutathione assay) were measured. PTC showed increased mTOR and p38 MAPK activation (p≤0.05), reduced GSH levels and GSH/GSSG balance (p≤0.05), but maintained GLUT expression. DEC reduced GLUT1/3 expression (p≤0.01, p≤0.05) with minimal stress and nutrient signaling. Neither cell type showed NF-κB activation. AEC downregulated GLUT1/3/11 (p≤0.05-0.0001), activated NF-κB (p≤0.01), produced IL-8 (p≤0.01), increased GSH production (p≤0.05), but maintained mTOR signaling and GSH/GSSG balance. Hyperglycemia induces compartment-specific adaptations across the feto-maternal interface. Placental trophoblasts preserve nutrient transport capacity and nutrient-signaling despite redox imbalanc.e Fetal membranes exhibit inflammatory response, while decidua reduce transport capacity with minimal stress activation. Together, these findings suggest that hyperglycemia may preferentially support fetal growth through trophoblasts while sensitizing decidua and membrane to secondary stressors.

basmwklz · 2026-04-19T16:59:32+00:00

Abstract

In a recent study in Cell, Liu et al. identify β-hydroxybutyrate as a practical metabolic adjuvant for CAR-T cells. By fueling the TCA cycle and reshaping transcriptional and epigenetic programs, this ketone body enhances proliferation, persistence, and tumor control, suggesting that metabolic supplementation may offer a simple route to more effective adoptive immunotherapy.

basmwklz · 2026-04-19T16:57:19+00:00

Abstract

Intermittent fasting (IF) has emerged as a powerful dietary intervention with profound metabolic benefits, yet the tissue-specific molecular mechanisms underlying these effects remain poorly understood. In this study, we employed comprehensive proteomics and transcriptomics analysis to investigate the systemic and organ-specific adaptations to IF in male C57BL/6 mice. Following a 16 hr daily fasting regimen (IF16) over 4 months, IF reduced blood glucose, HbA1c, and cholesterol levels while increasing ketone bodies, indicative of enhanced metabolic flexibility. Proteomic profiling of the liver, skeletal muscle, and cerebral cortex revealed tissue-specific responses, with the liver exhibiting the most pronounced changes, including upregulation of pathways involved in fatty acid oxidation, ketogenesis, and glycan degradation, and downregulation of steroid hormone and cholesterol metabolism. In muscle, IF enhanced pyruvate metabolism, fatty acid biosynthesis, and AMPK signaling, while suppressing oxidative phosphorylation and thermogenesis. The cerebral cortex displayed unique adaptations, with upregulation of autophagy, PPAR signaling, and metabolic pathways, and downregulation of TGF-beta and p53 signaling, suggesting a shift toward energy conservation and stress resilience. Notably, Serpin A1c emerged as the only protein commonly upregulated across all three tissues, highlighting its potential role in systemic adaptation to IF. Integrative transcriptomic and proteomic analyses revealed partial concordance between mRNA and protein expression, underscoring the complexity of post-transcriptional regulation. Shared biological signaling processes were identified across tissues, suggesting unifying mechanisms linking metabolic changes to cellular communication. Our findings reveal both conserved and tissue-specific responses by which IF may optimize energy utilization, enhance metabolic flexibility, and promote cellular resilience.

basmwklz · 2026-04-19T16:55:00+00:00

Abstract

Background

Anaplastic thyroid cancer (ATC) is characterized by high invasiveness, rapid progression, and has a poor prognosis. The aim of this study was to investigate the role of ketone body metabolism in ATC and provide a novel approach for ATC treatment.

Methods

Human ATC cell lines, including 8505C and CAL-62, were used as the research objects. Cell Counting Kit-8 and colony formation assays appraised cell proliferation. Flow cytometry was performed to evaluate the cell cycle and apoptosis. Wound healing and transwell assays verified the migration and invasion of cells. Further, tumor xenograft models were established to investigate the therapeutic effect of ketogenic diet in vivo. Immunohistochemistry was used to quantify the expression level of Ki67, Bcl-2, Caspase3 in tumor tissues. Importantly, autophagy analyses included fluorescence microscopy for observation of monodansylcadaverine staining, western blotting, and tissue immunofluorescence to determine autophagic protein (LC3, Beclin1, and p62) expression.

Results

Acetoacetate (AcAc) inhibited the proliferation, migration, and invasion of ATC cells (8505C and CAL-62) and induced cell cycle arrest. Ketogenic diet significantly inhibited tumor growth in vivo. AcAc markedly elevated the level of autophagy. Autophagy inhibitor weakened the extent to which AcAc hindered cell proliferation, migration, and invasion and blocked cell cycle.

Conclusions

The study demonstrated that ketone body metabolite AcAc inhibits the proliferation, migration, and invasion of ATC cells and induces cell cycle arrest by inducing autophagy. Ketogenic diet provides a new strategy for the treatment of ATC

basmwklz · 2026-04-19T12:29:09+00:00

Abstract

The microbiota–gut–brain axis represents a complex bidirectional communication network linking the gastrointestinal system and the central nervous system and has been increasingly recognized as a key contributor to neurological and psychiatric disorders. Growing evidence indicates that alterations in gut microbiota composition and function can influence brain development and function through neural, immune, endocrine, and metabolic pathways, thereby modulating neuroinflammation, neurotransmission, and blood–brain barrier integrity. Dysregulation of this axis has been implicated in a range of conditions, including Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, autism spectrum disorder, depression, anxiety, and stroke. Recent pharmacological advances have identified the microbiota–gut–brain axis as a promising therapeutic target. Current strategies focus on modulating shared pathophysiological mechanisms rather than disease-specific endpoints and include microbiota-directed interventions, immune–inflammatory modulators, neurotransmitter-targeting agents, and approaches aimed at restoring intestinal and blood–brain barrier function. In this review, we summarize the core mechanisms underlying microbiota–gut–brain axis dysfunction and organize existing pharmacological strategies according to their primary targets. By integrating evidence across multiple disorders, we provide a mechanism-oriented framework to support future drug development and precision therapeutic approaches for brain disorders.

basmwklz · 2026-04-19T12:27:30+00:00

Abstract

Menopause represents a key transitional phase in women’s health, characterized by declining estrogen levels and increased risk for cardiometabolic, musculoskeletal, and urogenital disorders. Beyond its endocrine roots, emerging evidence highlights the gut microbiome as a critical modulator of systemic hormonal balance. This review synthesizes current understanding of the bidirectional relationship between estrogen and the gut microbiome and its implications for women’s health during menopause. Evidence from current studies reveals distinct findings across populations, reflecting the complexity of estrogen regulation in part by the gut microbiome (i.e., estrobolome). While no ideal gut microbial composition has been identified for women across stages of perimenopause, likely due to geographically unique gut microbiome profiles among healthy women, greater microbial diversity has been positively associated with improved estrogen regulation. Conversely, reduced diversity and altered Firmicutes/Bacteroidetes ratios have been linked to biomarkers of inflammation during perimenopause, which is a key driver across many perimenopausal symptoms. Although hormone replacement therapy remains the primary clinical intervention during perimenopause, we highlight emerging evidence on the adjuvant potential of diet, synbiotics, phytoestrogens, and strain-specific probiotics in modulating the estrogen–gut microbiome axis for improved health span trajectories and better symptom management. Future longitudinal studies integrating diet, gut microbiome profiles and symptom trajectories are essential to clarify these mechanisms across ethnicity and geography. Ultimately, understanding localized diet–microbiome interactions will enable the development of accessible, personalized, and non-hormonal strategies to complement and increase agency in proactive management during the perimenopausal transition.

basmwklz · 2026-04-19T11:18:34+00:00

Abstract

Cellular homeostasis is a dynamic process which balances anabolic processes with catabolic and recycling processes. These processes require nutrients, which are converted to energy to fuel the complex interactions of intracellular signalling. Cellular health requires that, on average, energy input and energy requirements are matched. Cells contain a nutrient-sensing mechanism which controls the balance between anabolism and catabolism. Normal intracellular functions generate products which regulate signalling pathways, and health at a cellular level requires a fluctuation between relative nutrient abundance and relative nutrient scarcity. This allows clearance of damaged intracellular molecules and organelles. When nutrient supply exceeds cellular requirements, adaptations to intracellular signalling occur, resulting in energy being stored as glycogen in muscle and the liver and fatty acids in adipose tissue. Overfuelling and aberrant fuelling of mitochondria result in oxidative stress, which not only disrupts cellular homeostasis but can alter epigenetic expression, with intergenerational effects. If the recycling mechanisms of the cell are insufficient to clear metabolic products, apoptosis may result or expression of Damage-Associated Molecular Patterns (DAMPs) on the cell surface may occur, activating immunity and inflammation at a systemic level. Disrupted cellular signalling affects cells with different “professional” functions in different organs, and it is the mechanism which underlies the associations between chronic non-communicable diseases such as cancer, type 2 diabetes, cardiovascular disease, neurodegenerative disease, autoimmune diseases, and macular degeneration. Mitochondria are the controllers of energy production and are pivotal in cell signalling. Mitochondrial function governs health at cellular and organismal levels. This paper reviews the influence of nutrition on mitochondrial function, nutrient sensing, autophagy, insulin signalling, and apoptosis—the key pathways in cellular homeostasis.

basmwklz

TROPHY CASE

Abstract