Atherosclerosis (AS) remains a leading cause of cardiovascular disease and mortality globally. This chronic condition is characterized by inflammation, lipid accumulation, and the deposition of cellular components within arterial walls. Emerging evidence has highlighted the multifaceted therapeutic potential of short-chain fatty acids (SCFAs) in mitigating AS progression. SCFAs have demonstrated anti-inflammatory properties and the ability to regulate immune responses, metabolic pathways, vascular integrity, and intestinal barrier function in animal models of AS. Consequently, SCFAs have garnered significant attention as a promising approach for the prevention and treatment of AS. However, further clinical trials and studies are necessary to fully elucidate the underlying mechanisms and effects of SCFAs. Additionally, different types of SCFAs may exert distinct impacts, necessitating more in-depth investigation into their specific roles and mechanisms. This review provides an overview of the diverse cellular mechanisms contributing to AS formation, as well as a discussion of the significance of SCFAs in AS pathogenesis and their multifaceted therapeutic potential. Nonetheless, additional research is warranted to comprehensively understand and harness the potential of various SCFAs in the context of AS.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and emotional instability, primarily resulting from the abnormal accumulation of mutant huntingtin protein. Growing research highlights the role of intestinal microbiota and their metabolites, particularly short-chain fatty acids (SCFAs), in modulating HD progression. SCFAs, including acetate, propionate, and butyrate, are produced by gut bacteria through dietary fiber fermentation and are recognized for their neuroprotective properties. Evidence suggests that SCFAs regulate neuroinflammation, neuronal communication, and metabolic functions within the central nervous system (CNS). In HD, these compounds may support neuronal health, reduce oxidative stress, and enhance blood-brain barrier (BBB) integrity. Their mechanisms of action involve binding to G-protein-coupled receptors (GPCRs) and modulating gene expression through epigenetic pathways, underscoring their therapeutic potential. This analysis examines the significance of SCFAs in HD, emphasizing the gut-brain axis and the benefits of dietary interventions aimed at modifying gut microbiota composition and promoting SCFA production. Further research into these pathways may pave the way for novel HD management strategies and improved therapeutic outcomes.

The free fatty acid receptor 2 (FFA2) is a G protein-coupled receptor (GPCR) that selectively recognizes short-chain fatty acids to regulate metabolic and immune functions. As a promising therapeutic target, FFA2 has been the focus of intensive development of synthetic ligands. However, the mechanisms by which endogenous and synthetic ligands modulate FFA2 activity remain unclear. Here, we present the structures of the human FFA2-Gi complex activated by the synthetic orthosteric agonist TUG-1375 and the positive allosteric modulator/allosteric agonist 4-CMTB, along with the structure of the inactive FFA2 bound to the antagonist GLPG0974. Structural comparisons with FFA1 and mutational studies reveal how FFA2 selects specific fatty acid chain lengths. Moreover, our structures reveal that GLPG0974 functions as an allosteric antagonist by binding adjacent to the orthosteric pocket to block agonist binding, whereas 4-CMTB binds the outer surface of transmembrane helices 6 and 7 to directly activate the receptor. Supported by computational and functional studies, these insights illuminate diverse mechanisms of ligand action, paving the way for precise GPCR-targeted drug design.

This study investigates the gut microbiota components associated with metabolic syndrome in patients living with HIV-1 at Bafoussam Regional Hospital, West Cameroon, it focuses on gastrointestinal mucosal barrier disruption and dysbiosis, and their effects on persistent inflammation and metabolic disorders.

A pilot study was conducted involving fourteen patients living with HIV-1. The patients were divided into two groups of seven in each group. One group consisted of patients with metabolic syndrome, and the other group included patients without metabolic syndrome. Gut microbiota was characterized using 16 S rRNA gene-targeted sequencing to analyze microbial diversity and composition. Beta diversity and the relative abundance of bacterial taxa were compared between patients with and without metabolic syndrome.

Patients living with HIV-1 and metabolic syndrome showed significantly altered beta diversity compared to those without metabolic syndrome. A higher relative abundance of Firmicutes and increased proliferation of Proteobacteria were observed in patients with metabolic syndrome. Additionally, a decrease in metabolically beneficial bacteria, such as Bifidobacterium sp., Lactobacillus sp., Akkermansia sp., and Faecalibacterium sp., was noted. Several beneficial bacterial species were associated with participants' metadata, suggesting potential links between gut microbiota and metabolic syndrome.

This preliminary study highlights that gut microbial balance, rather than the presence of specific bacteria, plays a crucial role in managing metabolic health in patients living with HIV-1. The altered gut microbiota in participants with metabolic syndrome emphasizes the need for further research into the optimal gut microbial structure. Understanding the interaction between gut microbiota changes and the chemical environment in these patients could guide targeted interventions to improve metabolic outcomes.

Recent advancements in multi-omics technologies have provided unprecedented opportunities to identify biomarkers associated with prediabetes, offering novel insights into its diagnosis and management. This review synthesizes the latest findings on prediabetes from multiple omics domains, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, and radiomics. We explore how these technologies elucidate the molecular and cellular mechanisms underlying prediabetes and analyze potential biomarkers with predictive value in disease progression. Integrating multi-omics data helps address the limitations of traditional diagnostic methods, enabling early detection, personalized interventions, and improved patient outcomes. However, challenges such as data integration, standardization, and clinical validation and translation remain to be resolved. Future research leveraging artificial intelligence and machine learning is expected to further enhance the predictive power of multi-omics technologies, contributing to the precision diagnosis and tailored management of prediabetes.

The gut-brain axis, i.e. the bidirectional communication system between the gut and the brain, has become of central importance in Parkinson disease (PD) research over the past 20 years.

We aimed to describe the milestones of the gut-brain axis research in PD and the development of theories proposing the involvement of the gastrointestinal tract in PD pathogenesis.

We searched PubMed using the terms 'gut-brain axis' AND 'Parkinson disease', and selected relevant articles to provide the foundation for reconstructing an historical overview of the gut-brain axis research in PD.

Mounting evidence from preclinical, clinical and post-mortem studies suggests that a subgroup of PD patients present with a range of prodromal symptoms (e.g., autonomic dysfunction, rapid eye movement sleep behaviour disorder) which reflect initial accumulation and later spread of pathological α-synuclein rostrally from the gastrointestinal tract ("body-first" PD). Through neural connections along the gut-brain axis, pathological α-synuclein may spread to the brain, producing clinically manifest disease. Recently, two mechanisms involving the gut-brain axis have attracted increasing attention for their role in PD pathogenesis and progression, namely the perturbation of the composition of the microorganisms living in the gut (the gut microbiome), and the dysfunction of enteroendocrine cells.

Treatments targeting the gut-brain axis, especially the gut microbiome and the enteroendocrine cells pathway, could potentially slow disease progression or even prevent disease onset. Among these, pre/probiotics, faecal microbiota transplantation, and glucagon-like peptide-1 receptor agonists, have entered advanced stages of clinical trials in humans and shown potential symptomatic and disease-modifying effects.

Arginine (ARG) improves meat quality and fat deposition; however, its effects on gut microbiota-mediated lipid metabolism in lambs remain unclear. Twenty-four lambs were divided into control (fed a basal diet) and ARG groups (with 1 % ARG added). In the ARG group, backfat thickness, shear force in the longissimus thoracis (LT) muscle, and C16:0 and SFA contents in the subcutaneous adipose tissue (SAT) were reduced, whereas the eye muscle area, a* value, and intramuscular fat, C18:2n-6c, C20:4n-6, C20:5n-3, and PUFA contents in the LT were elevated. Moreover, the ARG group exhibited higher levels of Prevotella, Akkermansia, Faecalibacterium, SCFAs, and GLP-1 in the colon, and lower serum triglyceride and glucose levels. Interestingly, ARG differentially regulated lipid metabolism in the SAT and LT via the GLP-1R/AMPK and triglyceride metabolism signalling pathways. Overall, ARG addition may optimise gut microbiota composition, fat deposition, and meat quality, providing application guidance for regulating fat deposition in lambs.

Background/Objectives: Sodium acetate (NaA) has demonstrated potential in improving non-alcoholic fatty liver disease (NAFLD) by targeting hepatocytes and Kupffer cells. However, its clinical application is hindered by low oral bioavailability and insufficient liver concentrations. Liposomes, with their capacity to encapsulate water-soluble drugs and be surface-modified, offer a promising solution for targeted oral drug delivery. Methods: We designed NaA-loaded liposomes modified with sodium cholate (SC) and mannose (MAN) (NaA@SC/MAN-LPs) to target hepatocytes and Kupffer cells. Results: The NaA@SC/MAN-LPs had a mean diameter of approximately 100 nm with a positive surface charge. Compared to free NaA, NaA@SC/MAN-LPs significantly extended the serum half-life from 2.85 h to 15.58 h, substantially improving in vivo bioavailability. In vivo distribution studies revealed that NaA@SC/MAN-LPs extended the acetate peak time in the liver from 15 min to 60 min and increased hepatic acetate accumulation to 3.75 times that of free NaA. In in vitro cell experiments, NaA@SC/MAN-LPs significantly reduced the lipid droplet, triglycerides (TG), and total cholesterol (TC) in a fatty acid-induced hepatocyte steatosis model and suppressed proinflammation in a lipopolysaccharide (LPS)-activated Kupffer cell inflammation model. Free NaA effectively improved hepatic lipid deposition in NAFLD mice. Furthermore, NaA@SC/MAN-LPs decreased hepatic TG, TC, and the relative area of lipid droplets by 30.44%, 15.26%, and 55.83%, compared to free NaA. Furthermore, the liposomes reduced macrophage infiltration and pro-inflammatory response. Conclusions: The NaA@SC/MAN-LPs demonstrated effective dual targeting effects on hepatocytes and Kupffer cells, significantly improving the pathogenesis of NAFLD, compared to free NaA. This study provides a new strategy for developing effective and safe oral drugs for NAFLD.

Inflammatory bowel disease (IBD) is associated with a higher risk of developing colorectal cancer, according to the inflammation-dysplasia-cancer (IDC) sequence from inflammation to colitis-associated colorectal cancer (CAC). The objective of this study was to identify and generate a transcriptomic signature and score, related to the IDC sequence, that could ultimately classify dysplasia and cancer in IBD.

Demographics, clinical parameters, histological characteristics, and RNA-sequencing data were evaluated on 134 formalin-fixed paraffin-embedded lesions from 2 independent cohorts of IBD patients with low- or high-grade dysplasia (LGD, HGD) and/or CAC. An ordinal logistic regression screened for significant IDC sequence-associated genes that were computed in a transcriptomic signature score.

Principal component analysis and unsupervised clustering on 1% of the most variable genes showed a good clustering between the 4 lesion groups (Normal Mucosa, Inflamed Mucosa, LGD/HGD, and CAC). A gene signature was identified on 27 genes that correlated with the lesion groups in the exploratory cohort. The most weighted gene in this transcriptomic signature was the long non-coding regulatory RNA KCNQ1OT1, a gatekeeper against genomic instability and transposon activation. Based on the expression of these 27 genes, we built and validated a transcriptomic signature score to classify dysplasia and CAC. The overall accuracy of the transcriptomic signature score was 85.71% in the exploratory cohort and 90.91% in the validation cohort.

We identified a tissue-based transcriptomic score to classify IDC lesions in IBD patients and uncovered some of the pivotal genes in carcinogenesis related to inflammation in IBD.

We aimed to investigate whether gut microbiota could predict the treatment response to pharmacological agents among metabolic dysfunction-associated steatotic liver disease (MASLD) patients without diabetes mellitus (DM), as data are lacking.

We prospectively followed up non-diabetic MASLD patients who used empagliflozin. Clinical, anthropometric, laboratory assessments and magnetic resonance imaging-proton density fat fraction (MRI-PDFF) were performed from baseline to week 52 (EOT). Baseline stool samples were collected, and shotgun DNA metagenomic sequencing was performed to profile microbiome. The primary outcome was treatment response to empagliflozin at EOT, defined as MRI-PDFF decline ≥ 30% at EOT from baseline. Linear discriminant analysis [LDA] effect size was used to identify putative bacterial species. Multivariable logistic regression was used to derive adjusted odds ratio (aOR) of outcome with bacterial species by adjusting for clinical factors.

Twenty-two (48.9%) of 45 patients (median age: 56.9 years [IQR: 51.0-63.2]; male: 23 [51.1%]) achieved treatment response at EOT. There was difference in alpha diversity (Shannon index: p < 0.001; Simpson index: p = 0.001) and beta diversity (p = 0.048) in baseline microbiome between treatment response and non-response groups. Faecalibacterium prausnitzii (log10LDAscore = 4.27), Lachnospira pectinoschiza (log10LDAscore = 3.99), Anaerostipes hadrus (log10LDAscore = 3.98), Roseburia faecis (log10LDAscore = 3.97), Roseburia inulinivorans (log10LDAscore = 3.58) and Agathobaculum butyriciproducens (log10LDAscore = 2.77) were enriched in the treatment response group. L. pectinoschiza (aOR: 34.1; p = 0.015), A. hadrus (aOR:35.0; p = 0.032) and A. butyriciproducens (aOR:22.3; p = 0.023) independently predicted treatment response but not clinical factors. These three species collectively predicted treatment response with AUROC of 0.89 (95% CI: 0.80-0.99).

Certain gut bacterial species, particularly the combination of A. hadrus, L. pectinoschiza and A. butyriciproducens, may predict treatment response to empagliflozin in MAFLD patients without DM.

Disorders of Gut-Brain Interaction (DGBI) are widely prevalent and commonly encountered in gastroenterology practice. While several peripheral and central mechanisms have been implicated in the pathogenesis of DGBI, a recent body of work suggests an important role for the gut microbiome. In this review, we highlight how gut microbiota and their metabolites affect physiologic changes underlying symptoms in DGBI, with a particular focus on their mechanistic influence on GI transit, visceral sensitivity, intestinal barrier function and secretion, and CNS processing. This review emphasizes the complexity of local and distant effects of microbial metabolites on physiological function, influenced by factors such as metabolite concentration, duration of metabolite exposure, receptor location, host genetics, and underlying disease state. Large-scale in vitro work has elucidated interactions between host receptors and the microbial metabolome but there is a need for future research to integrate such preclinical findings with clinical studies. The development of novel, targeted therapeutic strategies for DGBI hinges on a deeper understanding of these metabolite-host interactions, offering exciting possibilities for the future of treatment of DGBI.

Obesity is a major health challenge due to its high prevalence and associated comorbidities. The excessive intake of a diet rich in fat and sugars leads to a persistent imbalance between energy intake and energy expenditure, which increases adiposity. Here, we provide an update on relevant diet-microbe-host interactions contributing to or protecting from obesity. In particular, we focus on how unhealthy diets shape the gut microbiota and thus impact crucial intestinal neuroendocrine and immune system functions. We describe how these interactions promote dysfunction in gut-to-brain neuroendocrine pathways involved in food intake control and postprandial metabolism and elevate the intestinal proinflammatory tone, promoting obesity and metabolic complications. In addition, we provide examples of how this knowledge may inspire microbiome-based interventions, such as fecal microbiota transplants, probiotics, and biotherapeutics, to effectively combat obesity-related disorders. We also discuss the current limitations and gaps in knowledge of gut microbiota research in obesity.

Evidence is accumulating that short-chain fatty acids (SCFAs) produced by the gut microbiota play pivotal roles in host metabolism. They contribute to the metabolic regulation and energy homeostasis of the host not only by preserving intestinal health and serving as energy substrates but also by entering the systemic circulation as signaling molecules, affecting the gut-brain axis and neuroendocrine-immune network. This review critically summarizes the current knowledge regarding the effects of SCFAs in the fine-tuning of the pathogenesis of type 2 diabetes mellitus (T2DM) and insulin resistance, with an emphasis on the complex relationships among diet, microbiota-derived metabolites, T2DM inflammation, glucose metabolism, and the underlying mechanisms involved. We hold an optimistic view that elucidating how diet can influence gut bacterial composition and activity, SCFA production, and metabolic functions in the host will advance our understanding of the mutual interactions of the intestinal microbiota with other metabolically active organs, and may pave the way for harnessing these pathways to develop novel personalized therapeutics for glucometabolic disorders.

Numerous studies indicate that Schisandra chinensis (Turcz.) Baill (SC) has anti-type 2 diabetes mellitus (T2DM) effects, and its processed products are commonly used in clinical practice. However, limited reports exist on the mechanisms of polysaccharides from its vinegar products and their role in T2DM. We purified a novel polysaccharide from vinegar-processed Schisandra chinensis (VSC) and used intestinal microbiota 16S rRNA analysis and metabolomics to study changes in T2DM mice after vinegar-processed Schisandra chinensis polysaccharide (VSP) intervention, aiming to elucidate how VSP alleviates T2DM. VSP has shown significant therapeutic effects in T2DM mice, which can regulate the imbalance of glucose and lipid metabolism, alleviate pancreatic and liver damage, restore the integrity of the intestinal barrier, and inhibit the inflammatory response. Serum metabolomics and microbiological analysis showed that VSP could significantly regulate 104 endogenous metabolites and rectify gut microbiota disorders in T2DM mice. Additionally, VSP enhanced the levels of short-chain fatty acids (SCFAs) and the expression of GPR41/43 in the colon of T2DM mice. Correlation analysis revealed significant correlations among specific gut microbiota, serum metabolites, and fecal SCFAs. Overall, these findings will provide a basis for further VSP development.

Gastrointestinal hormones, such as glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide, and peptide YY (PYY) are important for reducing malnutrition at older ages because they are related to assimilation and feeding behavior. Medium-chain triacylglycerol (MCT) ameliorates metabolic symptoms and frailty in adults; however, whether it has the same effect in old age is unknown. To address this, we examined the changes in insulin and gastrointestinal hormones in aged Brd4 (+/-) mice exhibiting symptoms of old age.

Aged male wild-type and Brd4 (+/-) mice were fed a long-chain triacylglycerol (LCT)- or MCT diet. Feeding, blood glucose, and plasma active GLP-1 protein concentrations were determined at 9 weeks using a meal tolerance test, and those gastrointestinal hormone genes were determined at 10 weeks.

The liver and stomach weights and mRNA expression of Gcg (encodes GLP-1 protein) and Pyy in the colon were lower in LCT-fed Brd4 (+/-) mice than those in LCT-fed wild-type mice; these were restored by the MCT diet. The blood concentration of active GLP-1 protein at 15 and 30 minutes postload was higher in MCT-fed Brd4 (+/-) mice than that in those fed an LCT diet.

Aged Brd4 (+/-) mice showed lower mRNA expression of Gcg and Pyy genes, and active GLP-1 protein secretion in the blood, which were as restored and enhanced with MCT feeding.

The gut microbiome, comprising bacteria, viruses, fungi, and bacteriophages, is one of the largest microbial ecosystems in the human body and plays a crucial role in various physiological processes. This review explores the interaction between the gut microbiome and enteroendocrine cells (EECs), specialized hormone-secreting cells within the intestinal epithelium. EECs, which constitute less than 1% of intestinal epithelial cells, are key regulators of gut-brain communication, energy metabolism, gut motility, and satiety. Recent evidence shows that gut microbiota directly influence EEC function, maturation, and hormone secretion. For instance, commensal bacteria regulate the production of hormones like glucagon-like peptide 1 and peptide YY by modulating gene expression and vesicle cycling in EE cells. Additionally, metabolites such as short-chain fatty acids, derived from microbial fermentation, play a central role in regulating EEC signaling pathways that affect metabolism, gut motility, and immune responses. Furthermore, the interplay between gut microbiota, EECs, and metabolic diseases, such as obesity and diabetes, is examined, emphasizing the microbiome's dual role in promoting health and contributing to disease states. This intricate relationship between the gut microbiome and EECs offers new insights into potential therapeutic strategies for metabolic and gut disorders.

Bee pollen, a natural honeybee product, is hailed as a treasure trove of human nutrition. Among the nourishing substances of bee pollen, the constituents with a low molecular weight (such as phenolic acids and flavonoid glycosides) have been extensively studied in the past decades, whereas the polysaccharides with a relatively high molecular weight have received much less attention. To deepen our understanding of bee pollen polysaccharides, this review summarizes the published findings related to their preparation technologies, structural characteristics and biological activities. Among the preparation technologies, ultrasonic-assisted extraction is currently the most effective technology for the recovery of polysaccharides from bee pollen, because ultrasound can crack the pollen exine into fragments and facilitate the release of polysaccharides present in the pollen intine. The preliminary structures, including the molecular weight and monosaccharide composition, of bee pollen polysaccharides have been widely reported, but their fine structures have not fully elucidated. Moreover, bee pollen polysaccharides have antioxidant, immunomodulatory, and antitumor activities, exhibiting potential application in functional foods. Furthermore, bee pollen polysaccharides can modulate the composition of gut microbiota and promote the production of short-chain fatty acids. It is expected that this review can provide inspiration for the development and utilization of bee pollen polysaccharides.

The vagus nerve is proposed to enable communication between the gut microbiome and the brain, but activity-based evidence is lacking. We find that mice reared germ-free exhibit decreased vagal tone relative to colonized controls, which is reversed via microbiota restoration. Perfusing antibiotics into the small intestines of conventional mice, but not germ-free mice, acutely decreases vagal activity which is restored upon re-perfusion with intestinal filtrates from conventional, but not germ-free, mice. Microbiome-dependent short-chain fatty acids, bile acids, and 3-indoxyl sulfate indirectly stimulate vagal activity in a receptor-dependent manner. Serial perfusion of each metabolite class activates both shared and distinct neuronal subsets with varied response kinetics. Metabolite-induced and receptor-dependent increases in vagal activity correspond with the activation of brainstem neurons. Results from this study reveal that the gut microbiome regulates select metabolites in the intestinal lumen that differentially activate vagal afferent neurons, thereby enabling the microbial modulation of chemosensory signals for gut-brain communication.

The human microbiota, a complex ecosystem of microorganisms, plays a pivotal role in regulating host immunity and metabolism. This review investigates the interplay between microbiota and inflammatory markers, emphasizing their impact on metabolic and autoimmune disorders. Key inflammatory biomarkers, such as C-reactive protein (CRP), interleukin-6 (IL-6), lipopolysaccharides (LPS), zonulin (ZO-1), and netrin-1 (Ntn1), are discussed in the context of intestinal barrier integrity and chronic inflammation. Dysbiosis, characterized by alterations in microbial composition and function, directly modulates the levels and activity of these biomarkers, exacerbating inflammatory responses and compromising epithelial barriers. The disruption of microbiota is further correlated with increased intestinal permeability and chronic inflammation, serving as a precursor to conditions like type 2 diabetes (T2D), obesity, and non-alcoholic fatty liver disease. Additionally, this review examines therapeutic strategies, including probiotics and prebiotics, designed to restore microbial balance, mitigate inflammation, and enhance metabolic homeostasis. Emerging evidence positions microbiota-targeted interventions as critical components in the advancement of precision medicine, offering promising avenues for diagnosing and treating inflammatory and metabolic disorders.

Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone mainly secreted by enteroendocrine intestinal L-cells. GLP-1 is also secreted by α-cells of the pancreas and the central nervous system (CNS). GLP-1 secretion is stimulated by nutrient intake and exerts its effects on glucose homeostasis by stimulating insulin secretion, gastric emptying confiding the food intake, and β-cell proliferation. The insulinotropic effects of GLP-1, and the reduction of its effects in type 2 diabetes mellitus (T2DM), have made GLP-1 an attractive option for the treatment of T2DM. Furthermore, GLP-1-based medications such as GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, have been shown to improve diabetes control in preclinical and clinical trials with human subjects. Importantly, increasing the endogenous production of GLP-1 by different mechanisms or by increasing the number of intestinal L-cells that tend to produce this hormone may be another effective therapeutic approach to managing T2DM. Herein, we briefly describe therapeutic agents/compounds that enhance GLP-1 function. Then, we will discuss the approaches that can increase the endogenous production of GLP-1 through various stimuli. Finally, we introduce the potential of L-cell differentiation as an attractive future therapeutic approach to increase GLP-1 production as an attractive therapeutic alternative for T2DM.

G-protein coupled receptors (GPCRs), the largest family of integral membrane proteins, enable cells to sense and appropriately respond to the environment through mediating extracellular signaling to intercellular messenger molecules. GPCRs' pairing with a diverse array of G protein subunits and related downstream secondary messengers, combined with their ligand versatility-from conventional peptide hormone to numerous bioactive metabolites, allow GPCRs to comprehensively regulate metabolism and physiology. Consequently, GPCRs have garnered significant attention for their therapeutic potential in metabolic diseases. This review focuses on six GPCRs, GPR40, GPR120, GLP-1R, and ß-adrenergic receptors (ADRB1, ADRB2, and ADRB3), with GLP-1R recognized as a prominent regulator of system-level metabolism, while the roles of GPR40, GPR120 and ß-adrenergic receptors in central carbon metabolism and energy homeostasis are increasingly appreciated. Here, we discuss their physiological functions in metabolism, the current pharmacological landscape, and the intricacies of their signaling pathways via G protein and ß-arrestin activation. Additionally, we discuss the limitations of existing GPCR-targeted strategies for treating metabolic diseases and offer insights into future perspectives for advancing GPCR pharmacology.

Numerous recent studies have suggested that the composition of the intestinal microbiota can trigger metabolic disorders, such as diabetes, prediabetes, obesity, metabolic syndrome, sarcopenia, dyslipidemia, hyperhomocysteinemia, and non-alcoholic fatty liver disease. Since then, considerable effort has been made to understand the link between the composition of intestinal microbiota and metabolic disorders, as well as the role of probiotics in the modulation of the intestinal microbiota. The aim of this review was to summarize the reviews and individual articles on the state of the art regarding ideal therapy with probiotics and prebiotics in order to obtain the reversion of dysbiosis (alteration in microbiota) to eubiosis during metabolic diseases, such as diabetes, prediabetes, obesity, hyperhomocysteinemia, dyslipidemia, sarcopenia, and non-alcoholic fatty liver diseases. This review includes 245 eligible studies. In conclusion, a condition of dysbiosis, or in general, alteration of the intestinal microbiota, could be implicated in the development of metabolic disorders through different mechanisms, mainly linked to the release of pro-inflammatory factors. Several studies have already demonstrated the potential of using probiotics and prebiotics in the treatment of this condition, detecting significant improvements in the specific symptoms of metabolic diseases. These findings reinforce the hypothesis that a condition of dysbiosis can lead to a generalized inflammatory picture with negative consequences on different organs and systems. Moreover, this review confirms that the beneficial effects of probiotics on metabolic diseases are promising, but more research is needed to determine the optimal probiotic strains, doses, and administration forms for specific metabolic conditions.

Dietary fiber can suppress excess adipose tissue and weight gain in rodents and humans when fed high fat diets. The gut microbiome is thought to have a key role, although exactly how remains unclear. In a tightly controlled murine study, we explored how different types of dietary fiber and doses affect the gut microbiota and gut epithelial gene expression. We show that 10% pectin and 10% FOS suppress high fat diet (HFD)-induced weight gain, effects not seen at 2% doses. Furthermore, 2 and 10% mixtures of dietary fiber were also without effect. Each fiber treatment stimulated a distinct gut microbiota profile at the family and operational taxonomic unit (OTU) level. Mechanistically it is likely that the single 10% fiber dose shifted selected bacteria above some threshold abundance, required to suppress body weight, which was not achieved by the 10% Mix, composed of 4 fibers each at 2.5%. Plasma levels of the gut hormone PYY were elevated by 10% pectin and FOS, but not 10% mixed fibers, and similarly RNA seq revealed some distinct effects of the 10% single fibers on gut epithelial gene expression. These data show how the ability of dietary fiber to suppress HFD-induced weight gain is dependent upon both fiber type and dose. It also shows that the microbial response to dietary fiber is distinct and that there is not a single microbial response associated with the inhibition of adiposity and weight gain. PYY seems key to the latter response, although the role of other factors such as Reg3γ and CCK needs to be explored.

The gut microbiota plays a crucial role in the communication between the gut, liver, and brain through the production of short chain fatty acids (SCFAs). SCFAs serve as key mediators in the Gut-Liver-Brain Axis, influencing various physiological processes and contributing to overall health. SCFAs are produced by bacterial fermentation of dietary fiber in the gut, and they exert systemic effects by signaling through various pathways. In the Gut-Liver axis, SCFAs regulate liver metabolism through peroxisome proliferator-activated receptor-γ (PPAR-γ), AMP-activated protein kinase (AMPK) and other pathways, promotes fat oxidation, modulate inflammation through mTOR pathway, and impact metabolic health. In the Gut-Brain axis, SCFAs influence brain function, behavior, and may have implications for neurological disorders, in which G-protein coupled receptors (GPCRs) play an essential role, along with other pathways such as hypothalamic-pituitary-adrenal (HPA) pathway. Understanding the mechanisms by which SCFAs mediate communication between the gut, liver, and brain is crucial for elucidating the complex interplay of the Gut-Liver-Brain Axis. This review aims to provide insight into the role of gut microbiota-derived SCFAs as mediators of the Gut-Liver-Brain Axis and their potential therapeutic implications. Further research in this area will be instrumental in developing novel strategies to target the Gut-Liver-Brain Axis for the prevention and treatment of various health conditions.

Metabolic syndrome (Mets) is an important contributor to morbidity and mortality in cardiovascular, liver, neurological, and reproductive diseases. Short-chain fatty acid (SCFA), an organismal energy donor, has recently been demonstrated in an increasing number of studies to be an important molecule in ameliorating immuno-inflammation, an important causative factor of Mets, and to improve lipid distribution, blood glucose, and body weight levels in animal models of Mets. This study reviews recent research advances on SCFA in Mets from an immune-inflammatory perspective, including complications dominated by chronic inflammation, as well as the fact that these findings also contribute to the understanding of the specific mechanisms by which gut flora metabolites contribute to metabolic processes in humans. This review proposes an emerging role for SCFA in the inflammatory Mets, followed by the identification of major ambiguities to further understand the anti-inflammatory potential of this substance in Mets. In addition, this study proposes novel strategies to modulate SCFA for the treatment of Mets that may help to mitigate the prognosis of Mets and its complications.

Objective: In our study, we aimed to investigate the differences in metabolic parameters, serum asprosin and peptide tyrosine tyrosine (PYY) levels in a bipolar disorder manic (BD-M) group, a euthymic group and in healthy controls; we also aimed to evaluate the relationship of asprosin and PYY levels with metabolic parameters and psychopathology in patients. Methods: The study included 54 manic patients, 40 euthymic patients and 39 healthy controls. The sociodemographic characteristics of the participants were recorded, and biochemical parameters and asprosin and PYY levels were measured. The Young Mania Rating Scale (YMRS) and the Hamilton Depression Rating Scale (HAM-D) were completed. Results: Body mass index (BMI) showed significant differences between the three groups (p < 0.001); the lowest was found in the control group and the highest in the euthymic group. Triglyceride levels were significantly higher in the euthymic group compared with the BD-M group and controls (p = 0.003). Glucose levels were significantly higher in the BD-M group compared with euthymic (pmanic-euthymic = 0.008) and controls (pmanic-control < 0.001). Asprosin (pmanic-control < 0.001, peuthymic-control = 0.046, pmanic-euthymic = 0.015) and PYY (pmanic-control < 0.001, peuthymic-control = 0.037, pmanic-euthymic = 0.002) levels were significantly different between the three groups, with the lowest levels in the BD-M group and the highest levels in the control group. The eta squared = 0.18 for asprosin and 0.21 for PYY. In the BD-M group, a moderate negative correlation was found between YMRS and asprosin (r = -0.345; p = 0.011) and PYY (r = -0.376; p = 0.005) levels. ROC analysis results showed that asprosin and PYY could be used to predict the manic period in BD-I (AUCasprosin:0.775; AUCPYY:0.760). After adjusting for asprosin as a covariate using ANCOVA, the difference in PYY between groups remained significant (manic-euthymic groups, p = 0.040; manic-control groups, p = 0.013). Conclusions: The study results revealed that asprosin and PYY levels were low, and metabolic parameters were impaired in the patients. Low asprosin and PYY levels may be indicators of impaired energy homeostasis in BD-I. PYY may be a state marker for manic episodes.

Tryptophan is an essential amino acid that is metabolized in the intestine by gut bacteria into indole derivatives, including tryptamine. However, little is known about which bacterial tryptophan metabolites directly influence obesity. In this study, we identified tryptamine as a bacterial metabolite that significantly reduced fat mass following the intraperitoneal injection of five bacterial tryptophan end-products in a diet-induced obese mouse model. Interestingly, tryptamine, a serotonin analog, inhibited both lipogenesis and lipolysis in adipose tissue, which was further confirmed in a 3T3-L1 adipocyte cell culture study. Moreover, oral tryptamine supplementation markedly reduced fat mass and improved insulin sensitivity in a long-term, high-fat-diet, pair-feeding model. These studies demonstrate the therapeutic potential of tryptamine, a bacterial tryptophan metabolite, in ameliorating obesity and insulin resistance by directly regulating lipogenesis and lipolysis in white adipose tissue.

Cellular senescence, a complex biological process resulting in permanent cell-cycle arrest, is central to aging and age-related diseases. A key concept in understanding cellular senescence is the Hayflick Limit, which refers to the limited capacity of normal human cells to divide, after which they become senescent. Senescent cells (SC) accumulate with age, releasing pro-inflammatory and tissue-remodeling factors collectively known as the senescence-associated secretory phenotype (SASP). The causes of senescence are multifaceted, including telomere attrition, oxidative stress, and genotoxic damage, and they extend to influences from microbial sources. Research increasingly emphasizes the role of the microbiome, especially gut microbiota (GM), in modulating host senescence processes. Beneficial microbial metabolites, such as short-chain fatty acids (SCFAs), support host health by maintaining antioxidant defenses and reducing inflammation, potentially mitigating senescence onset. Conversely, pathogenic bacteria like Pseudomonas aeruginosa and Helicobacter pylori introduce factors that damage host DNA or increase ROS, accelerating senescence via pathways such as NF-κB and p53-p21. This review explores the impact of bacterial factors on cellular senescence, highlighting the role of specific bacterial toxins in promoting senescence. Additionally, it discusses how dysbiosis and the loss of beneficial microbial species further contribute to age-related cellular deterioration. Modulating the gut microbiome to delay cellular senescence opens a path toward targeted anti-aging strategies. This work underscores the need for deeper investigation into microbial influence on aging, supporting innovative interventions to manage and potentially reverse cellular senescence.

This case report presents a 46-year-old woman with type 2 diabetes mellitus (T2DM) who sought to discontinue glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) therapy while maintaining her weight and metabolic health. Her desire to reduce medication dependency, combined with her apprehension about potential metabolic regression following discontinuation of the drug, highlights a challenge often faced by patients managing chronic conditions, and the value of naturopathic adjunctive therapies to support these individuals in their wellness goals. This report details a comprehensive intervention strategy combining probiotics, nutrient supplementation, and lifestyle modifications to address her concerns. Over an 8-week period post-GLP-1 RAs therapy discontinuation, she maintained weight loss, improved glycemic control and lipid profile, demonstrated improvements in micronutrient levels, and experienced improvements in her quality of life. This case contributes to the growing body of evidence suggesting that targeted naturopathic interventions can play a supportive role in managing T2DM and mitigating the reliance on pharmacotherapy without compromising health outcomes.

Despite significant evidence on the anti-diabetic effect of chayote fruit and phenolic compounds, research on the mechanism of chayote (Sechium edule) pectin (CP) regulating blood glucose in type 2 diabetes mellitus (T2DM) is scarce. Therefore, this study aims to explore the potential mechanisms by which CP modulates blood glucose levels through an 8-week administration in db/db mice. The results showed that the CP treatment in db/db mice resulted in an elevation in glucagon-like peptide (GLP-1) secretion, an increase in hepatic glycogen storage, and a decrease in homeostasis model assessment-insulin resistance (HOMA-IR). Western blotting results showed that CP intervention significantly upregulated the expression of phosphatidylinositol 3 kinase (PI3K), phosphorylated protein kinase B (P-AKT) and downregulated the expression of fork-head transcription factor O1(FoxO1), glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Moreover, CP effectively upregulated the protein expression of hepatic G protein-coupled receptor 43 (GPR43) and phosphorylated adenosine 5'-monophosphate (AMP)-activated protein kinase (P-AMPK). Furthermore, CP rearranged the gut microbiota structure by increasing beneficial bacteria (unclassified_Ruminococcaceae, Muribaculaceae, Alloprevotella, Rikenella, and Parabacteroides) and reducing the Firmicutes/Bacteroidetes ratio. Additionally, CP improved the gut barrier by increasing the number and area of goblet cells and significantly upregulating the expression of Claudin-1 and Mucin-2. Overall, these findings suggest that CP regulated blood glucose by activating the gut-liver axis signaling pathway: gut microbiota/ SCFAs/ GLP-1, PI3K/AKT/FoxO1, and GPR43/AMPK/FoxO1. This study provides a scientific basis for the development and application of pectin-based functional foods.

Objectives: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic disorder of the liver and affects many people worldwide. Intestinal bacteria are thought to be involved in the pathological progression of NAFLD; therefore, improving the intestinal microbiota may be important in controlling NAFLD. In this study, we assessed the effects of water-soluble cellulose acetate (WSCA) on the intestinal microbiota in a non-alcoholic steatohepatitis (NASH) mouse model. Methods: NASH model (STAM mice) was created by streptozotocin injection and feeding the mice a high-fat diet. The serum biochemical parameters were analyzed. Intestinal bacterial populations were analyzed using paired-end sequencing of 16S rRNA, 18S rRNA, and internal transcribed spacer gene. Results: Our findings indicated that WSCA administration tends to improve the serum alanine aminotransferase and glucose levels in STAM mice and decreased the alpha diversity and altered the beta diversity of their intestinal microbiota. Additionally, WSCA intake resulted in an increase in the abundance of Coriobacteriaceae_UCG-002 and a decrease in the abundance of Enterobacter. Conclusions: WSCA intake can alter specific microbial compositions to improve blood glucose levels and liver functions and may improve the pathogenesis of NAFLD.

The gut microbiome is a complex system that directly interacts with and influences many systems in the body. This delicate balance of microbiota plays an important role in health and disease and is highly influenced by lifestyle factors and the surrounding environment. As further research emerges, understanding the full potential of the gut microbiome and the impact of using nutraceuticals to positively influence its function may open the door to greater therapeutic outcomes in the treatment and prevention of disease. Curcumin, a bioactive compound derived from the turmeric rhizome, has been studied in depth for its influence on human health as a potent anti-inflammatory and antioxidant properties. However, the therapeutic activity of curcumin is limited by its low oral bioavailability. While most available research has primarily focused on the curcuminoid compounds of turmeric, the non-curcuminoid compounds hold promise to offer therapeutic benefits while synergistically enhancing the bioavailability of curcumin and supporting the gut microbiome. This review summarizes current knowledge of the relationship between the gut and the various systems within the body, and how dysbiosis, or disruption in the gut microbial balance, leads to inflammation and increased risk of chronic disease. The review also summarizes recent research that focuses on the bioactivity of both the curcuminoid and non-curcuminoid compounds that comprise the whole turmeric root and their synergistic role in enhancing bioavailability to support a healthy gut microbiome and promising use in the treatment and prevention of disease.

The intestinal microbiota is a complex community of organisms present in the human gastrointestinal tract, some of which can produce short-chain fatty acids (SCFAs) through the fermentation of dietary fiber. SCFAs play a major role in mediating the intestinal microbiota's regulation of host immunity and intestinal homeostasis. Respiratory syncytial virus (RSV) can cause an imbalance between anti-inflammatory and proinflammatory responses in the host. In addition, changes in SCFA levels and the structure of the intestinal microbiota have been observed after RSV infection. Therefore, there may be a link between SCFAs and RSV infection, and SCFAs are expected to be therapeutic targets for RSV infection.

For a long time, traditional medicine has acknowledged the gut's impact on general health. Contemporary science substantiates this association through investigations of the gut microbiota, the extensive community of microorganisms inhabiting our gastrointestinal system. These microscopic residents considerably improve digestive processes, nutritional absorption, immunological function, and pathogen defense. Nevertheless, a variety of gastrointestinal and extra-intestinal disorders can result from dysbiosis, an imbalance of the microbial composition of the gut microbiota. A groundbreaking discovery is the gut-brain axis, a complex communication network that links the enteric and central nervous system (CNS). This bidirectional communication allows the brain to influence gut activities and vice versa, impacting mental health and mood disorders like anxiety and depression. The gut microbiota can influence this communication by creating neurotransmitters and short-chain fatty acids, among other biochemical processes. These factors may affect our mental state, our ability to regulate our emotions, and the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to explore the complex interrelationships between the brain and the gut microbiota. We also conducted a thorough examination of the existing understanding in the area of how microbiota affects social behaviors, including emotions, stress responses, and cognitive functions. We also explored the potential of interventions that focus on the connection between the gut and the brain, such as using probiotics to treat diseases of the CNS. This research opens up new possibilities for addressing mental health and neurological conditions in an innovative manner.

Mounting evidence indicates that the short-chain fatty acid butyrate protects against obesity and associated comorbidities, partially through the induction of adipose tissue thermogenesis. However, the effects of butyrate on white adipose tissue (WAT) browning and its molecular mechanism are still elusive. The objective of this study was to investigate butyrate-induced thermogenesis in white adipose tissue and its underlying mechanism.

We studied the effects of butyrate on diet-induced obesity in the humanized APOE*3-Leiden.CETP transgenic mouse model and explored factors related to white adipose browning. Specifically, mice were challenged with a high-fat diet supplemented with butyrate. Adiposity was measured to assess obesity development. Energy metabolism was detected using an indirect calorimetry system. RNA-seq analysis was conducted to analyze the transcription landscape of WAT and responsible targets. Furthermore, the revealed molecular mechanism was verified in vitro.

Butyrate alleviated high-fat diet-induced obesity and promoted energy expenditure accompanied by brown adipose tissue activation and WAT browning. Mechanistically, RNA-seq analysis revealed that butyrate downregulated HDAC9 in WAT. Additionally, butyrate decreased HDAC9 while increasing thermogenesis in vitro. Inhibition of HDAC9 with TMP269 promoted thermogenic gene expression, mimicking the effects of butyrate.

Butyrate protects against diet-induced obesity accompanied by decreasing the expression of HDAC9 in white adipose tissue and inducing browning. This study reveals a new mechanism whereby butyrate activates adaptive thermogenesis and provides new insights for the development of weight-loss drugs targeting adipose HDAC9.

Female infertility is a multifactorial condition influenced by various genetic, environmental, and lifestyle factors. Recent research has investigated the significant impact of gut microbiome dysbiosis on systemic inflammation, metabolic dysfunction, and hormonal imbalances, which can potentially impair fertility. The gut-brain axis, a bidirectional communication system between the gut and the brain, also plays a significant role in regulating reproductive functions. Emerging evidence suggests that the gut microbiome can influence brain functions and behavior, further emphasizing the importance of the microbiota-gut-brain axis in reproduction. Given their role as a major modulator of the gut microbiome, diet and dietary factors, including dietary patterns and nutrient intake, have been implicated in the development and management of female infertility. Hence, this review aims to highlight the impact of dietary patterns, such as the Western diet (WD) and Mediterranean diet (MD), and to decipher their modulatory action on the microbiota-gut-brain axis in infertile women. By contrasting the detrimental effects of WD with the therapeutic potential of MD, we emphasize the pivotal role of a balanced diet rich in nutrients in promoting a healthy gut microbiome. These insights underscore the potential of targeted dietary interventions and lifestyle modifications as promising strategies to enhance reproductive outcomes in subfertile women.

Exercise elicits cardiometabolic benefits, reducing the risks of cardiovascular diseases and type 2 diabetes. This study aimed to investigate the vascular and metabolic effects of gut microbiota from exercise-trained donors on sedentary mice with type 2 diabetes and the potential mechanism.

Leptin receptor-deficient diabetic (db/db) and nondiabetic (db/m+) mice underwent running treadmill exercise for 8 weeks, during which fecal microbiota transplantation (FMT) was parallelly performed from exercise-trained to sedentary diabetic (db/db) mice. Endothelial function, glucose homeostasis, physical performance, and vascular signaling of recipient mice were assessed. Vascular and intestinal stresses, including inflammation, oxidative stress, and endoplasmic reticulum (ER) stress, were investigated. RNA sequencing analysis on mouse aortic and intestinal tissues was performed. Gut microbiota profiles of recipient mice were evaluated by metagenomic sequencing.

Chronic exercise improved vascular and metabolic abnormalities in donor mice. Likewise, FMT from exercised donors retarded body weight gain and slightly improved grip strength and rotarod performance in recipient mice. Exercise-associated FMT enhanced endothelial function in different arteries, suppressed vascular and intestinal stresses, and improved glucose homeostasis in recipient mice, with noted microRNA-181b upregulation in aortas and intestines. Altered gut microbiota profiles and gut-derived factors (e.g., short-chain fatty acids and glucagon-like peptide-1) as well as improved intestinal integrity shall contribute to the cardiometabolic benefits, implying a gut‒vascular connection.

This proof-of-concept study indicates that exercised microbiota confers cardiometabolic benefits on sedentary db/db mice, extending the beneficial mechanism of exercise through gut‒vascular communication. The findings open up new therapeutic opportunities for cardiometabolic diseases and shed light on the development of exercise mimetics by targeting the gut microbiota.

The gut and the gut microbiome communicate with the nervous system through the gut-brain axis via neuroimmune and neuroendocrine mechanisms. Despite existing research, studies exploring this link in aging dogs are limited. This study aims to examine multiple blood and fecal biomarkers of intestinal health, along with various behavioral indicators based on saliva, blood, observations, and activity, in different age populations (junior: <2 y.o.; adult: 2-7 y.o.; senior: >7 y.o.) of thirty-seven Beagle dogs. In our study, Bacteroides were significantly higher in senior dogs. The relative abundance of Faecalibacterium and Blautia showed age-related trends, higher in senior and junior dogs, respectively. Fecal short-chain fatty acid concentration, especially acetate, increased with age, while propionate was higher in junior dogs. For the behavioral indicators we considered, blood thyroxine concentration, playing, exploring, and total activity were higher in junior dogs. The differences observed between the biomarkers of gut health and behavior, particularly those significant for the age correlations, emphasize the importance of considering age-related factors when studying the gut microbiome and behavior. However, further research is needed to better understand the mechanisms and specific pathways involved in the relationship between the studied biomarkers and age.