This report summarizes the deliberations of a working group convened by the International Scientific Association for Probiotics and Prebiotics (ISAPP) at their 2025 annual meeting to identify the key targets that mediate the host response to biotics. Probiotics, prebiotics, synbiotics, and postbiotics have been explored in numerous contexts, but results of clinical trials are mixed. In most studies performed to date, a therapeutic product and its dose and administration strategy were selected based on factors other than rigorous mechanistic evidence. Given recent advances in our understanding of interactions between biotics, the host, and the gut microbiome, we sought to determine whether a more rational, informed approach might now guide the more precise selection of a biotic for a specific indication. The panel addressed biotic modulation of the immune system, host metabolism, the enteric nervous system, human commensal microbes, and the gut-brain axis and developed five recommendations to increase the likelihood that biotic interventions will lead to meaningful clinical impacts. Interventions should: (1) strive to modulate or refine, rather than "boost," host metabolism and the immune system to achieve specific outcomes; (2) consider the human metabolome, in addition to the microbiome, as a readout and therapeutic target; (3) determine context-dependent responses to biotics in terms of spatial location within the gut, host genetics, environmental influences, and diet; (4) explore a wide range of microbial fermentation substrates that yield biologically active products in addition to prebiotic fibers; and (5) leverage new approach methods including ex vivo human tissue-based approaches, novel in vitro methods, and advanced computational tools including artificial intelligence to complement human studies. The roadmap proposed by this panel aims to accelerate the translation of biotic research into discoveries that will more readily impact clinical practice.

This multicenter, parallel-arm, superiority, randomized, double-blind, placebo-controlled study evaluates the efficacy of Totum-63 (T63), a polyphenol-rich blend of plant extracts, in improving fasting plasma glucose (FPG) in individuals with prediabetes or early-stage type 2 diabetes (T2D). Individuals from seven European countries with FPG between 110-220 mg/dL were randomized to receive placebo (PBO, n = 210), T63 (5 g/d) distributed thrice daily (T63 TID, n = 212) or twice daily (T63 BID, open-label arm, n = 214) over six months. Individuals were randomly assigned using a dynamic randomization algorithm, stratified by their glycemic status at baseline (FPG < 126 mg/dL or FPG ≥ 126) and the investigational site country. The primary outcome was the FPG change in T63 TID compared to PBO in the intention-to-treat population. Secondary assessments included changes in diabetes biomarkers, lipid profile, anthropometric measurements and subpopulation analyses based on glycemic status. During the whole study, neither the investigators nor the subjects were aware of the product they tested, except in the open arm. After six months, FPG was significantly reduced in the T63 TID group (PBO-adjusted mixed model estimated difference, PBO-AD = -3.8 mg/dL, 95% CI: [-5.9; -1.7], p = 0.0149) and the T63 BID group (PBO-AD = -5.5 mg/dL, 95% CI: [-9.7; -1.3] p < 0.001). Hence, T63 may represent a non-pharmaceutical strategy for T2D prevention. ClinicalTrials.gov Identifier: NCT04423302. Funding: This trial was funded by Valbiotis®.

Red raspberries have been shown to exert beneficial effects on immunometabolic health in numerous studies; however, these effects are subject to interindividual variability. Building on a previous transcriptomic-based clustering analysis from an 8-week randomized controlled trial in which 24 individuals consumed 280 g of red raspberries daily, we investigated whether functional metagenomic profiling may enhance our understanding of the observed interindividual variability in metabolic responses. Participants were classified as responders (n = 13) or non-responders (n = 11) based on prior clustering approaches, which identified significant reductions in plasma levels of C-reactive protein (CRP), triglycerides, and total cholesterol in responders. Microbial DNA extracted from fecal samples collected before and after the intervention was sequenced, and carbohydrate-active enzyme (CAZyme) counts were generated using a bioinformatics pipeline. Differential analysis revealed distinct functional metagenomic profiles between responders and non-responders. Multiple linear regressions identified potential associations between baseline CAZyme levels and changes in CRP, with contrasting trends observed between responders and non-responders. CBM8 and CBM49 were among the highlighted CAZymes. GH5 and several GH5 subfamilies were also identified as candidate CAZymes associated with interindividual variability observed in metabolic responses. These findings support the integration of microbiome-derived functional data alongside other omics to improve precision nutrition strategies.

Nutritional strategies to mitigate obesity and type 2 diabetes (T2D) have largely focused on dietary fat and carbohydrate composition, with less attention given to protein sources. While total dietary protein intake is recognized as an important modulator of energy balance and glucose metabolism, it remains unclear how the composition of dietary proteins can influence energy metabolism and body weight gain. Here, we investigated the metabolic effects of three distinct protein sources from meat (pork), dairy (casein) and plant (soy) on either a low-fat low sucrose (LFLS) or a high-fat high sucrose (HFHS) diet. While protein sources failed to influence metabolic homeostasis on LFLS, mice kept on the HFHS diet were distinctly impacted by the dietary protein sources. Pork and to a lesser extent soy protein feeding exacerbated obesity, glucose intolerance, and hepatic insulin resistance. Remarkably, livers of mice fed pork or soy protein on the HFHS diet were characterized by extensive microvesicular steatosis compared to the predominant macrovesicular steatosis in HFHS fed mice fed casein protein. Liver transcriptomic and metabolomic signatures in pork and soy protein fed mice were consistent with increased mitochondrial beta-oxidation. Intake of pork and soy proteins in HFHS fed mice lead to a striking reduction in hepatic acetyl CoA carboxylase 2 (ACC2) protein levels relative to casein fed HFHS mice. Pork and soy feeding raised carnitine exposure in the post-prandial period and we determined that exposure of hepatocytes to carnitine provokes downregulation of ACC2 and hepatic insulin resistance in the presence of palmitate:oleate and fructose. Collectively, these findings identify a novel mechanism by which dietary proteins modulate obesity and associated metabolic disturbances through a carnitine-mediated regulation of ACC2 protein and mitochondrial lipid handling in liver.

Metabolic dysfunction-associated steatotic liver disease (MASLD), type 2 diabetes (T2D), and cardiovascular disease (CVD) constitute a tightly interconnected axis that drives global cardiometabolic mortality. Yet their causal and temporal relationships remain difficult to disentangle. Here, we introduce a humanized mouse platform that integrates a fast-food mimicking diet (FFMD), thermoneutral housing, and genetic diversity within a sex-aware framework to resolve the hierarchy between MASLD, T2D, and CVD. FFMD feeding increases liver weight fourfold and rapidly induces severe, fully penetrant steatohepatitis (MASH) and marked hyperinsulinemia in wild-type mice, outperforming standard Western diets. Despite comparable body weight, liver fat, and liver enzymes, weight-matched diabetic db/db mice, develop MASH in only 27% of cases, compared to 100% in FFMD-fed wild-type mice, thereby uncoupling advanced liver disease from overt diabetes. Longitudinal and crossover studies in CVD-prone mice further reveal that ambient temperature dictates the transition from early MASLD to cirrhosis and aortic mineralization, implicating MASH - rather than T2D - as the main driver of advanced cardiohepatic injury. Together, this model positions ambient temperature as a tunable determinant of disease progression and provides a translational platform to interrogate and therapeutically target the MASLD-T2D-CVD triad.

Background: Inflammatory bowel disease is a complex intestinal inflammatory disorder linked to immune dysregulation, oxidative stress, and an imbalance in the gut microbiota. Grape seed flour (GSF), a winemaking by-product rich in polyphenols and fibres, displays antioxidant and anti-inflammatory properties and may help maintain gut homeostasis. Methods: The phenolic composition and antioxidant capacity of our GSF were evaluated. We assessed whether a diet containing 10% (w/w) GSF protects against dextran sulphate sodium (DSS)-induced acute colitis in BALB/c mice. Animals received either a standard diet or a GSF-supplemented diet before and during DSS exposure. Body weight and disease activity index were monitored. At sacrifice, colon length and colonic histology scoring were measured. The study of the faecal microbiota and predicted genome was performed using PICRUSt. Caecal metabolites, including short-chain fatty acids, were also quantified. Results: GSF is rich in fibres (64%) and exhibits a very high polyphenolic content and high antioxidant capacity. GSF supplementation attenuated DSS-induced weight loss and disease activity and limited colonic shortening and histological damage. It also improved biomarkers of colon, mesenteric lymph nodes (MLNs), and liver injury. At the molecular level, GSF downregulated key pro-inflammatory mediators in the colon and liver, while enhancing anti-inflammatory (e.g., IL-10) and antioxidant markers, indicating reinforcement of regulatory and redox-protective pathways along the gut–liver axis. At the gut microbiota level, GSF supplementation modulated α-diversity. Further analysis demonstrated that GSF reshaped the GM profile by preventing the blooming of some taxa, including UBA1819, Akkermansia, and Bacteroides caecimuris, and enriching butyrate-producing bacteria, such as Muribaculaceae and Ruminococcus. These shifts were accompanied by lower acetone and ethyl acetate levels and higher indole levels, which are known to support epithelial barrier integrity and mucosal homeostasis. Conclusions: Overall, GSF mitigates DSS-induced colitis through combined actions on inflammatory signalling, oxidative stress, immune regulation, microbiota composition and microbiota-derived metabolites, supporting its potential as a functional prebiotic ingredient for intestinal health.

Src homology region 2-containing phosphatase 1 (SHP-1), encoded by the protein tyrosine phosphatase non-receptor type 6 (PTPN6), regulates immune and metabolic signaling pathways. Although its functions in immune cells and insulin-responsive tissues are separately established, its integrative function in immunometabolic regulation remains unclear. A damaging variant in the PTPN6 gene (Ala455Thr) was discovered in a French-Canadian family and found to be the cause of early-onset emphysema. Using mice carrying this whole-body human-relevant mutation, we studied immunometabolic phenotypes across aging. Old mutant mice showed decreased body, liver and adipose tissue weights, improved glucose tolerance, and enhanced hepatic insulin sensitivity. Despite improved metabolic parameters, aged mutant mice developed liver abnormalities, including increased fibrosis and aberrant immune cell infiltration. Transcriptomic and histological analyses revealed an age-associated accumulation of intrahepatic B lymphocytes and macrophages, accompanied by increased SHP-1 protein levels and activation of Signal transducer and activator of transcription 3 (STAT3) signaling. Experiments in primary hepatocytes and old hepatocyte-specific Ptpn6 knockout mice suggest that these alterations are driven by immune rather than intrinsic hepatocyte mechanisms. These findings identify SHP-1 as a critical modulator of liver immune homeostasis during aging and demonstrate that immune cell infiltration contributes to age-related hepatic remodeling under SHP-1 deficiency.

Dietary polyphenols, including proanthocyanidins, have emerged as potential modulators of metabolic health. Evidence supports benefits on glucose and hepatic metabolism in diet-induced obesity. However, reported effects vary widely across polyphenol sources and experimental design, and the key physiological mediators of benefit in established obesity remain incompletely defined. Moreover, ambient temperature, a key determinant of metabolic phenotype that may influence therapeutic responses, is rarely considered. Here we aim to determine the metabolic effects and mechanisms of action of a proanthocyanidin-rich cranberry extract (PRCE) in established diet-induced obesity under cold (10°C) and thermoneutral (30°C) housing conditions. Male mice with established obesity were supplemented with PRCE or vehicle while housed at 10°C or 30°C. Metabolic phenotyping included body composition, glucose homeostasis, intestinal carbohydrate digestion and glucose absorption, circadian profiling of peripheral and central clocks, and gut microbiota analysis. PRCE supplementation significantly improved glycemia and glucose tolerance independently of temperature, without altering body weight, adiposity, thermogenic gene expression, or circadian expression of clock genes centrally and peripherally. Mechanistically, PRCE inhibited α-amylase activity and delayed early intestinal glucose absorption. These effects were accompanied by selective remodeling of the gut microbiota, including increased abundance of Akkermansia muciniphila. We conclude that PRCE improves glucose homeostasis in established obesity through intestinal mechanisms involving reduced carbohydrate digestion, delayed glucose absorption, and selective remodeling of the gut microbiota.

Industrialization alters the gut microbiome, increasing chronic disease risk. In a recent study published in Cell, Li et al. show that a diet mimicking non-industrialized patterns ("Restore" diet) enhances Limosilactobacillus reuteri persistence and improves microbiome-derived metabolites, leading to cardiometabolic benefits and highlighting the potential of interventions aimed at restoring the gut microbiota.

BACKGROUND:Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve metabolic and cardiovascular outcomes, but the mechanisms remain incompletely understood. We utilized cardiovascular magnetic resonance (CMR) and complementary methods to investigate whether preventive SGLT2 inhibitor administration attenuates the development of metabolic heart disease in a high-fat, high-sucrose diet (HFHSD) mouse model. METHODS:Male wild-type (WT) C57BL/6 J mice were fed an HFHSD for 18 weeks to induce obesity, coronary microvascular disease, and diastolic dysfunction. WT mice treated preventively with an SGLT2 inhibitor, empagliflozin (EMPA), were compared to untreated WT mice, and mice fed either an HFHSD or standard chow diet with myeloid cell-specific knockout of the Nos2 gene (Nos2LysMCre) were compared to floxed controls (Nos2fl/fl). CMR assessed epicardial adipose tissue (EAT) volume, fatty acid composition (FAC), proton density fat fraction (PDFF), and T1, and myocardial perfusion, and strain. EAT FAC, PDFF, and T1 were quantified using an inversion-recovery multi-echo gradient-echo sequence and a multi-resonance triglyceride model. EAT volume was quantified using cine images. Myocardial perfusion reserve (MPR) and strain were measured using arterial spin labeling, and displacement encoding with stimulated echoes (DENSE), respectively. Histology and flow cytometry assessed EAT remodeling and macrophage polarization. RESULTS:EMPA treatment reduced EAT volume (0.36±0.18 µL/g vs 0.61±0.25 µL/g, p<0.01) and saturated fatty acid fraction (38.81 [32.83-47.71]% vs 48.06 [43.82-52.65]%, p<0.05), increased EAT T1 (0.799 [0.764-0.859] s vs 0.755 [0.678-0.772] s, p<0.05), and decreased EAT NOS2+ macrophages (34.74 [21.38-42.098]% vs 46.36 [38.08-61.30]%, p<0.05) compared to controls. EMPA improved diastolic strain rate (2.96 [2.61-3.99] s-1 vs 1.68 [1.21-2.80] s-1, p<0.01) and adenosine MPR (2.00±0.54 vs 1.37±0.40, p<0.01) compared to controls. Myeloid cell NOS2 knockout mice fed an HFHSD exhibited improved adenosine MPR (1.90±0.47 vs 1.39±0.38, p<0.01) compared to floxed controls. CONCLUSIONS:In this obesity-related metabolic heart disease model, EMPA treatment prevents cardiometabolic dysfunction by improving EAT quantity and quality, coronary microvascular function, and diastolic function. These benefits are mediated in part through macrophage NOS2.

Obesity, characterized by chronic low-grade inflammation, promotes numerous complications such as type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD). A class of lipid mediators known as specialized pro-resolving mediators (SPMs) has garnered interest in this field due to their capacity to promote the resolution of inflammation. One such SPM is Protectin DX (PDX), the stereoisomer of Protectin D1 (PD1). We previously reported that PDX treatment protects against lipid-induced and obesity-linked insulin resistance and attenuates end-stage renal failure in T2D animal models. Our group recently developed a cost-efficient synthesis of PDX and structural analogues to accelerate research on PDX functions and to scale up the production of these molecules to facilitate their pharmaceutical development. After synthesizing and screening over 30 PDX analogues for their bioactivity in relevant cellular models, two analogues, AN-44 and AN-48, were selected for their ability to reduce macrophage inflammation and stimulate muscle glucose uptake in vitro. Since AN-48 also lowers plasma TNF-α in a hamster model of metabolic endotoxemia, it was selected for longer-term in vivo studies. AN-48 (50 ng/g) administered orally daily was found to fully prevent hepatic triglyceride accretion in diet-induced obese hamsters. AN-48 also prevented fasting hyperinsulinemia, insulin resistance, and reduced hepatic inflammation as compared to vehicle or PDX treatments. These results identify AN-48 as a cost-efficient and novel PDX analogue with high therapeutic potential against obesity-linked T2D and MASLD.

Cranberry juice (CJ), a natural source of anthocyanins, may provide additional health benefits when enriched, as anthocyanins have been shown to influence gut microbiota composition. This study investigated the effects of varying anthocyanin and mineral concentrations in CJ on gut microbiota in mice. Using electrodialysis with filtration membranes (EDFM), five CJ samples with different anthocyanin/mineral enrichment levels (0/0, −31/−85%, −19/−70%, 26/−32%, and 44/−60%) were produced and administered to C57BL/6J mice for four weeks. Gut microbiota composition was analyzed via 16S rRNA sequencing, and inflammation was determined in macroscopic observations of intestinal tissues. While α and β diversity remained unchanged, differential abundance analysis revealed that gut microbiota changes were influenced by anthocyanin and mineral concentrations. Synergistic trends were observed for Colidextribacter and Oscillibacter (increasing with both compounds) and for Turicibacter, Romboutsia, Enterorhabdus, and Bifidobacterium (decreasing with both compounds). Antagonistic trends emerged for Dubosiella, Acetatifactor, A2, Ruminococcus, and Intestinimonas (decreasing with anthocyanins and increasing with minerals), and the reverse was found for Ligilactobacillus. The most significant microbiota shifts occurred with the −31/−85% CJ, suggesting a strong effect of its low anthocyanin and mineral content. But further analysis is needed to assess their metabolic effects and impact on intestinal health.

Research and clinical experience in nutrition have emphasized the merits of some dietary patterns, e.g., the Mediterranean diet, to obtain health-related benefits. This has also been the case of specific foods such as yogurt which has been tested using different approaches and under various conditions. As described in this paper, there is a quasi-consensus among population studies about the protective relationship of regular yogurt consumption with incidence of overweight and type 2 diabetes. This is concordant with laboratory-based experimentation and clinical trials showing that yogurt consumption induces favorable effects on many key components of metabolic homeostasis and energy balance. The benefits of yogurt consumption also seem to be partly explained by its status of fermented food which involves the influence of yogurt on the gut microbiota and the reciprocal role of some bacterial-derived molecules on metabolic regulation. In clinical nutrition, novel education approaches benefit from the versatility of yogurt and its high nutrient density to promote healthy eating behaviors and habits as well as cardiometabolic benefits. In summary, yogurt, especially plain yogurt, should be part of healthy eating habits because of its high nutritional value, its flexible food matrix, its beneficial bacterial components, and its versatility under usual feeding conditions.

Background: Maple syrup, a minimally transformed sweetener rich in polyphenols, can exert a action and improve metabolic parameters in animal models. However, no randomized clinical trial has investigated this. Objectives: This study aims to determine whether replacing refined sugars with an equivalent quantity of maple syrup could decrease key cardiometabolic risk factors in individuals with mild metabolic alterations. Methods: In a randomized, double-blind, controlled crossover trial with 42 overweight adults with mild cardiometabolic alterations, participants were instructed to substitute 5% of their total caloric intake from added sugars with either maple syrup or an artificially flavored sucrose syrup for 8 wk. The primary outcome included changes in glucose homeostasis, whereas secondary outcomes were changes in other cardiometabolic risk factors such as blood pressure, anthropometric indices, and blood lipid profiles. Exploratory outcomes involved analyzing changes in gut microbiota composition. Results: Replacing refined sugars with maple syrup over 8 wk decreased the glucose area under the curve when compared with substituting refined sugars with sucrose syrup, as determined during the oral glucose tolerance test, leading to a significant difference between the intervention arms (-50.59 +/- 201.92 compared with 29.93 +/- 154.90; P < 0.047). Substituting refined sugar with maple syrup also significantly decreased android fat mass (-7.83 +/- 175.05 g compared with 67.61 +/- 206.71 g; P = 0.02) and systolic blood pressure (-2.72 +/- 8.73 mm Hg compared with 0.87 +/- 8.99 mm Hg; P = 0.03). No changes in the blood lipid profile were observed. As an exploratory outcome, we further observed that substituting refined sugars with maple syrup promoted selective taxonomic changes in the gut microbiota such as a significant reduction in the abundance of Klebsiella species and decreased microbial functions associated with bacterial-induced cytokine response, when compared with substitution with sucrose syrup. Conclusions: Substituting refined sugars with maple syrup in individuals with mild metabolic alterations result in a significantly greater reduction of key cardiometabolic risk factors compared with substitution with sucrose syrup, in association with specific changes in gut microbiota. The role of the gut microbiota in these effects remains to be further explored.

This study was designed to investigate the effects of three hypoabsorptive bariatric surgeries, namely Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS), and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S), on bile acids (BAs) and to assess whether the changes in BA plasma levels were associated with the metabolic and homeostatic effects of the surgeries. Male Wistar rats, either fed a high- (HF) or a low-fat (LF) diet, were divided into seven groups: RYGB HF, BPD-DS HF, SADI-S HF, sleeve-gastrectomy (SG) HF, sham-operated (Sham) HF, Sham LF, and Sham HF-pair-weighed to BPD-DS (Sham HF-PW). The rats were treated for 56 days. The results demonstrate the ability of RYGB, BPD-DS, and SADI-S to raise plasma levels of BAs, whose elevations were likely due to changes in gene expression of transporters, enzymes, and receptors in the liver and small intestine. This increase, most notably of the secondary BAs (deoxycholic acid, ursodeoxycholic acid, and lithocholic acid), was negatively associated with body weight gain, fat gain, and fasting insulin levels, and positively with plasma peptide tyrosine-tyrosine (PYY). Plasma BAs also correlated positively with the fecal levels of Clostridium, Sutterella, and Enterobacteriaceae and negatively with Clostridiales_f_g_2, Christensenellaceae, Ruminococcaceae_g_2, Oscillibacter, and Oscillospira. In addition, they are associated positively with the short-chain fatty acid (SCFA) levels of propionate, butyrate, isobutyrate, valerate, and isovalerate. Altogether, the present study emphasizes the ability of RYGB, BPD-DS, and SADI-S to induce circulating BA elevations that predict the beneficial consequences of those hypoabsorptive bariatric surgeries on energy and glucose homeostasis and circulating levels of PYY. The present results also reveal close associations between plasma BAs and SCFAs, whose variations following hypoabsorptive surgeries are linked to significant fat losses and metabolic health improvements. NEW & NOTEWORTHY The study emphasizes the ability of RYGB, BPD-DS, and SADI-S to induce elevated circulating bile acids levels and changes in the gene expression of transporters, enzymes and receptors in the liver and small intestine, predicting positive effects on energy and glucose homeostasis as well as PYY levels. The present results also reveal close associations between plasma BAs and SCFAs, whose variations following hypoabsorptive surgeries are also linked to significant fat losses and metabolic health improvements. These findings provide valuable insights into the mechanisms underlying the positive effects of these surgical interventions.

Introduction High prostate eicosapentaenoic fatty acid (EPA) levels have been associated with a significant reduction of prostate cancer upgrading to grade group (GG) ≥2 in men with GG1 prostate cancer on active surveillance. The current phase IIb randomized pre-prostatectomy placebo-controlled trial assessed the effect of a monoacylglyceride-EPA (MAG-EPA) supplement on prostate cancer aggressiveness in 130 men diagnosed with prostate cancer. Methods Men diagnosed with GG ≥2 prostate cancer and undergoing radical prostatectomy between 2015-2017 were randomized to either 3g/day of MAG-EPA (n=65) or placebo (n=65) for seven weeks prior to radical prostatectomy and for up to one year after surgery (NCT02333435). The primary outcome was the cancer proliferation index quantified by automated image analysis of tumor nuclear Ki-67 expression using standardized prostatectomy tissue microarrays. One exploratory clinical outcome was grade reclassification from baseline biopsy at prostatectomy. Stool samples were collected in a sub-group of consent patients (n=42) for gut microbiome and fecal short-chain fatty acid analyses, using 16srRNA sequencing and targeted metabolomics, respectively. Results Men randomized to MAG-EPA had four-fold higher EPA levels in prostate tissues compared to those on placebo. The primary outcome was the cancer proliferation index measured by Ki-67 expression which was not statistically different between intervention (3.10%) and placebo (2.85%) groups. In the per protocol analyses, the adjusted estimated effect of MAG-EPA was greater but remained non-significant. However, there was a significant increase in size and proliferative index of tumor lymphoid aggregates in MAG-EPA treated prostate cancer, suggesting an immune mediated effect. In exploratory analyses, the MAG-EPA group had more cancer pathological downgrade and less cancer upgrade at prostatectomy, compared to the placebo group (p=0.024). Gut microbiota analysis revealed that the cancer up-grading reduction in pre-prostatectomy prostate cancer patients taking MAG-EPA was associated with a reduction of gut Ruminococaceae and fecal butyrate levels. Conclusions Our results suggest that lowering gut butyrate, a known immune modulator, may partly explain the beneficial effect of MAG-EPA on prostate cancer aggressiveness. More studies are needed to better understand the biological and clinical outcomes following this concentrated EPA supplementation and determine if and how it can benefit prostate cancer patients.

Antiviral therapy based on neuraminidase (oseltamivir) or polymerase (baloxavir marboxil) inhibitors plays an important role in the management of influenza infections. However, the emergence of drug resistance and the uncontrolled inflammatory response are major limitations in the treatment of severe influenza disease. Protectins D1 (PD1) and DX (PDX), part of a family of pro-resolving mediators, have previously demonstrated anti-influenza activity as well as anti-inflammatory properties in various clinical contexts. Herein, we synthetized a series of simplified PDX analogs and assessed their in vitro antiviral activity against influenza A(H1N1) viruses, including oseltamivir- and baloxavir-resistant variants. In ST6GalI-MDCK cells, the PDX analog AN-137B reduced viral replication in a dose-dependent manner with IC50 values of 23.8 for A/Puerto Rico/8/1934 (H1N1) and between 32.6 and 36.7 mu M for susceptible and resistant A(H1N1)pdm09 viruses. In MTS-based cell viability experiments, AN-137B showed a 50% cellular cytotoxicity (CC50) of 638.7 mu M with a resulting selectivity index of 26.8. Of greater importance, the combination of AN-137B with oseltamivir or baloxavir resulted in synergistic and additive in vitro effects, respectively. Treatment of lipopolysaccharide (LPS)-stimulated macrophages with AN-137B resulted in a decrease of iNOS activity as shown by the reduction of nitrite production, suggesting an anti-inflammatory effect. In conclusion, our results indicate that the protectin analog AN-137B constitutes an interesting therapeutic modality against influenza A virus, warranting further evaluation in animal models.

Overconsumption of added sugars has been pointed out as a major culprit in the increasing rates of obesity worldwide, contributing to the rising popularity of non-caloric sweeteners. In order to satisfy the growing demand, industrial efforts have been made to purify the sweet-tasting molecules found in the natural sweetener stevia, which are characterized by a sweet taste free of unpleasant aftertaste. Although the use of artificial sweeteners has raised many concerns regarding metabolic health, the impact of purified stevia components on the latter remains poorly studied. The objective of this project was to evaluate the impact of two purified sweet-tasting components of stevia, rebaudioside A and D (RebA and RebD), on the development of obesity, insulin resistance, hepatic health, bile acid profile, and gut microbiota in a mouse model of diet-induced obesity. Male C57BL/6 J mice were fed an obesogenic high-fat/high-sucrose (HFHS) diet and orally treated with 50 mg/kg of RebA, RebD or vehicle (water) for 12 weeks. An additional group of chow-fed mice treated with the vehicle was included as a healthy reference. At weeks 10 and 12, insulin and oral glucose tolerance tests were performed. Liver lipids content was analyzed. Whole-genome shotgun sequencing was performed to profile the gut microbiota. Bile acids were measured in the feces, plasma, and liver. Liver lipid content and gene expression were analyzed. As compared to the HFHS-vehicle treatment group, mice administered RebD showed a reduced weight gain, as evidenced by decreased visceral adipose tissue weight. Liver triglycerides and cholesterol from RebD-treated mice were lower and lipid peroxidation was decreased. Interestingly, administration of RebD was associated with a significant enrichment of Faecalibaculum rodentium in the gut microbiota and an increased secondary bile acid metabolism. Moreover, RebD decreased the level of lipopolysaccharide-binding protein (LBP). Neither RebA nor RebD treatments were found to impact glucose homeostasis. The daily consumption of two stevia components has no detrimental effects on metabolic health. In contrast, RebD treatment was found to reduce adiposity, alleviate hepatic steatosis and lipid peroxidation, and decrease LBP, a marker of metabolic endotoxemia in a mouse model of diet-induced obesity.