Acetate is reported as a regulator of fat mass but also as lipogenic source for cancer cells. Breast cancer is surrounded by adipose tissue and has been associated with obesity. However, whether ...acetate contributes to cancer cell metabolism as lipogenic substrate and/or by changing fat storage and eventually obesity‐induced breast cancer progression remains unknown. Therefore, we studied the contribution of acetate to breast cancer metabolism and progression. In vitro, we found that acetate is not a bioenergetic substrate under normoxia and did not result in a significant change of growth. However, by using lipidomic approaches, we discovered that acetate changes the lipid profiles of the cells under hypoxia. Moreover, while mice fed a high‐fat diet (HFD) developed bigger tumours than their lean counterparts, exogenous acetate supplementation leads to a complete abolishment of fat mass gain without reverting the HFD‐induced obesity‐driven tumour progression. In conclusion, although acetate protects against diet‐induced obesity, our data suggest that it is not affecting HFD‐driven tumour progression.
Bioluminescence imaging has become an essential non-invasive tool in cancer research for monitoring various cellular processes and tumor progression in vivo. In this article, we aimed to propose a ...transduction and selection protocol for reliable in vivo bioluminescent measurements in immunocompetent mouse models. Using two different heterogenous luciferase-expressing cell models, we underlined factors influencing transduction. The protocol was tested through an in vitro luciferase activity assay as well as using in vivo longitudinal monitoring of metastases formation (In Vivo Imaging System®). The data were cross validated with histological assessment. Our results demonstrated stable and proportional in vitro and in vivo bioluminescent signals correlating with actual metastatic burden. Furthermore, ex vivo analysis confirmed the accuracy of bioluminescent imaging in quantifying metastatic surface area. This protocol should ensure reliable and reproducible measurements in cancer research utilizing luciferase-positive cell lines, confirming the validity and accuracy of preclinical studies in immunocompetent models.
•Transduction and selection protocol validated in vitro and in vivo for cancer research.•Work in immunocompetent mouse models with heterogenous luciferase-expressing cell lines.•Critical considerations in protocol design for reliable bioluminescent measurements.
Summary
Because the development of adipose tissue involves remodelling of the extracellular matrix (ECM), which requires matrix metalloproteinase (MMP) activity, we examined whether MMP inhibitors ...may have the potential to affect adipose tissue mass in obese mice.
Administration of the relatively gelatinase‐specific MMP inhibitor tolylsam ((R)‐3‐methyl‐2‐4‐(3‐p‐tolyl‐1,2,4oxadiazol‐5‐yl)‐benzenesulphonylamino‐butyric acid; 100 mg/kg per day) for 7 weeks to obese wild‐type mice on a high‐fat diet resulted in significantly lower bodyweight (P < 0.05), lower subcutaneous (SC) and gonadal (GON) adipose tissue mass (both P < 0.05) and smaller adipocytes in both SC (P < 0.005) and GON (P < 0.0005) adipose tissues.
Magnetic resonance imaging confirmed a lower total body fat content in tolylsam‐treated mice (P < 0.0005). In addition, tolylsam treatment of wild‐type mice was associated with a marked enhancement in metabolic rate.
Electron microscopy analysis of tissue sections at the end of the 7 week feeding period revealed significantly higher collagen accumulation in the ECM of SC adipose tissues of tolylsam‐treated mice (P < 0.001).
Thus, the relatively gelatinase‐specific MMP inhibitor tolylsam has the potential to affect fat tissue growth in obese mice.
Gut - brain communications disorders in irritable bowel syndrome (IBS) are associated with intestinal microbiota composition, increased gut permeability, and psychosocial disturbances. Symptoms of ...IBS are difficult to medicate, and hence much research is being made into alternative approaches. This study assesses the potential of a treatment with pasteurized Akkermansia muciniphila for alleviating IBS-like symptoms in two mouse models of IBS with different etiologies. Two clinically relevant animal models were used to mimic IBS-like symptoms in C57BL6/J mice: the neonatal maternal separation (NMS) paradigm and the Citrobacter rodentium infection model. In both models, gut permeability, colonic sensitivity, fecal microbiota composition and colonic IL-22 expression were evaluated. The cognitive performance and emotional state of the animals were also assessed by several tests in the C. rodentium infection model. The neuromodulation ability of pasteurized A. muciniphila was assessed on primary neuronal cells from mice dorsal root ganglia using a ratiometric calcium imaging approach. The administration of pasteurized A. muciniphila significantly reduced colonic hypersensitivity in both IBS mouse models, accompanied by a reinforcement of the intestinal barrier function. Beneficial effects of pasteurized A. muciniphila treatment have also been observed on anxiety-like behavior and memory defects in the C. rodentium infection model. Finally, a neuroinhibitory effect exerted by pasteurized A. muciniphila was observed on neuronal cells stimulated with two algogenic substances such as capsaicin and inflammatory soup. Our findings demonstrate novel anti-hyperalgesic and neuroinhibitory properties of pasteurized A. muciniphila, which therefore may have beneficial effects in relieving pain and anxiety in subjects with IBS.
Excessive hedonic consumption is one of the main drivers for weight gain. Identifying contributors of this dysregulation would help to tackle obesity. The gut microbiome is altered during obesity and ...regulates host metabolism including food intake.
By using fecal material transplantation (FMT) from lean or obese mice into recipient mice, we demonstrated that gut microbes play a role in the regulation of food reward (i.e., wanting and learning processes associated with hedonic food intake) and could be responsible for excessive motivation to obtain sucrose pellets and alterations in dopaminergic and opioid markers in reward-related brain areas. Through untargeted metabolomic approach, we identified the 3-(3'-hydroxyphenyl)propanoic acid (33HPP) as highly positively correlated with the motivation. By administrating 33HPP in mice, we revealed its effects on food reward.
Our data suggest that targeting the gut microbiota and its metabolites would be an interesting therapeutic strategy for compulsive eating, preventing inappropriate hedonic food intake. Video Abstract.
Current treatments for inflammatory bowel disease (IBD) treatment consist of anti-inflammatory products. In this study, we sought to induce the physiological secretion of glucagon-like peptide 2, a ...peptide with intestinal growth-promoting activity, via nanoparticles while simultaneously providing with immunomodulation by tailoring the nanoparticle surface. To this end, we developed hybrid lipid hyaluronate-KPV conjugated nanoparticles loaded with teduglutide for combination therapy in IBD. The nanocarriers induced (or did not induce) immunosuppression depending on the presence (or absence) of a hyaluronan-KPV functionalization. This strategy holds promise as a nanoparticle platform for combined mucosal healing and immunomodulation in IBD treatment.
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•As proof-of -concept, we have demonstrated that lipid nanocapsules per se increased GLP-2 secretion in vitro and in vivo in a murine acute colitis model (DSS) while increasing citrulline (mucosal healing marker) and decreasing the colon weight/length ratio (hallmark of this model).•We encapsulated teduglutide within lipid nanocapsules and tested in vivo in two acute models of colitis (DSS and TNBS) the mucosal healing and anti-inflammatory properties of the formulation, demonstrating no immunomodulatory effect of the nanocarriers per se with increased GLP-2 levels.•We synthesized hyaluronan-KPV conjugates and functionalized our teduglutide-loaded nanocarriers demonstrating combined anti-inflammatory and mucosal healing properties in an acute DSS model and in a chronic DSS model (50 days) upon intermittent administration.•The pharmacological effect exerted by our nanocarriers induced sufficient stimulus as per providing with mucosal healing upon intermittent administration of our formulation during 3 consecutive days, 3 times over 50 days, 9 doses in total.
Anastomotic leakage is a major complication following colorectal surgery leading to peritonitis, complications, and mortality. Akkermansia muciniphila has shown beneficial effects on the gut barrier ...function. Whether A. muciniphila reduces peritonitis and mortality during colonic leakage is unknown. Whether A. muciniphila can directly modulate the expression of genes in the colonic mucosa in humans has never been studied. We investigated the effects of a pretreatment (14 days) with live A. muciniphila prior to surgical colonic perforation on peritonitis, mortality, and wound healing. We used mice with an inducible intestinal-epithelial-cell-specific deletion of MyD88 (IEC-MyD88 KO) to investigate the role of the innate immune system in this context. In a proof-of-concept pilot study, healthy humans were exposed to A. muciniphila for 2 h and colonic biopsies taken before and after colonic instillation for transcriptomic analysis. Seven days after colonic perforation, A.-muciniphila-treated mice had significantly lower mortality and severity of peritonitis. This effect was associated with significant improvements of wound histological healing scores, higher production of IL22, but no changes in the mucus layer thickness or genes involved in cell renewal, proliferation, or differentiation. All these effects were abolished in IEC-MyD88 KO mice. Finally, human subjects exposed to A. muciniphila exhibited an increased level of the bacterium at the mucus level 2 h after instillation and significant changes in the expression of different genes involved in the regulation of cell cycling, gene transcription, immunity, and inflammation in their colonic mucosa. A. muciniphila improves wound healing during transmural colonic wall defect through mechanisms possibly involving IL22 signaling and requiring MyD88 in the intestinal cells. In healthy humans, colonic administration of A. muciniphila is well tolerated and changes the expression of genes involved in the immune pathways.
Obesity is associated with a cluster of metabolic disorders, chronic low-grade inflammation, altered gut microbiota, increased intestinal permeability, and alterations of the lipid mediators of the ...expanded endocannabinoid (eCB) signaling system, or endocannabinoidome (eCBome). In the present study, we characterized the profile of the eCBome and related oxylipins in the small and large intestines of genetically obese (
) and diabetic (
) mice to decipher possible correlations between these mediators and intestinal inflammation and gut microbiota composition. Basal lipid and gene expression profiles, measured by LC/MS-MS-based targeted lipidomics and qPCR transcriptomics, respectively, highlighted a differentially altered intestinal eCBome and oxylipin tone, possibly linked to increased mRNA levels of inflammatory markers in
mice. In particular, the duodenal levels of several 2-monoacylglycerols and
-acylethanolamines were increased and decreased, respectively, in
mice, which displayed more pronounced intestinal inflammation. To a little extent, these differences were explained by changes in the expression of the corresponding metabolic enzymes. Correlation analyses suggested possible interactions between eCBome/oxylipin mediators, cytokines, and bacterial components and bacterial taxa closely related to intestinal inflammation. Collectively, this study reveals that
mice present a higher inflammatory state in the intestine as compared to
mice, and that this difference is associated with profound and potentially adaptive or maladaptive, and partly intestinal segment-specific alterations in eCBome and oxylipin signaling. This study opens the way to future investigations on the biological role of several poorly investigated eCBome mediators and oxylipins in the context of obesity and diabetes-induced gut dysbiosis and inflammation.
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