Hubert Vidal

The implication of gut microbiota in the pathophysiology of type 2 diabetes, one of the major health concerns worldwide, has demonstrated the benefits of using probiotics to improve dysbiosis. Facing the lack of defined research strategy to found and qualify bacterial with real antidiabetic activity, we have developed a program to identify, select and validate novel strains able to improve metabolic alterations in type 2 diabetes. Among potential candidates, we identified Bacteroides faecichinchillae (named BAfa hereafter), and the present work presents the validation of the antidiabetic potential of the ST37 (DSMZ 26883) BAfa strain in mice fed a high-fat high-sucrose (HFS) diet for 10 weeks followed by 4 weeks of treatment. Daily gavage with live, but not heat inactivated, BAfa improved glucose tolerance, fasting hyperinsulinemia and liver triglyceride content in HFS fed mice. Furthermore, these beneficial effects were retained after lyophilization. Using this preclinical model, we characterised BAfa mechanism of action, showing that four weeks of treatment was associated with reduced hepatic accumulation of ceramides, key actors of insulin resistance. The underlying mechanism could be related to BAfa-induced changes in the intestinal bile acid profile and inhibition of the Fxr-Fgf15 pathway in the ileum. BAfa supplementation during 4 weeks in HFS fed mice was also associated with mild modifications of gut microbiota composition, with the upregulation of several species known for their beneficial metabolic actions (such as Lactobacillus johnsonii , Limosilactobacillus reutei , Roseburia , Turicimonas muris , Phocaeicola dorei or Akkermansia muciniphila ) and for being up-regulated during metformin treatment. Altogether, these data indicate that BAfa and related B. faecichinchillae strains could be considered for developing next-generation probiotics to treat type 2 diabetes, potentially in combination with the anti-diabetic drug metformin.

The multicomponent intervention effectively modulated the gut microbiome, improving the inflammatory profile and cardiovascular variables, including blood pressure and autonomic function, in children with obesity.

The polarization of tissue-resident macrophages is influenced by a variety of signals from the immune system and the local tissue environment, including nutrition. Although it is known that the quality and quantity of ingested lipids have a significant effect on the lipid composition of extracellular vesicles and their fate, it is unknown how the nutritional environment modifies the release and the function of macrophage-derived EVs. In this study, we used a combination of palmitate and oleate (1:2, FFA) to generate lipid-associated TREM2-expressing macrophages (LAM/TREM2 ⁺ ) in vitro . Using various electron microscopy techniques (TEM, SEM, CryoEM) and fluorophores, we found that FFA overload not only induces lipid storage in LAM/TREM2 ⁺ macrophages, but also alters their morphology and reduces the diversity and the number of the lipid-derived structures they release. In addition, LAM/TREM2 ⁺ macrophages accumulated lipid droplets (LDs) below the plasma membrane and we discovered for the first time that they export and disseminate full LDs into their environment, in addition to extracellular vesicles, by using a cellular pathway associated to CD81. The use of ¹⁴ C-palmitate confirmed the presence of ¹⁴ C-triacylglycerols in the large extracellular vesicle pellet. LAM/TREM2 ⁺ macrophage-derived EVs induced TREM2 and Il-10 expression in recipient M0 macrophages. These data provide potential insights into how dietary factors and metabolic perturbations can shape the functions of macrophage-derived EVs in the context of metabolic diseases such as diabetes and obesity. In addition, LAM/TREM2 ⁺ macrophage-derived EVs modulated insulin-sensitivity, mitochondrial oxidative capacity, lipid profiles and the expressions of genes encoding extracellular matrix components in recipient skeletal muscle cells. Although previously postulated but never demonstrated, these data also highlight the LAM/TREM2+ macrophage-derived EVs as important players in SkM tissue renewal and metabolic homeostasis.

Obesity represents a serious socioeconomic and public health problem worldwide. It is therefore urgent to seek more effective therapeutic interventions. There is now clear evidence that the gut microbiota is a pivotal environmental factor which contributes to the onset and progression of obesity. Indeed, obesity is associated with alterations of gut microbiota composition and functions. Targeting these alterations is becoming an emerging strategy in the management of metabolic diseases. The use of probiotics to control or counteract weight gain and obesity has been widely studied. Lactobacilli and bifidobacteria have been at the forefront of the development of microbiome-based therapeutic products. Indeed, many strains showed promising effects on body weight management through various mechanisms acting on immune and metabolic functions as well as by restructuring the gut microbiota, restoring the gut barrier function, and stimulating the gut–brain axis. Expanding knowledge on the gut microbiome also allowed the development of next-generation probiotics which are now starting to be approved as medicinal products. Further clinical trials are required to better determine the safety, dose, and long-term impact on host body weight and metabolism. This chapter will summarize the recent discoveries on the most promising candidates.

Supplementation with probiotics has emerged as a promising therapeutic tool to manage metabolic diseases. We investigated the effects of a mix of Bifidobacterium animalis subsp. lactis LA804 and Lactobacillus gasseri LA806 on high-fat (HF) diet -induced metabolic disease in mice. Supplementation with the probiotic mix in HF diet-fed mice (HF-Pr2) reduced weight and fat mass gains, decreased hepatic lipid accumulation, and lowered plasma triglyceride peak during an oral lipid tolerance test. At the molecular level, the probiotic mix protected against HF-induced rise in mRNA levels of genes related to lipid uptake, metabolism, and storage in the liver and white adipose tissues, and strongly decreased mRNA levels of genes related to inflammation in the white adipose tissue and to oxidative stress in the liver. Regarding intestinal homeostasis, the probiotic mix did not prevent HF-induced gut permeability but slightly modified microbiota composition without correcting the dysbiosis induced by the HF diet. Probiotic supplementation also modified the cecal bile acid (BA) profile, leading to an increase in the Farnesoid-X-Receptor (FXR) antagonist/agonist ratio between BA species. In agreement, HF-Pr2 mice exhibited a strong inhibition of FXR signaling pathway in the ileum, which was associated with lipid metabolism protection. This is consistent with recent reports proposing that inhibition of intestinal FXR activity could be a potent mechanism to overcome metabolic disorders. Altogether, our results demonstrate that the probiotic mix evaluated, when administered preventively to HF diet-fed mice could limit obesity and associated lipid metabolism disorders, likely through the inhibition of FXR signaling in the intestinal tract.

Background: Obesity is a well-known risk factor for cancer. We have previously reported the role of adipose-tissue-derived mesenchymal stem cells from obese individuals (ob-ASC) in the promotion of pathogenic Th17 cells and immune check point (ICP) upregulation. Thus, we postulated herein that this mechanism could contribute to breast cancer (BC) aggressiveness. Methods: Conditioning medium (CM) from mitogen-activated ob-ASC and immune cell co-cultures were added to two human breast cancer cell line (BCCL) cultures. Expressions of pro-inflammatory cytokines, angiogenesis markers, metalloproteinases, and PD-L1 (a major ICP) were measured at the mRNA and/or protein levels. BCCL migration was explored in wound healing assays. Anti-cytokine neutralizing antibodies (Ab) were added to co-cultures. Results: CM from ob-ASC/MNC co-cultures increased IL-1β, IL-8, IL-6, VEGF-A, MMP-9, and PD-L1 expressions in both BCCLs and accelerated their migration. The use of Abs demonstrated differential effects for IL-17A and IFNγ on BCCL pro-inflammatory cytokine over-expression or PD-L1 upregulation, respectively, but potentiating effects on BCCL migration. Finally, co-cultures with ob-ASC, but not lean ASC, enhanced PD-L1 expression. Conclusions: Our results demonstrate increased inflammation and ICP markers and accelerated BCCL migration following the activation of pathogenic Th17 cells by ob-ASC, which could represent a new mechanism linking obesity with BC progression.