Inhibition of intestinal FXR activity as a possible mechanism for the beneficial effects of a probiotic mix supplementation on lipid metabolism alterations and weight gain in mice fed a high fat diet

ABSTRACT

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.

KEYWORDS:

• Metabolic syndrome
• high-fat diet
• bifidobacterium animalis
• lactobacillus gasseri
• gut microbiota
• bile acids
• intestinal FXR signaling
• lipid metabolism

Acknowledgments

We thank Dr. Dominique Rainteau and his colleagues (at Centre de Recherche Saint-Antoine, Paris) for the analysis of cecal bile acids and Prof. G.G. Muccioli and his colleagues (at Université Catholique de Louvain, Belgium) for the analysis of endocannabinoids. Fecal microbiota sequencing was performed by ProfileXpert (at the Faculté de Médecine et de Pharmacie Rockefeller, Lyon, France). Mrs Claude Blondeau (PiLeJe Laboratoire) was acknowledged for draft review.

Disclosure statement

Sophie Holowacz and Elsa Jacouton are employees of PiLeJe Laboratoire. No other conflict of interest was reported by the authors.

Authors’ contributions

MLB, EJ, MCM, and HV conceived and designed the study. AB, BB, MLB, and EM performed the experiments and data analysis. AP, CC, CP, EL, SC, AVM, MG, and FL contributed to study design, samples collection, or biological or data analyses. VS performed the analysis of short chain fatty acids. AB, BB, MLB, EM, EJ, MCM, and HV performed the interpretation. AB, BB, and HV wrote the first version of the paper. CC, EJ, SH, and MCM critically revised the manuscript. All authors approved the final version before submission.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request. The data of 16S sequencing have been deposited in the French repository at “Recherche.data.gouv.fr” and can be accessible with the following link: https://doi.org/10.57745/MXOF51.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2281015

Additional information

Funding

This work was supported by the Pileje Laboratoire and by a research grant from INSERM (Transversal Program on Microbiota 2019–2022).