Experimental diets dictate the metabolic benefits of probiotics in obesity

ABSTRACT

Growing evidence supports the use of probiotics to prevent or mitigate obesity-related dysmetabolism and non-alcoholic fatty liver disease (NAFLD). However, frequent reports of responders versus non-responders to probiotic treatment warrant a better understanding of key modifiers of host–microbe interactions. The influence of host diet on probiotic efficacy, in particular against metabolic diseases, remains elusive. We fed C57BL6/J mice a low fat reference diet or one of two energy-matched high fat and high sucrose diets for 12 weeks; a classical high fat diet (HFD) and a customized fast food-mimicking diet (FFMD). During the studies, mice fed either obesogenic diet were gavaged daily with one of two probiotic lactic acid bacteria (LAB) strains previously classified as Lactobaccillus, namely Limosilactobacillus reuteri (L. reuteri)or Lacticaseibacillus paracaseisubsp. paracasei (L. paracasei), or vehicle. The tested probiotics exhibited a reproducible efficacy but dichotomous response according to the obesogenic diets used. Indeed, L. paracaseiprevented weight gain, improved insulin sensitivity, and protected against NAFLD development in mice fed HFD, but not FFMD. Conversely, L. reuteri improved glucoregulatory capacity, reduced NAFLD development, and increased distal gut bile acid levels associated with changes in predicted functions of the gut microbiota exclusively in the context of FFMD-feeding. We found that the probiotic efficacy of two LAB strains is highly dependent on experimental obesogenic diets. These findings highlight the need to carefully consider the confounding impact of diet in order to improve both the reproducibility of preclinical probiotic studies and their clinical research translatability.

GRAPHICAL ABSTRACT

KEYWORDS:

• Probiotics
• diet-induced obesity
• insulin resistance
• microbiota
• dietary interaction
• NAFLD
• NASH
• MAFLD

Acknowledgments

We thank Joanie Dupont-Morissette, Christine Dallaire, Jacinthe Julien, Laurence Morin, and Jenny Rancourt-Mercier from IUCPQ, Laval University, for excellent technical assistance for in vivo protocols. Additionally, we thank Marie-Julie Dubois and Michael Schwab from IUCPQ for data generation during the manuscript revision process. Sincere gratitude to Lea B. S. Hansen for essential bioinformatic input. Additionally, we thank Torsten Schröder from the Institute of Nutritional Medicine for data generation as well as Jeffrey Schultchen from NZ for providing the probiotic LAB strains.

Disclosure statement

This study was partly funded by Novozymes A/S (NZ) which provided the bacterial strains and was granted a patent related to the findings (WO20084051). NZ contributed to study design and parts of the analyses but had no role in data integration, interpretation, and conclusion.

Author Contributions

BAHJ, ISL, NNK, AM and BSYC conceived and designed the studies. ISL, BAHJ, and BSYC carried out the in vivo studies. ISL, BSYC, BF, AO, RFH, PBO, and DS generated data. BAHJ designed the diets and supervised all parts of the study; AM and CS supervised parts of the study. ISL integrated the data and wrote the first drafts of the manuscript, which was revised by all the authors, who agreed upon the submitted manuscript.

Data availability statement

The data that support the findings of this study are available in Mendeley Data at doi: http://doi.org/10.17632/72j8tkm36g.1

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2192547

Additional information

Funding

BAHJ was supported by Lundbeck Foundation (grant number: R232-2016-2425) and Novo Nordisk Foundation (grant numbers: NNF17OC0026698; NNF21OC0066931). AM was supported by the Canadian Institutes of Health Research (grant numbers: FDN-143247 and MRT-168045) and was the holder of a Pfizer/CIHR partner Chair in the pathogenesis of insulin resistance and cardiovascular diseases. BSYC was funded by doctoral scholarships from Natural Sciences and Engineering Research Council (NSERC) and from the Sentinel North program. BF and CS were supported by the German research society (DFG) IRTG 1911 Project. CS was endowed Chair of Nutritional Medicine supported by Fresenius Kabi. DS was partly supported by a grant from the German Federal Ministry of Education and Research (BMBF) from the Good Bacteria and Bioactive in Industry (GOBI) Consortium (Grant number: BMBF 031B0074A).