Design of a proteolytic module for improved metabolic modeling of Bacteroides caccae

Author:

Paulay Amandine123ORCID,Grimaud Ghjuvan M.2,Caballero Raphaël1,Laroche Béatrice34,Leclerc Marion15,Labarthe Simon367ORCID,Maguin Emmanuelle1ORCID

Affiliation:

1. Université Paris-Saclay, INRAE, AgroParisTech, UMR1319 Micalis Institute, Jouy-en-Josas, France

2. Biomathematica, Ajaccio, France

3. Université Paris-Saclay, INRAE, MaIAGE, Jouy-en-Josas, France

4. Université Paris-Saclay, Inria, Centre Inria de Saclay, Palaiseau, France

5. Pendulum Therapeutics, San Francisco, California, USA

6. University of Bordeaux, INRAE, BIOGECO, Cestas, France

7. Inria, Univ. Bordeaux, INRAE, Talence, France

Abstract

ABSTRACT The gut microbiota plays a crucial role in health and is significantly modulated by human diets. In addition to Western diets which are rich in proteins, high-protein diets are used for specific populations or indications, mainly weight loss. In this study, we investigated the effect of protein supplementation on Bacteroides caccae , a Gram-negative gut symbiont. The supplementation with whey proteins led to a significant increase in growth rate, final biomass, and short-chain fatty acids production. A comprehensive genomic analysis revealed that B. caccae possesses a set of 156 proteases with putative intracellular and extracellular localization and allowed to identify amino acid transporters and metabolic pathways. We developed a fully curated genome-scale metabolic model of B. caccae that incorporated its proteolytic activity and simulated its growth and production of fermentation-related metabolites in response to the different growth media. We validated the model by comparing the predicted phenotype to experimental data. The model accurately predicted B. caccae ’s growth and metabolite production ( R 2 = 0.92 for the training set and R 2 = 0.89 for the validation set). We found that accounting for both ATP consumption related to proteolysis, and whey protein accessibility is necessary for accurate predictions of metabolites production. These results provide insights into B. caccae ’s adaptation to a high-protein diet and its ability to utilize proteins as a source of nutrition. The proposed model provides a useful tool for understanding the feeding mechanism of B. caccae in the gut microbiome. IMPORTANCE Microbial proteolysis is understudied despite the availability of dietary proteins for the gut microbiota. Here, the proteolytic potential of the gut symbiont Bacteroides caccae was analyzed for the first time using pan-genomics. This sketches a well-equipped bacteria for protein breakdown, capable of producing 156 different proteases with a broad spectrum of cleavage targets. This functional potential was confirmed by the enhancement of growth and metabolic activities at high protein levels. Proteolysis was included in a B. caccae metabolic model which was fitted with the experiments and validated on external data. This model pinpoints the links between protein availability and short-chain fatty acids production, and the importance for B. caccae to gain access to glutamate and asparagine to promote growth. This integrated approach can be generalized to other symbionts and upscaled to complex microbiota to get insights into the ecological impact of proteins on the gut microbiota.

Funder

Agence Nationale de la Recherche

Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement

Biomathematica

Publisher

American Society for Microbiology

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