A New Strain of Christensenella minuta as a Potential Biotherapy for Obesity and Associated Metabolic Diseases

Abstract

Obesity is associated with gut microbiota dysbiosis, characterized by a high Firmicutes/Bacteroidetes ratio. Gut-dwelling bacteria of the Christensenellaceae family have been proposed to act as keystones of the human gut ecosystem and to prevent adipogenesis. The objectives of the present study were to demonstrate the antiobesity potential of a new strain of Christensenella minuta in preclinical models and explore related mechanisms of action. The antiobesity potential of C. minuta DSM33407 was assessed in a diet-induced obesity mouse model. Changes in hepatic lipid metabolism were explored using targeted transcriptomics. Effects on gut microbiota were further assessed in a humanized Simulator of the Human Intestinal Microbial Ecosystem (SHIME®) model inoculated with obese fecal samples. Shotgun metagenomics was applied to study microbial community structures in both models. C. minuta DSM33407 protected from diet-induced obesity and regulated associated metabolic markers such as glycemia and leptin. It also regulated hepatic lipid metabolism through a strong inhibition of de novo lipogenesis and maintained gut epithelial integrity. In the humanized SHIME® model, these effects were associated with modulations of the intestinal microbiota characterized by a decreased Firmicutes/Bacteroidetes ratio. These data indicate that C. minuta DSM33407 is a convincing therapeutic candidate for the management of obesity and associated metabolic disorders.

Identifying a Novel Bile Salt Hydrolase from the Keystone Gut Bacterium Christensenella minuta

“…This study also suggested that enriching gut microbiomes with bacterial strains carrying a highly active BSH may be a strategy to alleviate excess body weight. Given that CmDSM33407 presents strong anti-obesity effects in animal models [8], its BSH activity may be an important keystone function in its mechanism of action that warrants further studies.…”

“…To date, only one strain of C. minuta (DSM 22607, referred to further in the text as CmDSM22607) is available in culture collections, which is the original type strain described by Morotomi et al in 2012 [7]. In a recently published study, we demonstrated the anti-obesity potential of the novel strain Christensenella minuta DSM 33407 (CmDSM33407) in a diet-induced obesity (DIO) mouse model [8]. In this article, we also evaluated the effects of this new strain on the gut microbiome of obese donors using a SHIME®model and demonstrated that it promotes gut bacterial diversity, restoring the altered Bacteroides/Firmicutes ratio typical of a dysbiotic obese microbiota [9].…”

“…In this article, we also evaluated the effects of this new strain on the gut microbiome of obese donors using a SHIME®model and demonstrated that it promotes gut bacterial diversity, restoring the altered Bacteroides/Firmicutes ratio typical of a dysbiotic obese microbiota [9]. This effect was associated with a stimulation of the production of short chain fatty acids (SCFAs) and tended to increase the cholic acid/taurocholic acid (CA/TCA) ratio in the distal part of the colon [8], indicating that the function of the microbiota supplemented with C. minuta DSM 33407 was shifted towards a higher saccharolytic metabolism associated with more efficient deconjugation of primary bile acids.…”

Next Generation Microbiome Research: Identification of Keystone Species in the Metabolic Regulation of Host-Gut Microbiota Interplay

“…Empirical (Centanni et al, 2018) Highly prevalent human breast milk (Lugli et al, 2020) Christensenella minuta Stimulate ecosystem diversity (Mazier et al, 2021); acetate producer (Morotomi et al, 2012); BSH activity (Déjean et al, 2021) Co-occurrence networks (Goodrich et al, 2014;Kumpitsch et al, 2020 ahead of publication) Empirical (Ruaud et al, 2020;Mazier et al, 2021) Obesity and metabolic diseases (Goodrich et al, 2014); Crohn's disease (Pascal et al, 2017) Faecalibacterium prausnitzii Butyrate producer Presence/absence (Leylabadlo et al, 2020) Crohn's disease (Sokol et al, 2008), Ulcerative Colitis (Varela et al, 2013) Methanobrevibacter smithii Produces methane from H 2 and acetate Empirical and co-occurrence networks (Goodrich et al, 2014;Kumpitsch et al, 2020 ahead of publication)…”

Entering First-in-Human Clinical Study With a Single-Strain Live Biotherapeutic Product: Input and Feedback Gained From the EMA and the FDA

“…- In order to reproduce as accurately as possible the human microbiome ecology, the non-clinical simulation of the effects of the AS ( C. minuta DSM 33407) was conducted using the ex vivo GI SHIME® model ( 30 , 31 ),…”