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.

The commensal bacterium Faecalibacterium prausnitzii has unique anti-inflammatory properties, at least some of which have been attributed to its production of MAM, the Microbial Anti-inflammatory Molecule. Previous phylogenetic studies of F. prausnitzii strains have revealed the existence of various phylogroups. In this work, we address the question of whether MAMs from different phylogroups display distinct anti-inflammatory properties. We first performed wide-scale identification, classification, and phylogenetic analysis of MAM-like proteins encoded in different genomes of F. prausnitzii. When combined with a gene context analysis, this approach distinguished at least 10 distinct clusters of MAMs, providing evidence for functional diversity within this protein. We then selected 11 MAMs from various clusters and evaluated their anti-inflammatory capacities in vitro. A wide range of anti-inflammatory activity was detected. MAM from the M21/2 strain had the highest inhibitory effect (96% inhibition), while MAM from reference strain A2-165 demonstrated only 56% inhibition, and MAM from strain CNCM4541 was almost inactive. These results were confirmed in vivo in murine models of acute and chronic colitis. This study provides insights into the family of MAM proteins and generates clues regarding the choice of F. prausnitzii strains as probiotics for use in targeting chronic inflammatory diseases.

Background: Most interactions between the host and its microbiota occur at the gut barrier, and primary colonizers are essential in the gut barrier maturation in the early life. The mother–offspring transmission of microorganisms is the most important factor influencing microbial colonization in mammals, and C-section delivery (CSD) is an important disruptive factor of this transfer. Recently, the deregulation of symbiotic host-microbe interactions in early life has been shown to alter the maturation of the immune system, predisposing the host to gut barrier dysfunction and inflammation. The main goal of this study is to decipher the role of the early-life gut microbiota-barrier alterations and its links with later-life risks of intestinal inflammation in a murine model of CSD. Results: The higher sensitivity to chemically induced inflammation in CSD mice is related to excessive exposure to a too diverse microbiota too early in life. This early microbial stimulus has short-term consequences on the host homeostasis. It switches the pup’s immune response to an inflammatory context and alters the epithelium structure and the mucus-producing cells, disrupting gut homeostasis. This presence of a too diverse microbiota in the very early life involves a disproportionate short-chain fatty acids ratio and an excessive antigen exposure across the vulnerable gut barrier in the first days of life, before the gut closure. Besides, as shown by microbiota transfer experiments, the microbiota is causal in the high sensitivity of CSD mice to chemical-induced colitis and in most of the phenotypical parameters found altered in early life. Finally, supplementation with lactobacilli, the main bacterial group impacted by CSD in mice, reverts the higher sensitivity to inflammation in ex-germ-free mice colonized by CSD pups’ microbiota. Conclusions: Early-life gut microbiota-host crosstalk alterations related to CSD could be the linchpin behind the phenotypic effects that lead to increased susceptibility to an induced inflammation later in life in mice.

Ricin is a highly potent toxin that has been used in various attempts at bioterrorism worldwide. Although a vaccine for preventing ricin poisoning (RiVax™) is in clinical development, there are currently no commercially available prophylaxis or treatments for ricin intoxication. Numerous studies have highlighted the potential of passive immunotherapy using anti-ricin monoclonal antibodies (mAbs) and have shown promising results in preclinical models. In this article, we describe the neutralizing and protective efficacy of a new generation of high-affinity anti-ricin mAbs, which bind and neutralize very efficiently both ricin isoforms D and E in vitro through cytotoxicity cell assays. In vivo, protection assay revealed that one of these mAbs (RicE5) conferred over 90% survival in a murine model challenged intranasally with a 5 LD₅₀ of ricin and treated by intravenous administration of the mAbs 6 h post-intoxication. Notably, a 35% survival rate was observed even when treatment was administered 24 h post-exposure. Moreover, all surviving mice exhibited long-term immunity to high ricin doses. These findings offer promising results for the clinical development of a therapeutic candidate against ricin intoxication and may also pave the way for novel vaccination strategies against ricin or other toxins.

Caractérisation des effets immunomodulateurs et bénéfiques de Christensenella minuta sur l’hôte: Le microbiote intestinal, composé de micro-organismes tels que des bactéries ou des virus, assure des fonctions métaboliques, barrières, immunes et protectives permettant le maintien de l’homéostasie générale chez l’hôte. Des études ont montré que la famille des Christensenellaceae étaient considérées comme une signature d’un microbiote intestinal en bonne santé. Elle a également été associée à la longévité du fait de sa présence chez des personnes centenaires et semi-supercentenaires en bonne santé. De plus, la famille des Christensenellaceae est également retrouvée appauvrie chez des patients atteints de maladies inflammatoires chroniques de l’intestin (MICI), comme la maladie de Crohn ou encore la rectocolite hémorragique. Nous nous sommes donc intéressés aux propriétés anti-inflammatoires et bénéfiques liées à la présence de Christensenella minuta DSM 22607, la souche type de la famille des Christensenellaceae. Nous avons i) caractérisé in vitro les propriétés fonctionnelles de notre bactérie d’intérêt ; ii) évalué ses effets sur un modèle d’inflammation pathologique in vivo et iii) déterminé son potentiel bénéfique sur un modèle in vivo d’inflammation physiologique observée lors du vieillissement. Nous avons pu observer que C. minuta DSM 22607 possédait des propriétés anti-inflammatoires in vitro et in vivo et ce dans l’ensemble des modèles étudiés. De plus, l’administration de C. minuta a permis de préserver l’intégrité de la barrière intestinale et de stimuler la production d’acide gras à chaînes courtes, permettant de protéger l’hôte. Ces résultats indiquent que C. minuta joue un rôle clé dans le maintien de l’homéostasie générale et pourrait être utilisée comme biothérapie dans le traitement de l’inflammation et de pathologies associées.

With age, low-grade inflammation tends to increase a process known as inflammaging, which is associated with the development of age-related diseases. Concurrently, the gut microbiota undergoes age-related changes in humans. In centenarians and supercentenarians, certain bacteria from the Christensenellaceae family have been found to increase with age and are associated with healthy aging. This study aimed to investigate the potential beneficial effects of Christensenella minuta DSM 22607, a well-characterized strain from this family, on the aging process. Fourteen-month-old male C57BL/6J mice (n = 40) were assigned to four groups receiving either C. minuta DSM 22607 (5 × 10 ⁹ CFU/mL) or vehicle, combined with ad libitum or calorie-restricted feeding, for 5 months. Intestinal permeability, inflammatory markers, gut microbiota composition, bile acid profiles, and metabolic parameters were assessed via fluorescein isothiocyanate (FITC)-Dextran, soluble CD14, multiplex assay, immune cell staining, short-chain fatty acids determination and 16sDNA sequencing. Data were analyzed using two-way ANOVA with Tukey’s post-hoc test or Mann-Whitney test, with significance set at p < 0.05. Young (6-month-old) and old (19-month-old) mice were compared to validate age-related phenotypes. The effects of DSM 22607 were then evaluated, using food restriction as a positive control. DSM 22607 was found to influence the intestinal barrier by modulating goblet cell populations. Moreover, administration exerted anti-inflammatory effects by reducing pro-inflammatory markers (IL-1β, IL-6) and modulating T lymphocyte, macrophage, and NK cell populations. In addition, DSM 22607 counteracted the effects of food restriction by restoring short-chain fatty acid levels and improving metabolic parameters and bile acid composition. These findings suggest that C. minuta DSM 22607 may represent a promising microbiota-based therapeutic strategy to support healthy aging.