Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota

Abstract

Manipulation of the gut microbiota holds great promise for the treatment of inflammatory and allergic diseases. Although numerous probiotic microorganisms have been identified, there remains a compelling need to discover organisms that elicit more robust therapeutic responses, are compatible with the host, and can affect a specific arm of the host immune system in a well-controlled, physiological manner. Here we use a rational approach to isolate CD4(+)FOXP3(+) regulatory T (Treg)-cell-inducing bacterial strains from the human indigenous microbiota. Starting with a healthy human faecal sample, a sequence of selection steps was applied to obtain mice colonized with human microbiota enriched in Treg-cell-inducing species. From these mice, we isolated and selected 17 strains of bacteria on the basis of their high potency in enhancing Treg cell abundance and inducing important anti-inflammatory molecules--including interleukin-10 (IL-) and inducible T-cell co-stimulator (ICOS)--in Treg cells upon inoculation into germ-free mice. Genome sequencing revealed that the 17 strains fall within clusters IV, XIVa and XVIII of Clostridia, which lack prominent toxins and virulence factors. The 17 strains act as a community to provide bacterial antigens and a TGF-β-rich environment to help expansion and differentiation of Treg cells. Oral administration of the combination of 17 strains to adult mice attenuated disease in models of colitis and allergic diarrhoea. Use of the isolated strains may allow for tailored therapeutic manipulation of human immune disorders.

Moving beyond microbiome-wide associations to causal microbe identification

“…However, MWAS have produced long lists of implicated microbes without clearly elucidating their causal role, correlations have not always held up in subsequent studies, and notable differences have been observed between human and animal studies 1–3 . Although many correlations may simply reflect biomarkers of disease, causal links between the microbiome and disease susceptibility have been sporadically defined in studies that have initially identified immunomodulatory bacteria, functionally categorized the microbiota on the basis of immune recognition, or used complex bioinformatic heuristics to identify disease-modulating bacteria 6–11 . Ultimately, a generalizable pathway that refines the catalog of differentially abundant microbes identified by MWAS to include only those most likely causally related to the phenotype is lacking.…”

Gut microbiome analysis in neuromyelitis optica reveals overabundance of Clostridium perfringens

“…Clostridium species in human gut can influence the balance between Th17 and regulatory T cells (Treg) 5. These observations, when taken together with our previous studies showing proinflammatory T‐cell polarization and cross‐reactivity between AQP4 and ABC‐TP in NMO, highlighted the need to evaluate the proposed connection between C. perfringens and NMO pathogenesis.…”

Microbiote intestinal et développement du système immunitaire

“…L'étude de souris gnotoxéniques montre aussi que la nature et l'intensité des réponses immunes adaptatives dépendent de la composition du microbiote et particulièrement de la présence de la bactérie segmentée filamenteuse (SFB) [42] (➜). Contrairement à la majorité des bactéries commensales 5 qui induisent une réponse IgA relativement modeste et des réponses T dominées par des réponses T régulatrices, notamment dans le côlon [18,[26][27][28], la SFB joue un rôle privilégié dans la maturation post-natale des réponses immunes innées et adaptatives chez son hôte [18,22] (Figure 2). Cette bactérie, cultivable seulement récemment [29], est apparentée au genre des Clostridium [30].…”