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The commensal bacterium Faecalibacterium prausnitzii plays a key role in inflammatory bowel disease (IBD) pathogenesis and serves as a general health biomarker in humans. However, the host molecular mechanisms that underlie its anti-inflammatory effects remain unknown. In this study we performed a transcriptomic approach on human intestinal epithelial cells (HT-29) stimulated with TNF-α and exposed to F. prausnitzii culture supernatant (SN) in order to determine the impact of this commensal bacterium on intestinal epithelial cells. Moreover, modulation of the most upregulated gene after F. prausnitzii SN contact was validated both in vitro and in vivo . Our results showed that F. prausnitzii SN upregulates the expression of Dact3 , a gene linked to the Wnt/JNK pathway. Interestingly, when we silenced Dact3 expression, the effect of F. prausnitzii SN was lost. Butyrate was identified as the F. prausnitzii effector responsible for Dact3 modulation. Dact3 upregulation was also validated in vivo in both healthy and inflamed mice treated with either F. prausnitzii SN or the live bacteria, respectively. Finally, we demonstrated by colon transcriptomics that gut microbiota directly influences Dact3 expression. This study provides new clues about the host molecular mechanisms involved in the anti-inflammatory effects of the beneficial commensal bacterium F. prausnitzii .

Lipidomic techniques can improve our understanding of complex lipid interactions that regulate metabolic diseases. Here, a serum phospholipidomics analysis identified associations between phosphatidylglycerols (PGs) and gut microbiota dysbiosis. Compared with the other phospholipids, serum PGs were the most elevated in patients with low microbiota gene richness, which were normalized after a dietary intervention that restored gut microbial diversity. Serum PG levels were positively correlated with metagenomic functional capacities for bacterial LPS synthesis and host markers of low-grade inflammation; transcriptome databases identified PG synthase, the first committed enzyme in PG synthesis, as a potential mediator. Experiments in mice and cultured human-derived macrophages demonstrated that LPS induces PG release. Acute PG treatment in mice altered adipose tissue gene expression toward remodeling and inhibited ex vivo lipolysis in adipose tissue, suggesting that PGs favor lipid storage. Indeed, several PG species were associated with the severity of obesity in mice and humans. Finally, despite enrichment in PGs in bacterial membranes, experiments employing gnotobiotic mice colonized with recombinant PG overproducing Lactococcus lactis showed limited direct contribution of microbial PGs to the host. In summary, PGs are inflammation-responsive lipids indirectly regulated by the gut microbiota via endotoxins and regulate adipose tissue homeostasis in obesity.-Kayser, B. D., Lhomme, M., Prifti, E., Da Cunha, C., Marquet, F., Chain, F., Naas, I., Pelloux, V., Dao, M.-C., Kontush, A., Rizkalla, S. W., Aron-Wisnewsky, J., Bermúdez-Humarán, L. G., Oakley, F., Langella, P., Clément, K., Dugail, I. Phosphatidylglycerols are induced by gut dysbiosis and inflammation, and favorably modulate adipose tissue remodeling in obesity.

The aims of this study were to develop strains of lactic acid bacteria (LAB) having both immunomodulatory and antioxidant properties and to evaluate their anti-inflammatory effects both in vitro, in different cellular models, and in vivo, in a mouse model of colitis. Different Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus strains were cocultured with primary cultures of mononuclear cells. Analysis of the pro- and anti-inflammatory cytokines secreted by these cells after coincubation with candidate bacteria revealed that L. delbrueckii subsp. bulgaricus CRL 864 and S. thermophilus CRL 807 display the highest anti-inflammatory profiles in vitro. Moreover, these results were confirmed in vivo by the determination of the cytokine profiles in large intestine samples of mice fed with these strains. S. thermophilus CRL 807 was then transformed with two different plasmids harboring the genes encoding catalase (CAT) or superoxide dismutase (SOD) antioxidant enzymes, and the anti-inflammatory effects of recombinant streptococci were evaluated in a mouse model of colitis induced by trinitrobenzenesulfonic acid (TNBS). Our results showed a decrease in weight loss, lower liver microbial translocation, lower macroscopic and microscopic damage scores, and modulation of the cytokine production in the large intestines of mice treated with either CAT- or SOD-producing streptococci compared to those in mice treated with the wild-type strain or control mice without any treatment. Furthermore, the greatest anti-inflammatory activity was observed in mice receiving a mixture of both CAT- and SOD-producing streptococci. The addition of L. delbrueckii subsp. bulgaricus CRL 864 to this mixture did not improve their beneficial effects. These findings show that genetically engineering a candidate bacterium (e.g., S. thermophilus CRL 807) with intrinsic immunomodulatory properties by introducing a gene expressing an antioxidant enzyme enhances its anti-inflammatory activities.

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine produced by TH17 cells that participates and contributes in host defense and autoimmune disease. We have recently reported antitumor properties of the probiotic strain of Lactobacillus casei BL23 in mice and TH17 cells was shown to play an important role in this beneficial effect. In order to better understand the role of IL-17A in cancer, we constructed a recombinant strain of Lactococcus lactis producing this cytokine and we determined its biological activity in: (i) a bioassay test for the induction of IL-6 production by murine fibroblasts 3T3 L1 cells line and (ii) in a mouse allograft model of human papilloma virus (HPV)-induced cancer. Our data show that recombinant L. lactis produces and efficiently secretes biologically active IL-17A cytokine. Interestingly, ∼26% of mice intranasally treated with L. lactis -IL-17A and challenged with TC-1 cells remained tumor free over the experiment, in contrast to control mice treated with the wild type strain of L. lactis which developed 100% of aggressive tumors. In addition, the median size of the ∼74% tumor-bearing mice treated with recombinant L. lactis -IL-17A, was significantly lower than mice treated with L. lactis -wt. Altogether, our results demonstrate that intranasal administration with L. lactis secreting IL-17A results in a partial protection against TC-1-induced tumors in mice, confirming antitumor effects of this cytokine in our cancer model. [ABSTRACT FROM AUTHOR]