Faecalibacterium prausnitzii-derived extracellular vesicles alleviate chronic colitis-related intestinal fibrosis by macrophage metabolic reprogramming.

Faecalibacterium prausnitzii (F. prausnitzii) has been recognized for its various intestinal and extraintestinal benefits to human. And reduction of F. prausnitzii has been linked to an increased risk of intestinal fibrosis in patients of Crohn's disease (CD). In this study, oral administration of either live F. prausnitzii or its extracellular vesicles (FEVs) can markedly mitigate the severity of fibrosis in mice induced by repetitive administration of DSS. In vitro experiment revealed that FEVs were capable of directing the polarization of peripheral blood mononuclear cells (PBMCs) towards an M2b macrophage phenotype, which has been associated with anti-fibrotic activities. This effect of FEV was found to be stable under various conditions that promote the development of pro-fibrotic M1/M2a/M2c macrophages. Proteomics and RNA sequencing were performed to uncover the molecular modulation of macrophages by FEVs. Notably, we found that FEVs reprogramed every metabolism of macrophages by damaging the mitochondria, and inhibited oxidative phosphorylation and glycolysis. Moreover, FEV-treated macrophages showed a decreased expression of PPARγ and an altered lipid processing phenotype characterized by decreased cholesterol efflux, which may promote energy reprogramming. Taken together, these findings identify FEV as a driver of macrophage reprogramming, suggesting that triggering M2b macrophage polarization by oral admiration of FEV may serve as strategy to alleviate hyperfibrotic intestine conditions in CD.

Faecalibacterium prausnitzii produces butyrate to decrease c-Myc-related metabolism and Th17 differentiation by inhibiting histone deacetylase 3.

Decreased levels of Faecalibacterium prausnitzii (F. prausnitzii), whose supernatant plays an anti-inflammatory effect, are frequently found in inflammatory bowel disease (IBD) patients. However, the anti-inflammatory products in F. prausnitzii supernatant and the mechanism have not been fully investigated. Here we found that F. prausnitzii and F. prausnitzii-derived butyrate were decreased in the intestines of IBD patients. Supplementation with F. prausnitzii supernatant and butyrate could ameliorate colitis in an animal model. Butyrate, but not other substances produced by F. prausnitzii, exerted an anti-inflammatory effect by inhibiting the differentiation of T helper 17 (Th17) cells. The mechanism underlying the anti-inflammatory effects of the butyrate produced by F. prausnitzii involved the enhancement of the acetylation-promoted degradation of c-Myc through histone deacetylase 3 (HDAC3) inhibition. In conclusion, F. prausnitzii produced butyrate to decrease Th17 differentiation and attenuate colitis through inhibiting HDAC3 and c-Myc-related metabolism in T cells. The use of F. prausnitzii may be an effective new approach to decrease the level of Th17 cells in the treatment of inflammatory diseases.

Structural and Functional Characterization of the Gut Microbiota in Elderly Women With Migraine.

Migraine is a very common, multifactorial, and recurrent central nervous system disorder that causes throbbing headache, photophobia, phonophobia, nausea, and disability. Migraine occurs more often in females, and its complex physiopathology is not yet fully understood. An increasing number of gastrointestinal disorders have been linked to the occurrence of migraine suggesting that gut microbiota might play a pivotal role in migraine through the gut-brain axis. In the present work, we performed a metagenome-wide association study (MWAS) to determine the relationship between gut microbiota and migraine by analyzing 108 shotgun-sequenced fecal samples obtained from elderly women who suffer from migraine and matched healthy controls. Notably, the alpha diversity was significantly decreased in the migraine group at species, genus, and Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologous levels. Firmicutes, especially the "unfriendly" Clostridium spp., were significantly enriched in the migraine group. Conversely, the healthy controls held more beneficial microorganisms, such as Faecalibacterium prausnitzii, Bifidobacterium adolescentis, and Methanobrevibacter smithii. For functional modules, the migraine group was enriched in gut-brain modules (GBMs) including kynurenine degradation and γ-aminobutyric acid (GABA) synthesis. However, the healthy controls held higher gut metabolic modules (GMMs) including glycolysis, homoacetogenesis, and GBMs including quinolinic acid degradation and S-adenosyl methionine (SAM) synthesis. The differences in gut microbiota composition and function between the migraine and healthy groups provided new information as well as novel therapeutic targets and strategies for migraine treatment, which could help to improve the early diagnosis of the disease, as well as the long-term prognosis and the life quality of patients suffering from migraine.

A reduction in the butyrate producing species Roseburia spp. and Faecalibacterium prausnitzii is associated with chronic kidney disease progression.

The human gut microbiota plays an important role in human health and might also be implicated in kidney disease. The interest in butyrate producing bacteria has recently increased and is a poorly understood faecal condition in chronic kidney disease (CKD). Therefore, we evaluated differences of the butyrate producing species Roseburia spp. and Faecalibacterium prausnitzii in the faeces of Chinese patients with CKD. A case-control study was carried out for 65 CKD patients and 20 healthy controls. Differences were quantitatively validated using quantitative real-time polymerase chain reaction (qPCR). Spearman rank correlation was used to analyse the correlation between gut microbiota and clinical variables. Roseburia spp. and F. prausnitzii were significantly different in CKD patients and controls (p = 0.001; p = 0.025, respectively) and reduced more markedly in end stage renal disease (p = 0.000; p = 0.003, respectively) and microinflammation (p = 0.004; p = 0.001, respectively). Roseburia spp. and F. prausnitzii were negatively associated with C-reactive protein in plasma (r = -0.493, p = 0.00; r = -0.528, p = 0.000; respectively) and Cystatin C (r = -0.321, p = 0.006; r = -0.445, p = 0.000; respectively). They were positively associated with eGFR (r = 0.347, p = 0.002; r = 0.416, p = 0.000; respectively). The negative correlation between Roseburia spp., F. prausnitzii and CRP and renal function suggested that the depletion of butyrate producing bacteria may contribute to CKD-associated inflammation and CKD progression. Roseburia spp. and F. prausnitzii may thus serve as 'microbiomarkers'.

Faecalibacterium prausnitzii supernatant ameliorates dextran sulfate sodium induced colitis by regulating Th17 cell differentiation.

AIM: To explore the preventive and therapeutic effects of Faecalibacterium prausnitzii (F. prausnitzii) supernatant on dextran sulfate sodium (DSS) induced colitis in mice. METHODS: Forty C57BL/6J male mice were randomly divided into four groups: control group, model group, treatment group, and prevention group. Mice were weighed daily. On day 10, the colon length was measured, the colorectal histopathologic damage score (HDS) was assessed, and plasma interleukin (IL)-17A, IL-6, and IL-4 levels were detected by enzyme-linked immunosorbent assay. The expression of transcription factor retinoic acid-related orphan receptor-γt (RORγt) and IL-17A in colon inflammatory mucosa tissue were determined by immunohistochemical assay, and the expression levels of RORγt mRNA, IL-17A mRNA, and IL-6 mRNA were detected by real-time quantitative polymerase chain reaction (PCR). The proportion of Th17 in mononuclear cells in spleen was assayed by fluorescence activated cell sorter. RESULTS: When compared with the model group, the colon length (P < 0.05) and body weight (P < 0.01) in the treatment and prevention groups were significantly increased, and the colon HDS was decreased (P < 0.05 and P < 0.01). There was no statistical difference between the treatment group and prevention group. After treatment with F. prausnitzii supernatant, the plasma levels of IL-17A and IL-6 (P < 0.05), the protein and mRNA expression of IL-17A and RORγt, and the Th17 cell ratio of spleen cells (P < 0.01) were significantly decreased compared to the model group. Plasma IL-4 level in the prevention group was significantly higher than that in the model group (P < 0.05), but there was no significant difference between these two groups in the expression of IL-6 in both the plasma and colon mucosa tissues. CONCLUSION: F. prausnitzii supernatant exerts protective and therapeutic effects on DSS-induced colitis in mice, probably via inhibition of Th17 differentiation and IL-17A secretion in the plasma and colon mucosa tissues. It can also improve colitis in mice by downregulating IL-6 and prevent colitis by upregulating IL-4.