Weaning process is commonly associated with gastrointestinal inflammation and dysbiosis of the intestinal microbes. In particular, the impact of gut bacteria and extracellular vesicles on the etiology of intestinal inflammation during weaning is not well understood. We have uncovered a potential link between gut inflammation and the corresponding variation of macrophage bacterial sensing and pro-inflammatory polarization during the weaning process of piglets through single-cell transcriptomic analyses. We conducted a comprehensive analysis of bacterial distribution across the gastrointestinal tract and pinpointed Bacteroides uniformis enriching in piglets undergoing weaning. Next, we found out that exposure to B. uniformis-derived extracellular vesicles (BEVs) exacerbated gut inflammation in a murine colitis model while recruiting and polarizing intestinal macrophages toward a pro-inflammatory phenotype. BEVs modulated the function of macrophages cultured in vitro by suppressing the granulocyte-macrophage colony-stimulating factor/signal transducer and activator of transcription 5/arginase 1 pathway, thereby affecting polarization toward an M1-like state. The effects of BEVs were verified both in the macrophage clearance murine model and by using an adoptive transfer assay. Our findings highlight the involvement of BEVs in facilitating the polarization of pro-inflammatory macrophages and promoting gut inflammation during weaning.

UNASSIGNED: Previous research has partially revealed distinct gut microbiota in ankylosing spondylitis (AS). In this study, we performed non-targeted fecal metabolomics in AS in order to discover the microbiome-metabolome interface in AS. Based on prospective cohort studies, we further explored the impact of the tumor necrosis factor inhibitor (TNFi) on the gut microbiota and metabolites in AS.
UNASSIGNED: To further understand the gut microbiota and metabolites in AS, along with the influence of TNFi, we initiated a prospective cohort study. Fecal samples were collected from 29 patients with AS before and after TNFi therapy and 31 healthy controls. Metagenomic and metabolomic experiments were performed on the fecal samples; moreover, validation experiments were conducted based on the association between the microbiota and metabolites.
UNASSIGNED: A total of 7,703 species were annotated using the metagenomic sequencing system and by profiling the microbial community taxonomic composition, while 50,046 metabolites were identified using metabolite profiling. Differential microbials and metabolites were discovered between patients with AS and healthy controls. Moreover, TNFi was confirmed to partially restore the gut microbiota and the metabolites. Multi-omics analysis of the microbiota and metabolites was performed to determine the associations between the differential microbes and metabolites, identifying compounds such as oxypurinol and biotin, which were correlated with the inhibition of the pathogenic bacteria Ruminococcus gnavus and the promotion of the probiotic bacteria Bacteroides uniformis. Through experimental studies, the relationship between microbes and metabolites was further confirmed, and the impact of these two types of microbes on the enterocytes and the inflammatory cytokine interleukin-18 (IL-18) was explored.
UNASSIGNED: In summary, multi-omics exploration elucidated the impact of TNFi on the gut microbiota and metabolites and proposed a novel therapeutic perspective: supplementation of compounds to inhibit potential pathogenic bacteria and to promote potential probiotics, therefore controlling inflammation in AS.

The mechanisms of how host-microbe mutualistic relationships are established at weaning contingently upon B-cell surveillance remain inadequately elucidated. We found that CD138+ plasmacyte (PC)-mediated promotion of IgA response regulates the symbiosis between Bacteroides uniformis (B. uniformis) and the host during the weaning period. The IgA-skewed response of CD138+ PCs is essential for B. uniformis to occupy a defined gut luminal niche, thereby fostering stable colonization. Furthermore, B. uniformis within the natural gut niche was perturbed in the absence of IgA, resulting in exacerbated gut inflammation in IgA-deficient mice and weaned piglets. Thus, we propose that the priming and maintenance of intestinal IgA response from CD138+ PCs are required for host-microbial symbiosis, whereas the perturbation of which would enhance inflammation in weaning process.

Hepatic immunity is one of the driving forces for the development of nonalcoholic steatohepatitis (NASH), and targeting gut microbiota is believed to affect the hepatic immune constitution. Here, we aimed to investigate the hepatic immunological state in NASH, with a specific emphasis on natural killer (NK) cells. In addition, we aimed to identify the contributing species that target hepatic immunity to provide new directions and support the feasibility of immunotherapy for NASH. A possible NASH population was determined by combination of long-term severe fatty liver, metabolic disorders and increased serum CK18 to detect serum immune factors and gut microbiota. NASH was induced in mice fed a high-fat diet to verify the prophylactic effect of the functional species on the immunopathology and development of NASH. Hepatic immunologic state was examined, and the effector functions of NK cells were detected. Hepatic transcriptome, proteomic, and fecal metagenome were performed. We observed a statistical increase in serum IL-10 (p < 0.001) and non-statistical decrease in interferon-γ and IL-6 in NASH population, hinting at the possibility of immune tolerance. Fecal Bacteroides uniformis and Bifidobacterium bifidum were abundant in healthy population but depleted in NASH patients. In NASH mice, hepatic CD8+T cells, macrophages, and dendritic cells were increased (p < 0.01), and NK cells were inhibited, which were identified with decreased granzyme B (p < 0.05). Bacteroides uniformis and Bifidobacterium bifidum improved hepatic pathological and metabolic cues, increased hepatic NK cells and reduced macrophages (p < 0.05). Bacteroides uniformis also restored hepatic NK cell function, which was identified as increased CD107a (p < 0.05). Transcriptional and translational profiling revealed that the functional species might restore the function of hepatic NK cells through multiple pathways, such as reduction of inhibitory molecules in NK cells. Bacteroides uniformis and Bifidobacterium bifidum are novel prophylactics for NASH that restore the impaired function of hepatic NK cells.

Previous studies have demonstrated that the intestinal abundance of Bacteroides uniformis is significantly higher in healthy controls than that in patients with ulcerative colitis (UC). However, what effect B. uniformis has on the development of UC has not been characterized. Here, we show for the first time that B. uniformis F18-22, an alginate-fermenting bacterium isolated from the healthy human colon, protects against dextran-sulfate-sodium (DSS)-induced UC in mice. Specifically, oral intake of B. uniformis F18-22 alleviated colon contraction, improved intestinal bleeding and attenuated mucosal damage in diseased mice. Additionally, B. uniformis F18-22 improved gut dysbiosis in UC mice by increasing the abundance of anti-inflammatory acetate-producing bacterium Eubacterium siraeum and decreasing the amount of pro-inflammatory pathogenetic bacteria Escherichia-Shigella spp. Moreover, B. uniformis F18-22 was well-tolerated in mice and showed no oral toxicity after repeated daily administration for 28 consecutive days. Taken together, our study illustrates that B. uniformis F18-22 is a safe and novel probiotic bacterium for the treatment of UC from the healthy human colon.

Lychee pulp phenolics (LPP) is mainly catabolized in the host colon, increasing the abundances of Bacteroides and Lactobacillus. Herein, five selected gut microbial strains (Bacteroides uniformis, B. thetaiotaomicron, Lactobacillus rhamnosus, L. plantarum, and L. acidophilus) were separately incubated with LPP to ascertain the specific strains participating in phenolic metabolism and the corresponding metabolites. The results indicated that B. uniformis, L. rhamnosus, and L. plantarum were involved in LPP utilization, contributing to 52.37, 28.33, and 45.11% of LPP degradation after 48 h fermentation, respectively. Unprecedentedly, the metabolic pathway of the major phenolic compound quercetin-3-O-rutinose-7-O-α-L-rhamnoside by L. plantarum, appeared to be the direct fission of C-ring at C2-O1 and C3-C4 bonds, which was proved from the occurrence of two substances with the deprotonated molecule [M-H]- ion at m/z 299 and 459, respectively. Meanwhile, it was fully confirmed that B. uniformis participated in the catabolism of isorhamnetin glycoside and procyanidin B2. In the B. uniformis culture, kaempferol was synthesized through dehydroxylation of quercetin which could be catabolized into alphitonin by L. rhamnosus. Furthermore, LPP metabolites exerted higher antioxidant activity than their precursors and gave clues to understand the interindividual differences for phenolic metabolism by gut microbiota.

Dietary habits and gut microbiota play an essential role in non-alcoholic fatty liver disease (NAFLD) and related factors such as insulin resistance and de novo lipogenesis. In this study, we investigated the protective effects of Bacteroides uniformis CBA7346, isolated from the gut of healthy Koreans, on mice with high-fat diet (HFD)-induced NAFLD. Administration of B. uniformis CBA7346 reduced body and liver weight gain, serum alanine aminotransferase and aspartate aminotransferase levels, liver steatosis, and liver triglyceride levels in mice on an HFD; the strain also decreased homeostatic model assessment for insulin resistance values, as well as serum cholesterol, triglyceride, lipopolysaccharide, leptin, and adiponectin levels in mice on an HFD. Moreover, B. uniformis CBA7346 controlled fatty liver disease by attenuating steatosis and inflammation and regulating de novo lipogenesis-related proteins in mice on an HFD. Taken together, these findings suggest that B. uniformis CBA7346 ameliorates HFD-induced NAFLD by reducing insulin resistance and regulating de novo lipogenesis in obese mice.

In our previous study the enrichment of the intestinal proteome of type 1 diabetes (T1D) children with Bacteroides proteins was observed, which led us to our current study that aimed to isolate and characterize Bacteroides species from fecal samples of T1D and control children. Repetitive sequence-based PCR (rep-PCR) was used for typing the isolated Bacteroides species. The antibiotic susceptibility and mucinolytic activity of the isolates was determined. The quantification of specific bacterial groups in the fecal samples was determined by qPCR. The ability to adhere and invade the human colonic cell line HT29-MTX-E12 of strains of P. dorei, B. uniformis and P. distasonis was determined and their whole genome sequencing was performed. The results showed similar numbers of Bacteroides species in T1D and control samples, but unique Bacteroides species and a higher recovery of P. distasonis from T1D samples was observed. Rep-PCR grouped the different Bacteroides species, but no discrimination by origin was achieved. T1D children showed a significant increase in Proteobacteria and a depletion in Lactobacillus sp. All tested P. dorei, B. uniformis and P. distasonis were able to adhere to HT29-MTX-E12 cells but significant differences (p < 0.05) in the ability to invade was observed. The highest ability to invade was exhibited by P. distasonis PtF D14MH1 and P. dorei PtFD16P1, while B. uniformis strains were unable to invade. The damage to tight junctions was also observed. The presence of Lactobacillus sp. inhibited the invasion ability of P. distasonis PtF D14MH1 but not P. dorei PtFD16P1. Sequences of agonist peptides of the human natural preproinsulin and the insulin B chain insB:9-23 peptide mimics were identified. The results reported in our study stresses the continued efforts required to clarify the link between T1D and gut microbiota.

Fecal microbiota transplantation following triple-antibiotic therapy (amoxicillin/fosfomycin/metronidazole) improves dysbiosis caused by reduced Bacteroidetes diversity in patients with ulcerative colitis (UC). We investigated the correlation between Bacteroidetes species abundance and UC activity. Fecal samples from 34 healthy controls and 52 patients with active UC (Lichtiger\'s clinical activity index ≥5 or Mayo endoscopic subscore ≥1) were subjected to next-generation sequencing with HSP60 as a target in bacterial metagenome analysis. A multiplex gene expression assay using colonoscopy-harvested mucosal tissues determined the involvement of Bacteroidetes species in the mucosal immune response. In patients with UC, six Bacteroides species exhibited significantly lower relative abundance, and twelve Bacteroidetes species were found significantly correlated with at least one metric of disease activity. The abundance of five Bacteroidetes species (Alistipes putredinis, Bacteroides stercoris, Bacteroides uniformis, Bacteroides rodentium, and Parabacteroides merdae) was correlated with three metrics, and their cumulative relative abundance was strongly correlated with the sum of Mayo endoscopic subscore (R = -0.71, p = 2 × 10-9). Five genes (TARP, C10ORF54, ITGAE, TNFSF9, and LCN2) associated with UC pathogenesis were expressed by the 12 key species. The loss of key species may exacerbate UC activity, serving as potential biomarkers.

The preventive effect of lychee pulp phenolics (LPP) on dextran sulfate sodium (DSS)-induced colitis of mice and its underlying mechanisms were investigated in this research. LPP supplementation mitigated DSS-induced breakage of the gut barrier as evidenced by the increased tight junction proteins and the enhanced integrity of epithelial cells. Both LPP and 5-ASA treatments could downregulate the expressions of toll-like receptor 4 (TLR-4), NOD protein-like receptor 3 (NLRP3), and proinflammatory cytokines to normal levels. Notably, treatment with LPP at a dosage of 500 mg/kg/day effectively upregulated FFAR2 and FFAR3 expression and contents of short-chain fatty acids (SCFAs), suggesting the activation of the SCFA-FFAR (free fatty acid receptor) pathway. Consistently, the abundances of probiotic taxa and microbiota (Akkermansia, Lactobacillus, Coprococcus, and Bacteroides uniformis) associated with SCFA synthesis were elevated, whereas harmful bacteria (Enterococcus and Aggregatibacter) were suppressed. These data indicate that LPP ameliorates gut barrier damage, activates the microbiota-SCFA-FFAR signaling cascade, and suppresses the TLR4/NLRP3-NF-κB pathway, and therefore, LPP supplementation could be a promising way to protect the intestinal tract.