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Cell Host & Microbe Mar 2023The intestinal microbiota plays an important role in colorectal cancer (CRC) progression. However, the effect of tissue-resident commensal bacteria on CRC immune...
The intestinal microbiota plays an important role in colorectal cancer (CRC) progression. However, the effect of tissue-resident commensal bacteria on CRC immune surveillance remains poorly understood. Here, we analyzed the intratissue bacteria from CRC patient colon tissues. We found that the commensal bacteria belonging to the Lachnospiraceae family, including Ruminococcus gnavus (Rg), Blautia producta (Bp), and Dorea formicigenerans (Df), were enriched in normal tissues, while Fusobacterium nucleatum (Fn) and Peptostreptococcus anaerobius (Pa) were abundant in tumor tissues. Tissue-resident Rg and Bp reduced colon tumor growth and promoted the activation of CD8 T cells in immunocompetent mice. Mechanistically, intratissue Rg and Bp degraded lyso-glycerophospholipids that inhibited CD8 T cell activity and maintained the immune surveillance function of CD8 T cells. Lyso-glycerophospholipids alone promoted tumor growth that was abrogated with Rg and Bp injection. Collectively, intratissue Lachnospiraceae family bacteria facilitate the immune surveillance function of CD8 T cells and control colorectal cancer progression.
Topics: Animals; Mice; Colorectal Neoplasms; CD8-Positive T-Lymphocytes; Carcinogenesis; Colonic Neoplasms; Fusobacterium nucleatum
PubMed: 36893736
DOI: 10.1016/j.chom.2023.01.013 -
Nature Communications Jan 2023The interplay between western diet and gut microbiota drives the development of non-alcoholic fatty liver disease and its progression to non-alcoholic steatohepatitis....
The interplay between western diet and gut microbiota drives the development of non-alcoholic fatty liver disease and its progression to non-alcoholic steatohepatitis. However, the specific microbial and metabolic mediators contributing to non-alcoholic steatohepatitis remain to be identified. Here, a choline-low high-fat and high-sugar diet, representing a typical western diet, named CL-HFS, successfully induces male mouse non-alcoholic steatohepatitis with some features of the human disease, such as hepatic inflammation, steatosis, and fibrosis. Metataxonomic and metabolomic studies identify Blautia producta and 2-oleoylglycerol as clinically relevant bacterial and metabolic mediators contributing to CL-HFS-induced non-alcoholic steatohepatitis. In vivo studies validate that both Blautia producta and 2-oleoylglycerol promote liver inflammation and hepatic fibrosis in normal diet- or CL-HFS-fed mice. Cellular and molecular studies reveal that the GPR119/TAK1/NF-κB/TGF-β1 signaling pathway mediates 2-oleoylglycerol-induced macrophage priming and subsequent hepatic stellate cell activation. These findings advance our understanding of non-alcoholic steatohepatitis pathogenesis and provide targets for developing microbiome/metabolite-based therapeutic strategies against non-alcoholic steatohepatitis.
Topics: Animals; Male; Mice; Diet, High-Fat; Diet, Western; Disease Models, Animal; Gastrointestinal Microbiome; Inflammation; Liver; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Receptors, G-Protein-Coupled
PubMed: 36646715
DOI: 10.1038/s41467-023-35861-1 -
Brain, Behavior, and Immunity Mar 2024Parkinson's disease (PD) is intricately linked to abnormal gut microbiota, yet the specific microbiota influencing clinical outcomes remain poorly understood. Our study...
Parkinson's disease (PD) is intricately linked to abnormal gut microbiota, yet the specific microbiota influencing clinical outcomes remain poorly understood. Our study identified a deficiency in the microbiota genus Blautia and a reduction in fecal short-chain fatty acid (SCFA) butyrate level in PD patients compared to healthy controls. The abundance of Blautia correlated with the clinical severity of PD. Supplementation with butyrate-producing bacterium B. producta demonstrated neuroprotective effects, attenuating neuroinflammation and dopaminergic neuronal death in mice, consequently ameliorating motor dysfunction. A pivotal inflammatory signaling pathway, the RAS-related pathway, modulated by butyrate, emerged as a key mechanism inhibiting microglial activation in PD. The change of RAS-NF-κB pathway in PD patients was observed. Furthermore, B. producta-derived butyrate demonstrated the inhibition of microglial activation in PD through regulation of the RAS-NF-κB pathway. These findings elucidate the causal relationship between specific gut microbiota and PD, presenting a novel microbiota-based treatment perspective for PD.
Topics: Humans; Animals; Mice; Microglia; Neuroinflammatory Diseases; NF-kappa B; Parkinson Disease; Microbiota; Butyrates; Clostridiales
PubMed: 38211635
DOI: 10.1016/j.bbi.2024.01.010 -
Biomedicine & Pharmacotherapy =... Nov 2022Berberine (BBR) is an effective cholesterol-lowering drug. Although gut microbiota has been implicated in the pharmacological activities of BBR, little evidence exists...
Berberine (BBR) is an effective cholesterol-lowering drug. Although gut microbiota has been implicated in the pharmacological activities of BBR, little evidence exists on the specific species of gut microbiota involved in its therapeutic effects, nor on linking gut bacteria to its recognized hypercholesterolemia-alleviating mechanism-upregulation of the low-density lipoprotein receptor (LDLR) in the liver. The present study was performed to identify the specific species of gut microbiota involved in the anti-hyperlipdemic effect of BBR, and interpret its mechanism through linking the gut microbiota and LDLR. The BBR-enriched gut bacterial species were identified by whole genome shotgun sequencing. Pure cultured B. producta was orally administered to C57BL/6 mice to evaluate its anti-hyperlipdemic effect. The LDLR-upregulating effect of B. producta was evaluated both in vitro and in vivo. Orally administration of BBR (200 mg/kg) decreased serum and liver lipid levels in HFD-induced hyperlipidemic mice. Microbiome analysis indicated that Blautia was closely associated with BBR's lipid-modulating activities. Further analysis revealed that BBR selectively promoted the growth of Blautia producta. Orally treatment of HFD mice with live B. producta reduced obesity and alleviated hyperlipidemia. Notably, the B. producta significantly increased LDLR expression in the liver, and its spent culture supernatant upregulated the LDLR level and promoted LDL uptake by HepG2 cells. Simultaneously, B. producta also linked butyrate-producing and bile salt hydrolase (BSH)-inhibiting effect of BBR. The gut microbiota, especially B. producta, may confers the hypercholesterolemia-alleviating effects of berberine. B. producta represents a novel probiotic that may be used for the treatment of dyslipidemia.
Topics: Mice; Animals; Diet, High-Fat; Berberine; Hyperlipidemias; Hypercholesterolemia; Mice, Inbred C57BL; Liver; Bacteria; Butyrates; Cholesterol; Lipoproteins, LDL
PubMed: 36174380
DOI: 10.1016/j.biopha.2022.113749 -
Biology Feb 2022Intestinal microflora has been associated with obesity. While visceral fat is more strongly associated with cardiovascular disorder, a complication linked to obesity,...
Intestinal microflora has been associated with obesity. While visceral fat is more strongly associated with cardiovascular disorder, a complication linked to obesity, than the body mass index (BMI), the association between intestinal microflora and obesity (as defined in terms of BMI) has been studied widely. However, the link between visceral fat area (VFA) and intestinal microflora has been little studied. In this study, we investigate the association between intestinal microflora and VFA and BMI using a longitudinal study on Japanese subjects with different VFA statuses ( = 767). Principal component analysis of the changes in intestinal microflora composition over the one-year study period revealed the different associations between intestinal microflora and VFA and BMI. As determined by 16S rRNA amplicon sequencing, changes in the abundance ratio of two microbial genera- and -were significantly associated with VFA changes and changes in the abundance ratio of four different microbial genera were significantly associated with BMI changes, suggesting that the associated intestinal microbes are different. Furthermore, as determined by metagenomic shotgun sequences, changes in the abundance ratios of two species- and -were significantly and negatively associated with VFA changes. Our findings might be used to develop a new treatment for visceral fat.
PubMed: 35205184
DOI: 10.3390/biology11020318 -
Gut Microbes 2023Compelling evidence has tightly linked gut microbiota with host metabolism homeostasis and inspired novel therapeutic potentials against metabolic diseases (e.g.,...
Compelling evidence has tightly linked gut microbiota with host metabolism homeostasis and inspired novel therapeutic potentials against metabolic diseases (e.g., hyperlipidemia). However, the regulatory profile of individual bacterial species and strain on lipid homeostasis remains largely unknown. Herein, we performed a large-scale screening of 2250 human gut bacterial strains (186 species) for the lipid-decreasing activity. Different strains in the same species usually displayed distinct lipid-modulatory actions, showing evident strain-specificity. Among the tested strains, exhibited the most potency to suppress cellular lipid accumulation and effectively ameliorated hyperlipidemia in high fat diet (HFD)-feeding mice. Taking a joint comparative approach of pharmacology, genomics and metabolomics, we identified an anteiso-fatty acid, 12-methylmyristic acid (12-MMA), as the key active metabolite of . experiment confirmed that 12-MMA could exert potent hyperlipidemia-ameliorating efficacy and improve glucose metabolism via activating G protein-coupled receptor 120 (GPR120). Altogether, our work reveals a previously unreported large-scale lipid-modulatory profile of gut microbes at the strain level, emphasizes the strain-specific function of gut bacteria, and provides a possibility to develop microbial therapeutics against hyperlipidemia based on and its metabolite.
Topics: Humans; Animals; Mice; Gastrointestinal Microbiome; Fatty Acids; Hyperlipidemias; Probiotics; Ruminococcus; Diet, High-Fat
PubMed: 37408362
DOI: 10.1080/19490976.2023.2228045 -
International Journal of Molecular... Mar 2022Xylan is one of the major structural components of the plant cell wall. Xylan present in the human diet reaches the large intestine undigested and becomes a substrate to...
Xylan is one of the major structural components of the plant cell wall. Xylan present in the human diet reaches the large intestine undigested and becomes a substrate to species of the gut microbiota. Here, we characterised the capacity of and strains to utilise xylan derivatives. We showed that ATCC 53608 and ATCC 27340 produced β-D-xylosidases, enabling growth on xylooligosaccharide (XOS). The recombinant enzymes were highly active on artificial (-nitrophenyl β-D-xylopyranoside) and natural (xylobiose, xylotriose, and xylotetraose) substrates, and showed transxylosylation activity and tolerance to xylose inhibition. The enzymes belong to glycoside hydrolase family 120 with Asp as nucleophile and Glu as proton donor, as shown by homology modelling and confirmed by site-directed mutagenesis. In silico analysis revealed that these enzymes were part of a gene cluster in but not in strains, and quantitative proteomics identified other enzymes and transporters involved in XOS utilisation. Based on these findings, we proposed a model for an XOS metabolism pathway in and strains. Together with phylogenetic analyses, the data also revealed the extended xylanolytic potential of the gut microbiota.
Topics: Bacteria; Glucuronates; Humans; Oligosaccharides; Phylogeny; Substrate Specificity; Xylans; Xylosidases
PubMed: 35328413
DOI: 10.3390/ijms23062992 -
The Journal of Biological Chemistry Jun 2023The β-glucans are structurally varied, naturally occurring components of the cell walls, and storage materials of a variety of plant and microbial species. In the human...
The β-glucans are structurally varied, naturally occurring components of the cell walls, and storage materials of a variety of plant and microbial species. In the human diet, mixed-linkage glucans [MLG - β-(1,3/4)-glucans] influence the gut microbiome and the host immune system. Although consumed daily, the molecular mechanism by which human gut Gram-positive bacteria utilize MLG largely remains unknown. In this study, we used Blautia producta ATCC 27340 as a model organism to develop an understanding of MLG utilization. B. producta encodes a gene locus comprising a multi-modular cell-anchored endo-glucanase (BpGH16), an ABC transporter, and a glycoside phosphorylase (BpGH94) for utilizing MLG, as evidenced by the upregulation of expression of the enzyme- and solute binding protein (SBP)-encoding genes in this cluster when the organism is grown on MLG. We determined that recombinant BpGH16 cleaved various types of β-glucan, generating oligosaccharides suitable for cellular uptake by B. producta. Cytoplasmic digestion of these oligosaccharides is then performed by recombinant BpGH94 and β-glucosidases (BpGH3-AR8 and BpGH3-X62). Using targeted deletion, we demonstrated BpSBP is essential for B. producta growth on barley β-glucan. Furthermore, we revealed that beneficial bacteria, such as Roseburia faecis JCM 17581, Bifidobacterium pseudocatenulatum JCM 1200T, Bifidobacterium adolescentis JCM 1275T, and Bifidobacterium bifidum JCM 1254, can also utilize oligosaccharides resulting from the action of BpGH16. Disentangling the β-glucan utilizing the capability of B. producta provides a rational basis on which to consider the probiotic potential of this class of organism.
Topics: Humans; beta-Glucans; Diet; Oligosaccharides; Dietary Carbohydrates; Hordeum; Probiotics; Clostridiales; Bifidobacterium; Gastrointestinal Microbiome
PubMed: 37172725
DOI: 10.1016/j.jbc.2023.104806 -
Oncoimmunology 2022The microbiome is now regarded as one of the hallmarks of cancer and several strategies to modify the gut microbiota to improve immune checkpoint inhibitor (ICI)...
The microbiome is now regarded as one of the hallmarks of cancer and several strategies to modify the gut microbiota to improve immune checkpoint inhibitor (ICI) activity are being evaluated in clinical trials. Preliminary data regarding the upper gastro-intestinal microbiota indicated that seropositivity was associated with a negative prognosis in patients amenable to ICI. In 97 patients with advanced melanoma treated with ICI, we assessed the impact of on outcomes and microbiome composition. We performed serology and profiled the fecal microbiome with metagenomics sequencing. Among the 97 patients, 22% were positive (Pos). Pos patients had a significantly shorter overall survival () compared to negative (Neg) patients. In addition, objective response rate and progression-free survival were decreased in Pos patients. Metagenomics sequencing did not reveal any difference in diversity indexes between the groups. At the taxa level, , and were increased in the Pos group, while and were over-represented in the Neg group. In a second independent cohort of patients with NSCLC, diversity indexes were similar in both groups and was increased in Neg patients. Our results demonstrated that the negative impact of on outcomes seem to be independent from the fecal microbiome composition. These findings warrant further validation and development of therapeutic strategies to eradicate in immuno-oncology arena.
Topics: Carcinoma, Non-Small-Cell Lung; Helicobacter Infections; Helicobacter pylori; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Melanoma; Syndrome
PubMed: 35832043
DOI: 10.1080/2162402X.2022.2096535 -
Microorganisms Apr 2021In recent years, has attracted attention for its role in ameliorating host diseases. In particular, DSM 2950 has been considered a potential probiotic due to its...
In recent years, has attracted attention for its role in ameliorating host diseases. In particular, DSM 2950 has been considered a potential probiotic due to its ability to mitigate inflammation in poly(I:C) induced HT-29 cells. Thus, to promote the development of indigenous intestinal microorganisms with potential probiotic function, we conducted a comprehensive experimental analysis of DSM 2950 to determine its safety. This comprised a study of its potential virulence genes, antibiotic resistance genes, genomic islands, antibiotic resistance, and hemolytic activity and a 14-day test of its acute oral toxicity in mice. The results indicated no toxin-related virulence genes in the DSM 2950 genome. Most of the genomic islands in DSM 2950 were related to metabolism, rather than virulence expression. DSM 2950 was sensitive to most of the tested antibiotics but was tolerant of treatment with kanamycin, neomycin, clindamycin, or ciprofloxacin, probably because it possessed the corresponding antibiotic resistance genes. Oral acute toxicity tests indicated that the consumption of DSM 2950 does not cause toxic side effects in mice. Overall, the safety profile of DSM 2950 confirmed that it could be a candidate probiotic for use in food and pharmaceutical preparations.
PubMed: 33922843
DOI: 10.3390/microorganisms9050908