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Research Square Apr 2024Malaria is a major public health problem, but many of the factors underlying the pathogenesis of this disease are not well understood. Here, we demonstrate in Malian...
Malaria is a major public health problem, but many of the factors underlying the pathogenesis of this disease are not well understood. Here, we demonstrate in Malian children that susceptibility to febrile malaria following infection with is associated with the composition of the gut microbiome prior to the malaria season. Gnotobiotic mice colonized with the fecal samples of malaria-susceptible children had a significantly higher parasite burden following infection compared to gnotobiotic mice colonized with the fecal samples of malaria-resistant children. The fecal microbiome of the susceptible children was enriched for bacteria associated with inflammation, mucin degradation, gut permeability and inflammatory bowel disorders (e.g., and sp. YL32). However, the susceptible children also had a greater abundance of bacteria known to produce anti-inflammatory short-chain fatty acids and those associated with favorable prognosis and remission following dysbiotic intestinal events (e.g., and . Metabolomics analysis of the human fecal samples corroborated the existence of inflammatory and recovery-associated features within the gut microbiome of the susceptible children. There was an enrichment of nitric oxide-derived DNA adducts (deoxyinosine and deoxyuridine) and long-chain fatty acids, the absorption of which has been shown to be inhibited by inflamed intestinal epithelial cells, and a decrease in the abundance of mucus phospholipids. Nevertheless, there were also increased levels of pseudouridine and hypoxanthine, which have been shown to be regulated in response to cellular stress and to promote recovery following injury or hypoxia. Overall, these results indicate that the gut microbiome may contribute malaria pathogenesis and suggest that therapies targeting intestinal inflammation could decrease malaria susceptibility.
PubMed: 38645126
DOI: 10.21203/rs.3.rs-3974068/v1 -
Frontiers in Nutrition 2024To produce the health-associated metabolite propionate, gut microbes require vitamin B12 as a cofactor to convert succinate to propionate. B12 is sourced in the human...
To produce the health-associated metabolite propionate, gut microbes require vitamin B12 as a cofactor to convert succinate to propionate. B12 is sourced in the human gut from the unabsorbed dietary fraction and microbial production. However, experimental data for B12 production by gut microbes is scarce, especially on their produced B12-analogues. Further, the promotion of propionate production by microbially-produced and dietary B12 is not yet fully understood. Here, we demonstrated B12 production in 6 out of 8 predicted B12-producing bacteria from the human gut. Next, we showed that B12 produced by , and promoted succinate to propionate conversion of two prevalent B12-auxotrophic gut bacteria, and . Finally, we examined the propiogenic effect of commercially available B12-analogues present in the human diet (cyano-B12, adenosyl-B12 and hydroxy-B12) at two doses. The low dose resulted in partial conversion of succinate to propionate for when grown with adenosyl-B12 (14.6 ± 2.4 mM succinate and 18.7 ± 0.6 mM propionate) and hydroxy-B12 (13.0 ± 1.1 mM and 21.9 ± 1.2 mM), in comparison to cyano-B12 (0.7 ± 0.1 mM and 34.1 ± 0.1 mM). Higher doses of adenosyl-B12 and hydroxy-B12 resulted in significantly more conversion of succinate to propionate in both propionate-producing species, compared to the low dose. B12 analogues have different potential to impact the propionate metabolism of prevalent propionate producers in the gut. These results could contribute to strategies for managing gut disorders associated with decreased propionate production.
PubMed: 38389799
DOI: 10.3389/fnut.2024.1360199 -
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 -
Microbiology Spectrum Dec 2023The identification of short open reading frame-encoded peptides (SEP) and different proteoforms in single cultures of gut microbes offers new insights into a largely...
The identification of short open reading frame-encoded peptides (SEP) and different proteoforms in single cultures of gut microbes offers new insights into a largely neglected part of the microbial proteome landscape. This is of particular importance as SEP provide various predicted functions, such as acting as antimicrobial peptides, maintaining cell homeostasis under stress conditions, or even contributing to the virulence pattern. They are, thus, taking a poorly understood role in structure and function of microbial networks in the human body. A better understanding of SEP in the context of human health requires a precise understanding of the abundance of SEP both in commensal microbes as well as pathogens. For the gut beneficial , we demonstrate the importance of specific environmental conditions for biosynthesis of SEP expanding previous findings about their role in microbial interactions.
Topics: Humans; Open Reading Frames; Peptides; Antimicrobial Peptides; Proteome
PubMed: 37782090
DOI: 10.1128/spectrum.02528-23 -
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 -
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 -
Metabolites Apr 2023Diet energy is a key component of pet food, but it is usually ignored during pet food development and pet owners also have limited knowledge of its importance. This...
Diet energy is a key component of pet food, but it is usually ignored during pet food development and pet owners also have limited knowledge of its importance. This study aimed to explore the effect of diet energy on the body condition, glucolipid metabolism, fecal microbiota and metabolites of adult beagles and analyze the relation between diet and host and gut microbiota. Eighteen healthy adult neutered male beagles were selected and randomly divided into three groups. Diets were formulated with three metabolizable energy (ME) levels: the low-energy (Le) group consumed a diet of 13.88 MJ/kg ME; the medium-energy (Me) group consumed a diet of 15.04 MJ/kg ME; and the high-energy (He) group consumed a diet of 17.05 MJ/kg ME. Moreover, the protein content of all these three diets was 29%. The experiment lasted 10 weeks, with a two-week acclimation period and an eight-week test phase. Body weight, body condition score (BCS), muscle condition score (MCS) and body fat index (BFI) decreased in the Le group, and the changes in these factors in the Le group were significantly higher than in the other groups ( < 0.05). The serum glucose and lipid levels of the Le and He groups changed over time ( < 0.05), but those of the Me group were stable ( > 0.05). The fecal pH of the Le and He groups decreased at the end of the trial ( < 0.05) and we found that the profiles of short-chain fatty acids (SCFAs) and bile acids (BAs) changed greatly, especially secondary BAs ( < 0.05). As SCFAs and secondary BAs are metabolites of the gut microbiota, the fecal microbiota was also measured. Fecal 16S rRNA gene sequencing found that the Me group had higher α-diversity indices ( < 0.05). The Me group had notably higher levels of gut probiotics, such as , and ( < 0.05). The diet-host-fecal microbiota interactions were determined by network analysis, and fecal metabolites may help to determine the best physical condition of dogs, assisting pet food development. Overall, feeding dogs low- or high-energy diets was harmful for glucostasis and promoted the relative abundance of pathogenic bacteria in the gut, while a medium-energy diet maintained an ideal body condition. We concluded that dogs that are fed a low-energy diet for an extended period may become lean and lose muscle mass, but diets with low energy levels and 29% protein may not supply enough protein for dogs losing weight.
PubMed: 37110212
DOI: 10.3390/metabo13040554 -
Cancer Research Communications Jan 2023Although short-term feeding studies demonstrated effects of grains, fiber, and gluten on gut microbiome composition, the impact of habitual intake of these dietary...
UNLABELLED
Although short-term feeding studies demonstrated effects of grains, fiber, and gluten on gut microbiome composition, the impact of habitual intake of these dietary factors is poorly understood. We examined whether habitual intakes of whole and refined grains, fiber, and gluten are associated with gut microbiota in a cross-sectional study. This study included 779 participants from the multi-ethnic Food and Microbiome Longitudinal Investigation study. Bacterial 16SV4 rRNA gene from baseline stool was amplified and sequenced using Illumina MiSeq. Read clustering and taxonomic assignment was performed using QIIME2. Usual dietary intake was assessed by a 137-item food frequency questionnaire. Association of diet with gut microbiota was assessed with respect to overall composition and specific taxon abundances. Whole grain intake was associated with overall composition, as measured by the Jensen-Shannon divergence (multivariable-adjusted for quartiles = 0.03). The highest intake quartile was associated with higher abundance of , , , and Erysipelotrichaceae and lower abundance of . These bacteria also varied by dietary fiber intake. Higher refined grain and gluten intake was associated with lower Shannon diversity ( < 0.05). These findings suggest that whole grain and dietary fiber are associated with overall gut microbiome structure, largely fiber-fermenting microbiota. Higher refined grain and gluten intakes may be associated with lower microbial diversity.
SIGNIFICANCE
Regular consumption of whole grains and dietary fiber was associated with greater abundance of gut bacteria that may lower risk of colorectal cancer. Further research on the association of refined grains and gluten with gut microbial composition is needed to understand their roles in health and disease.
Topics: Humans; Gastrointestinal Microbiome; Glutens; Cross-Sectional Studies; Diet; Bacteria; Dietary Fiber
PubMed: 36968219
DOI: 10.1158/2767-9764.CRC-22-0154 -
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