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Cell Host & Microbe Mar 2020Dietary fibers (DFs) impact the gut microbiome in ways often considered beneficial. However, it is unknown if precise and predictable manipulations of the gut... (Randomized Controlled Trial)
Randomized Controlled Trial
Dietary fibers (DFs) impact the gut microbiome in ways often considered beneficial. However, it is unknown if precise and predictable manipulations of the gut microbiota, and especially its metabolic activity, can be achieved through DFs with discrete chemical structures. Using a dose-response trial with three type-IV resistant starches (RS4s) in healthy humans, we found that crystalline and phosphate cross-linked starch structures induce divergent and highly specific effects on microbiome composition that are linked to directed shifts in the output of either propionate or butyrate. The dominant RS4-induced effects were remarkably consistent within treatment groups, dose-dependent plateauing at 35 g/day, and can be explained by substrate-specific binding and utilization of the RS4s by bacterial taxa with different pathways for starch metabolism. Overall, these findings support the potential of using discrete DF structures to achieve targeted manipulations of the gut microbiome and its metabolic functions relevant to health.
Topics: Adult; Butyrates; Dietary Fiber; Dietary Supplements; Fatty Acids, Volatile; Female; Gastrointestinal Microbiome; Humans; Male; Propionates; Starch; Young Adult
PubMed: 32004499
DOI: 10.1016/j.chom.2020.01.006 -
Cell Death & Disease Apr 2023Evidence shows that short-chain fatty acids (SCFAs) play an important role in health maintenance and disease development. In particular, butyrate is known to induce...
Evidence shows that short-chain fatty acids (SCFAs) play an important role in health maintenance and disease development. In particular, butyrate is known to induce apoptosis and autophagy. However, it remains largely unclear whether butyrate can regulate cell ferroptosis, and the mechanism by which has not been studied. In this study, we found that RAS-selective lethal compound 3 (RSL3)- and erastin-induced cell ferroptosis were enhanced by sodium butyrate (NaB). With regard to the underlying mechanism, our results showed that NaB promoted ferroptosis by inducing lipid ROS production via downregulating the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). Moreover, the FFAR2-AKT-NRF2 axis and FFAR2-mTORC1 axis accounts for the NaB-mediated downregulation of SLC7A11 and GPX4, respectively, in a cAMP-PKA-dependent manner. Functionally, we found that NaB can inhibit tumor growth and the inhibitory effect could be eliminated by administrating MHY1485 (mTORC1 activator) and Ferr-1 (ferroptosis inhibitor). Altogether, in vivo results suggest that NaB treatment is correlated to the mTOR-dependent ferroptosis and consequent tumor growth through xenografts and colitis-associated colorectal tumorigenesis, implicating the potential clinical applications of NaB for future colorectal cancer treatments. Based on all these findings, we have proposed a regulatory mechanism via which butyrate inhibits the mTOR pathway to control ferroptosis and consequent tumorigenesis.
Topics: Humans; Butyric Acid; Carcinogenesis; Cell Transformation, Neoplastic; Ferroptosis; Mechanistic Target of Rapamycin Complex 1; TOR Serine-Threonine Kinases
PubMed: 37185889
DOI: 10.1038/s41419-023-05778-0 -
Redox Biology Sep 2023Ferroptosis has emerged to be a promising approach in cancer therapies; however, colorectal cancer (CRC) is relatively insensitive to ferroptosis. Exactly how the gut...
Ferroptosis has emerged to be a promising approach in cancer therapies; however, colorectal cancer (CRC) is relatively insensitive to ferroptosis. Exactly how the gut microenvironment impacts the ferroptotic sensitivity of CRC remains unknown. Herein, by performing metabolomics, we discovered that butyrate concentrations were significantly decreased in CRC patients. Butyrate supplementation sensitized CRC mice to ferroptosis induction, showing great in vivo translatability. Particularly, butyrate treatment reduced ferroptotic resistance of cancer stem cells. Mechanistically, butyrate inhibited xCT expression and xCT-dependent glutathione synthesis. Moreover, we identified c-Fos as a novel xCT suppressor, and further elucidated that butyrate induced c-Fos expression via disrupting class I HDAC activity. In CRC patients, butyrate negatively correlated with tumor xCT expression and positively correlated with c-Fos expression. Finally, butyrate was found to boost the pro-ferroptotic function of oxaliplatin (OXA). Immunohistochemistry data showed that OXA non-responders exhibited higher xCT expression compared to OXA responders. Hence, butyrate supplementation is a promising approach to break the ferroptosis resistance in CRC.
Topics: Mice; Animals; Ferroptosis; Butyrates; Oxaliplatin; Colorectal Neoplasms; Tumor Microenvironment
PubMed: 37494767
DOI: 10.1016/j.redox.2023.102822 -
Immunity Dec 2018Nutritional supplementation with probiotics can prevent pathologic bone loss. Here we examined the impact of supplementation with Lactobacillus rhamnosus GG (LGG) on...
Nutritional supplementation with probiotics can prevent pathologic bone loss. Here we examined the impact of supplementation with Lactobacillus rhamnosus GG (LGG) on bone homeostasis in eugonadic young mice. Micro-computed tomography revealed that LGG increased trabecular bone volume in mice, which was due to increased bone formation. Butyrate produced in the gut following LGG ingestion, or butyrate fed directly to germ-free mice, induced the expansion of intestinal and bone marrow (BM) regulatory T (Treg) cells. Interaction of BM CD8 T cells with Treg cells resulted in increased secretion of Wnt10b, a bone anabolic Wnt ligand. Mechanistically, Treg cells promoted the assembly of a NFAT1-SMAD3 transcription complex in CD8 cells, which drove expression of Wnt10b. Reducing Treg cell numbers, or reconstitution of TCRβ mice with CD8 T cells from Wnt10b mice, prevented butyrate-induced bone formation and bone mass acquisition. Thus, butyrate concentrations regulate bone anabolism via Treg cell-mediated regulation of CD8 T cell Wnt10b production.
Topics: Animals; Butyrates; CD8-Positive T-Lymphocytes; Cell Communication; Cell Proliferation; Female; Lacticaseibacillus rhamnosus; Mice, Inbred C57BL; Mice, Knockout; Osteoblasts; Osteogenesis; Probiotics; T-Lymphocytes, Regulatory; Wnt Proteins
PubMed: 30446387
DOI: 10.1016/j.immuni.2018.10.013 -
Nature Communications May 2022The gut microbiota has been linked to many cancers, yet its role in acute myeloid leukaemia (AML) progression remains unclear. Here, we show decreased diversity in the...
The gut microbiota has been linked to many cancers, yet its role in acute myeloid leukaemia (AML) progression remains unclear. Here, we show decreased diversity in the gut microbiota of AML patients or murine models. Gut microbiota dysbiosis induced by antibiotic treatment accelerates murine AML progression while faecal microbiota transplantation reverses this process. Butyrate produced by the gut microbiota (especially Faecalibacterium) significantly decreases in faeces of AML patients, while gavage with butyrate or Faecalibacterium postpones murine AML progression. Furthermore, we find the intestinal barrier is damaged in mice with AML, which accelerates lipopolysaccharide (LPS) leakage into the blood. The increased LPS exacerbates leukaemia progression in vitro and in vivo. Butyrate can repair intestinal barrier damage and inhibit LPS absorption in AML mice. Collectively, we demonstrate that the gut microbiota promotes AML progression in a metabolite-dependent manner and that targeting the gut microbiota might provide a therapeutic option for AML.
Topics: Animals; Butyrates; Dysbiosis; Gastrointestinal Microbiome; Humans; Leukemia, Myeloid, Acute; Lipopolysaccharides; Mice
PubMed: 35534496
DOI: 10.1038/s41467-022-30240-8 -
Cell Reports Nov 2022The precise mechanism by which gut dysbiosis contributes to the pathogenesis of extraintestinal diseases and how commensal microbes mediate these processes remain...
The precise mechanism by which gut dysbiosis contributes to the pathogenesis of extraintestinal diseases and how commensal microbes mediate these processes remain unclear. Here, we show that cows with mastitis had marked gut dysbiosis, characterized by the enrichment of opportunistic pathogenic Escherichia_Shigella and the depletion of commensal Roseburia. Fecal microbiota transplantation from donor cows with mastitis (M-FMT) to recipient mice significantly caused mastitis and changed the gut and mammary microbiota in mice. Notably, M-FMT facilitated the translocation of pathobiont from the gut into the mammary gland, and the depletion of Enterobacteriaceae alleviated M-FMT-induced mastitis in mice. In contrast, commensal Roseburia intestinalis improved M-FMT-induced mastitis and microbial dysbiosis in the gut and mammary gland and limited bacterial translocation by producing butyrate, which was associated with inflammatory signaling inhibition and barrier repair. Our research suggests that commensal Roseburia alleviates gut-dysbiosis-induced mastitis, although further studies in dairy cows and humans are needed.
Topics: Female; Cattle; Mice; Animals; Humans; Dysbiosis; Bacterial Translocation; Butyrates; Gastrointestinal Microbiome; Mastitis
PubMed: 36417859
DOI: 10.1016/j.celrep.2022.111681 -
Proceedings of the National Academy of... May 2023Carbon-based nanomaterials (CNMs) have recently been found in humans raising a great concern over their adverse roles in the hosts. However, our knowledge of the...
Carbon-based nanomaterials (CNMs) have recently been found in humans raising a great concern over their adverse roles in the hosts. However, our knowledge of the in vivo behavior and fate of CNMs, especially their biological processes elicited by the gut microbiota, remains poor. Here, we uncovered the integration of CNMs (single-walled carbon nanotubes and graphene oxide) into the endogenous carbon flow through degradation and fermentation, mediated by the gut microbiota of mice using isotope tracing and gene sequencing. As a newly available carbon source for the gut microbiota, microbial fermentation leads to the incorporation of inorganic carbon from the CNMs into organic butyrate through the pyruvate pathway. Furthermore, the butyrate-producing bacteria are identified to show a preference for the CNMs as their favorable source, and excessive butyrate derived from microbial CNMs fermentation further impacts on the function (proliferation and differentiation) of intestinal stem cells in mouse and intestinal organoid models. Collectively, our results unlock the unknown fermentation processes of CNMs in the gut of hosts and underscore an urgent need for assessing the transformation of CNMs and their health risk via the gut-centric physiological and anatomical pathways.
Topics: Humans; Animals; Mice; Gastrointestinal Microbiome; Nanotubes, Carbon; Fermentation; Nanostructures; Butyrates
PubMed: 37155879
DOI: 10.1073/pnas.2218739120 -
Allergy May 2022Eosinophilic esophagitis (EoE) is a food allergen driven disease that is accompanied by interleukin (IL) 13 overexpression and esophageal barrier dysfunction allowing...
BACKGROUND
Eosinophilic esophagitis (EoE) is a food allergen driven disease that is accompanied by interleukin (IL) 13 overexpression and esophageal barrier dysfunction allowing transepithelial food allergen permeation. Nutraceuticals, such as short-chain fatty acids (SCFAs) that restore barrier function and increase immune fitness may be a promising tool in the management of EoE. Here, we investigated the effects of the SCFAs acetate, propionate, and butyrate on an IL-13-compromised human esophageal epithelial barrier, including the mechanisms involved.
METHODS
An air-liquid interface culture model of differentiated human EPC2-hTERT (EPC2) was used to study whether SCFAs could restore barrier function after IL-13-induced impairment. Esophageal epithelial barrier function was monitored by transepithelial electrical resistance (TEER) and FITC-dextran paracellular flux, and was further examined by qPCR and immunohistochemical analysis. G protein-coupled receptor (GPR) GPR41, GPR43, GPR109a, or histone deacetylase (HDAC) (ant)agonists were used to assess mechanisms of action of SCFAs.
RESULTS
IL-13 stimulation decreased TEER and increased FITC flux, which was counteracted by butyrate and propionate, but not acetate treatment. Barrier proteins FLG and DSG1 mRNA expression was upregulated following butyrate and propionate treatment, whereas expression of eosinophil chemoattractant CCL26 and protease CAPN14 was downregulated. Similarly, butyrate and propionate restored FLG and DSG1 protein expression. Similar effects were observed with an HDAC antagonist but not with GPR agonists.
CONCLUSION
Nutraceuticals butyrate and propionate restore the barrier function of esophageal epithelial cells after an inflammatory insult and may be of therapeutic benefit in the management of EoE.
Topics: Allergens; Butyrates; Eosinophilic Esophagitis; Fatty Acids, Volatile; Humans; Interleukin-13; Propionates
PubMed: 34458999
DOI: 10.1111/all.15069 -
Nature Communications Nov 2023The gut microbiome and its metabolites are increasingly implicated in several cardiovascular diseases, but their role in human myocardial infarction (MI) injury...
The gut microbiome and its metabolites are increasingly implicated in several cardiovascular diseases, but their role in human myocardial infarction (MI) injury responses have yet to be established. To address this, we examined stool samples from 77 ST-elevation MI (STEMI) patients using 16 S V3-V4 next-generation sequencing, metagenomics and machine learning. Our analysis identified an enriched population of butyrate-producing bacteria. These findings were then validated using a controlled ischemia/reperfusion model using eight nonhuman primates. To elucidate mechanisms, we inoculated gnotobiotic mice with these bacteria and found that they can produce beta-hydroxybutyrate, supporting cardiac function post-MI. This was further confirmed using HMGCS2-deficient mice which lack endogenous ketogenesis and have poor outcomes after MI. Inoculation increased plasma ketone levels and provided significant improvements in cardiac function post-MI. Together, this demonstrates a previously unknown role of gut butyrate-producers in the post-MI response.
Topics: Humans; Animals; Mice; Butyrates; Heart; Myocardial Infarction; ST Elevation Myocardial Infarction; Ketone Bodies
PubMed: 37945565
DOI: 10.1038/s41467-023-43167-5 -
Frontiers in Immunology 2022Osteoarthritis (OA) reduces the quality of life as a result of the pain caused by continuous joint destruction. Inactivated (LA-1) ameliorated osteoarthritis and...
Osteoarthritis (OA) reduces the quality of life as a result of the pain caused by continuous joint destruction. Inactivated (LA-1) ameliorated osteoarthritis and protected cartilage by modulating inflammation. In this study, we evaluated the mechanism by which live LA-1 ameliorated OA. To investigate the effect of live LA-1 on OA progression, we administered LA-1 into monosodium iodoacetate (MIA)-induced OA animals. The pain threshold, cartilage damage, and inflammation of the joint synovial membrane were improved by live LA-1. Furthermore, the analysis of intestinal tissues and feces in the disease model has been shown to affect the systems of the intestinal system and improve the microbiome environment. Interestingly, inflammation of the intestinal tissue was reduced, and the intestinal microbiome was altered by live LA-1. Live LA-1 administration led to an increase in the level of which is a short-chain fatty acid (SCFA) butyrate-producing bacteria. The daily supply of butyrate, a bacterial SCFA, showed a tendency to decrease necroptosis, a type of abnormal cell death, by inducing autophagy and reversing impaired autophagy by the inflammatory environment. These results suggest that OA is modulated by changes in the gut microbiome, suggesting that activation of autophagy can reduce aberrant cell death. In summary, live LA-1 or butyrate ameliorates OA progression by modulating the gut environment and autophagic flux. Our findings suggest the regulation of the gut microenvironment as a therapeutic target for OA.
Topics: Animals; Chondrocytes; Cartilage, Articular; Butyrates; Lactobacillus; Quality of Life; Disease Models, Animal; Osteoarthritis; Inflammation; Autophagy; Cell Death
PubMed: 36325344
DOI: 10.3389/fimmu.2022.930511