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Cell Communication and Signaling : CCS Aug 2023Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract. The absorption of SCFAs is... (Review)
Review
Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract. The absorption of SCFAs is mediated by substrate transporters, such as monocarboxylate transporter 1 and sodium-coupled monocarboxylate transporter 1, which promote cellular metabolism. An increasing number of studies have implicated metabolites produced by microorganisms as crucial executors of diet-based microbial influence on the host. SCFAs are important fuels for intestinal epithelial cells (IECs) and represent a major carbon flux from the diet, that is decomposed by the gut microbiota. SCFAs play a vital role in multiple molecular biological processes, such as promoting the secretion of glucagon-like peptide-1 by IECs to inhibit the elevation of blood glucose, increasing the expression of G protein-coupled receptors such as GPR41 and GPR43, and inhibiting histone deacetylases, which participate in the regulation of the proliferation, differentiation, and function of IECs. SCFAs affect intestinal motility, barrier function, and host metabolism. Furthermore, SCFAs play important regulatory roles in local, intermediate, and peripheral metabolisms. Acetate, propionate, and butyrate are the major SCFAs, they are involved in the regulation of immunity, apoptosis, inflammation, and lipid metabolism. Herein, we review the diverse functional roles of this major class of bacterial metabolites and reflect on their ability to affect intestine, metabolic, and other diseases. Video Abstract.
Topics: Fatty Acids, Volatile; Butyrates; Propionates; Gastrointestinal Tract; Apoptosis
PubMed: 37596634
DOI: 10.1186/s12964-023-01219-9 -
Immunity Sep 2023Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies...
Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8 T cell metabolism and effector function. βOHB directly increased CD8 T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8 Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8 T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8 T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8 T cell effector responses.
Topics: 3-Hydroxybutyric Acid; Acetylation; CD8-Positive T-Lymphocytes; Histones; Ketone Bodies; Animals; Mice
PubMed: 37516105
DOI: 10.1016/j.immuni.2023.07.002 -
Gut Nov 2023is a probiotic species that can suppress intestinal inflammation by producing metabolites. We aimed to study the role of in colorectal tumourigenesis and immunotherapy.
OBJECTIVE
is a probiotic species that can suppress intestinal inflammation by producing metabolites. We aimed to study the role of in colorectal tumourigenesis and immunotherapy.
DESIGN
abundance was evaluated in stools of patients with colorectal cancer (CRC) (n=444) and healthy controls (n=575). The effects of were studied in or azoxymethane (AOM)-induced CRC mouse models, and in syngeneic mouse xenograft models of CT26 (microsatellite instability (MSI)-low) or MC38 (MSI-high). The change of immune landscape was evaluated by multicolour flow cytometry and immunohistochemistry staining. Metabolites were profiled by metabolomic profiling.
RESULTS
was significantly depleted in stools of patients with CRC compared with healthy controls. administration significantly inhibited tumour formation in mice, which was confirmed in mice with AOM-induced CRC. restored gut barrier function as indicated by improved intestinal permeability and enhanced expression of tight junction proteins. Butyrate was identified as the functional metabolite generated by or butyrate suppressed tumour growth by inducing cytotoxic granzyme B, interferon (IFN)-γ and tumour necrosis factor (TNF)-α CD8 T cells in orthotopic mouse models of MC38 or CT26. or butyrate also significantly improved antiprogrammed cell death protein 1 (anti-PD-1) efficacy in mice bearing MSI-low CT26 tumours. Mechanistically, butyrate directly bound to toll-like receptor 5 (TLR5) receptor on CD8 T cells to induce its activity through activating nuclear factor kappa B (NF-κB) signalling.
CONCLUSION
protects against colorectal tumourigenesis by producing butyrate, which could also improve anti-PD-1 efficacy by inducing functional CD8 T cells. is a potential adjuvant to augment anti-PD-1 efficacy against CRC.
Topics: Humans; Mice; Animals; CD8-Positive T-Lymphocytes; Butyrates; Carcinogenesis; Cell Transformation, Neoplastic; Colorectal Neoplasms
PubMed: 37491158
DOI: 10.1136/gutjnl-2023-330291 -
Science Advances Nov 2023Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain...
Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain unclear. Here, we report the association of placental inflammation (tumor necrosis factor-α) and abnormal maternal glucose metabolism in patients with GDM, and a high fermentable dietary fiber (HFDF; ) could reduce GDM development through gut flora-short-chain fatty acid-placental inflammation axis in GDM mouse model. Mechanistically, HFDF increases abundances of and butyrate, reduces placental-derived inflammation by enhancing gut barrier and inhibiting the transfer of bacterial-derived lipopolysaccharide, and ultimately resists high-fat diet-induced insulin resistance. and butyrate have similar anti-GDM and anti-placental inflammation effects, and they can ameliorate placental function and pregnancy outcome effects probably by dampening placental immune dysfunction. These findings demonstrate the involvement of important placental inflammation-related mechanisms in the progression of GDM and the great potential of HFDFs to reduce susceptibility to GDM through gut-flora-placenta axis.
Topics: Animals; Mice; Pregnancy; Humans; Female; Diabetes, Gestational; Placenta; Insulin Resistance; Butyrates; Inflammation
PubMed: 37922350
DOI: 10.1126/sciadv.adi7337 -
Cell Reports. Medicine Apr 2024Most recurrences of lung cancer (LC) occur within 3 years after surgery, but the underlying mechanism remains unclear. Here, we collect LC tissues with shorter (<3...
Most recurrences of lung cancer (LC) occur within 3 years after surgery, but the underlying mechanism remains unclear. Here, we collect LC tissues with shorter (<3 years, recurrence group) and longer (>3 years, non-recurrence group) recurrence-free survival. By using 16S sequencing, we find that intratumor microbiome diversity is lower in the recurrence group and butyrate-producing bacteria are enriched in the recurrence group. The intratumor microbiome signature and circulating microbiome DNA can accurately predict LC recurrence. We prove that intratumor injection of butyrate-producing bacteria Roseburia can promote subcutaneous tumor growth. Mechanistically, bacteria-derived butyrate promotes LC metastasis by increasing expression of H19 in tumor cells through inhibiting HDAC2 and increasing H3K27 acetylation at the H19 promoter and inducing M2 macrophage polarization. Depletion of macrophages partially abolishes the metastasis-promoting effect of butyrate. Our results provide evidence for the cross-talk between the intratumor microbiome and LC metastasis and suggest the potential prognostic and therapeutic value of the intratumor microbiome.
Topics: Humans; Lung Neoplasms; Butyrates; Neoplasm Recurrence, Local; Microbiota; Macrophages
PubMed: 38565146
DOI: 10.1016/j.xcrm.2024.101488 -
Nature Aug 2023The human gut microbiota has gained interest as an environmental factor that may contribute to health or disease. The development of next-generation probiotics is a...
The human gut microbiota has gained interest as an environmental factor that may contribute to health or disease. The development of next-generation probiotics is a promising strategy to modulate the gut microbiota and improve human health; however, several key candidate next-generation probiotics are strictly anaerobic and may require synergy with other bacteria for optimal growth. Faecalibacterium prausnitzii is a highly prevalent and abundant human gut bacterium associated with human health, but it has not yet been developed into probiotic formulations. Here we describe the co-isolation of F. prausnitzii and Desulfovibrio piger, a sulfate-reducing bacterium, and their cross-feeding for growth and butyrate production. To produce a next-generation probiotic formulation, we adapted F. prausnitzii to tolerate oxygen exposure, and, in proof-of-concept studies, we demonstrate that the symbiotic product is tolerated by mice and humans (ClinicalTrials.gov identifier: NCT03728868 ) and is detected in the human gut in a subset of study participants. Our study describes a technology for the production of next-generation probiotics based on the adaptation of strictly anaerobic bacteria to tolerate oxygen exposures without a reduction in potential beneficial properties. Our technology may be used for the development of other strictly anaerobic strains as next-generation probiotics.
Topics: Animals; Humans; Mice; Butyrates; Gastrointestinal Microbiome; Oxygen; Probiotics; Aerobiosis; Faecalibacterium prausnitzii; Symbiosis; Biotechnology
PubMed: 37532933
DOI: 10.1038/s41586-023-06378-w -
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 -
JAMA Neurology Oct 2023Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system.
OBJECTIVE
To determine the time to onset of symptoms consistent with MS.
DESIGN, SETTING, AND PARTICIPANTS
From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144.
INTERVENTIONS
Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred.
MAIN OUTCOMES
Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs.
RESULTS
Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant.
CONCLUSION AND RELEVANCE
Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03122652.
Topics: Humans; Female; Adult; Multiple Sclerosis; Crotonates; Toluidines; Hydroxybutyrates; Demyelinating Diseases; Double-Blind Method
PubMed: 37603328
DOI: 10.1001/jamaneurol.2023.2815 -
International Journal of Clinical... Jun 2023There are increasing concerns regarding the abusive potential of gabapentinoids putting at risk patients with neuropathic pain requiring long-term pain management. The... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
There are increasing concerns regarding the abusive potential of gabapentinoids putting at risk patients with neuropathic pain requiring long-term pain management. The evidence to support this is rather inconcusive.
AIM
This systematic review aimed to evaluate the safety and efficacy of gabapentinoids in the management of neuropathic pain with a focus on randomised controlled trials (RCTs) and categorising the side effects according to the body systems they were affecting.
METHOD
Searches were conducted in MEDLINE (PubMed), EMBASE, Web of Science, PsycoINFO, and CINAHL (EBSCO), and included RCTs to identify and critically appraise studies investigating safety and therapeutic effects of gabapentionoids in adults with neuropathic pain. Data extraction was conducted using an established Cochrane form and the risk-of-bias tool was used in the assessment of quality.
RESULTS
50 studies (12,398 participants) were included. The majority of adverse events pertained to the nervous system (7 effects) or psychiatric (3 effects) disorders. There were more adverse effects reported with pregabalin (36 effects) than with gabapentin (22 effects). Six pregabalin studies reported euphoria as a side effect, while no studies reported euphoria with gabapentin. This was the only side effect that may correlate with addictive potential. Gabapentioids were reported to significantly reduce pain compared to placebo.
CONCLUSION
Despite RCTs documenting the adverse events of gabapentionoids on the nervous system, there was no evidence of gabapentinoid use leading to addiction, suggesting an urgent need to design studies investigating their abusive potential.
Topics: Adult; Humans; Gabapentin; Pregabalin; Analgesics; gamma-Aminobutyric Acid; Amines; Cyclohexanecarboxylic Acids; Neuralgia; Randomized Controlled Trials as Topic
PubMed: 36848024
DOI: 10.1007/s11096-022-01528-y -
Microbiome Sep 2023Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease that carries mutations in NOTCH3....
BACKGROUND
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease that carries mutations in NOTCH3. The clinical manifestations are influenced by genetic and environmental factors that may include gut microbiome.
RESULTS
We investigated the fecal metagenome, fecal metabolome, serum metabolome, neurotransmitters, and cytokines in a cohort of 24 CADASIL patients with 28 healthy household controls. The integrated-omics study showed CADASIL patients harbored an altered microbiota composition and functions. The abundance of bacterial coenzyme A, thiamin, and flavin-synthesizing pathways was depleted in patients. Neurotransmitter balance, represented by the glutamate/GABA (4-aminobutanoate) ratio, was disrupted in patients, which was consistent with the increased abundance of two major GABA-consuming bacteria, Megasphaera elsdenii and Eubacterium siraeum. Essential inflammatory cytokines were significantly elevated in patients, accompanied by an increased abundance of bacterial virulence gene homologs. The abundance of patient-enriched Fusobacterium varium positively correlated with the levels of IL-1β and IL-6. Random forest classification based on gut microbial species, serum cytokines, and neurotransmitters showed high predictivity for CADASIL with AUC = 0.89. Targeted culturomics and mechanisms study further showed that patient-derived F. varium infection caused systemic inflammation and behavior disorder in Notch3 mice potentially via induction of caspase-8-dependent noncanonical inflammasome activation in macrophages.
CONCLUSION
These findings suggested the potential linkage among the brain-gut-microbe axis in CADASIL. Video Abstract.
Topics: Animals; Mice; CADASIL; Gastrointestinal Microbiome; Mental Disorders; Cytokines; gamma-Aminobutyric Acid
PubMed: 37684694
DOI: 10.1186/s40168-023-01638-3