Connections between the gut and brain monitor the intestinal tissue and its microbial and dietary content
, regulating both physiological intestinal functions such as nutrient absorption and motility
..., and brain-wired feeding behaviour
. It is therefore plausible that circuits exist to detect gut microorganisms and relay this information to areas of the central nervous system that, in turn, regulate gut physiology
. Here we characterize the influence of the microbiota on enteric-associated neurons by combining gnotobiotic mouse models with transcriptomics, circuit-tracing methods and functional manipulations. We find that the gut microbiome modulates gut-extrinsic sympathetic neurons: microbiota depletion leads to increased expression of the neuronal transcription factor cFos, and colonization of germ-free mice with bacteria that produce short-chain fatty acids suppresses cFos expression in the gut sympathetic ganglia. Chemogenetic manipulations, translational profiling and anterograde tracing identify a subset of distal intestine-projecting vagal neurons that are positioned to have an afferent role in microbiota-mediated modulation of gut sympathetic neurons. Retrograde polysynaptic neuronal tracing from the intestinal wall identifies brainstem sensory nuclei that are activated during microbial depletion, as well as efferent sympathetic premotor glutamatergic neurons that regulate gastrointestinal transit. These results reveal microbiota-dependent control of gut-extrinsic sympathetic activation through a gut-brain circuit.
,
, and other members of the Enterobacteriaceae family are common human pathogens that have acquired broad antibiotic resistance, rendering infection by some strains virtually untreatable. ...Enterobacteriaceae are intestinal residents, but generally represent <1% of the adult colonic microbiota. Antibiotic-mediated destruction of the microbiota enables Enterobacteriaceae to expand to high densities in the colon, markedly increasing the risk of bloodstream invasion, sepsis, and death. Here, we demonstrate that an antibiotic-naive microbiota suppresses growth of antibiotic-resistant clinical isolates of
,
, and
by acidifying the proximal colon and triggering short chain fatty acid (SCFA)-mediated intracellular acidification. High concentrations of SCFAs and the acidic environment counter the competitive edge that O
and NO
respiration confer upon Enterobacteriaceae during expansion. Reestablishment of a microbiota that produces SCFAs enhances clearance of
,
, and
from the intestinal lumen and represents a potential therapeutic approach to enhance clearance of antibiotic-resistant pathogens.
Commensal bacteria are believed to have important roles in human health. The mechanisms by which they affect mammalian physiology remain poorly understood, but bacterial metabolites are likely to be ...key components of host interactions. Here we use bioinformatics and synthetic biology to mine the human microbiota for N-acyl amides that interact with G-protein-coupled receptors (GPCRs). We found that N-acyl amide synthase genes are enriched in gastrointestinal bacteria and the lipids that they encode interact with GPCRs that regulate gastrointestinal tract physiology. Mouse and cell-based models demonstrate that commensal GPR119 agonists regulate metabolic hormones and glucose homeostasis as efficiently as human ligands, although future studies are needed to define their potential physiological role in humans. Our results suggest that chemical mimicry of eukaryotic signalling molecules may be common among commensal bacteria and that manipulation of microbiota genes encoding metabolites that elicit host cellular responses represents a possible small-molecule therapeutic modality (microbiome-biosynthetic gene therapy).
Despite evidence linking the human microbiome to health and disease, how the microbiota affects human physiology remains largely unknown. Microbiota-encoded metabolites are expected to play an ...integral role in human health. Therefore, assigning function to these metabolites is critical to understanding these complex interactions and developing microbiota-inspired therapies. Here, we use large-scale functional screening of molecules produced by individual members of a simplified human microbiota to identify bacterial metabolites that agonize G-protein-coupled receptors (GPCRs). Multiple metabolites, including phenylpropanoic acid, cadaverine, 9-10-methylenehexadecanoic acid, and 12-methyltetradecanoic acid, were found to interact with GPCRs associated with diverse functions within the nervous and immune systems, among others. Collectively, these metabolite-receptor pairs indicate that diverse aspects of human health are potentially modulated by structurally simple metabolites arising from primary bacterial metabolism.
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•Metabolite library from human microbiota screened for direct agonism of 241 GPCRs•Taxa-specific primary metabolites agonize individual GPCRs or broad GPCR families•Bacteria agonize receptors linked to metabolism, neurotransmission, and immunity•Simple bacterial metabolites may play a role in modulating host pathways
Colosimo et al. use functional screening of small molecules produced by individual members of a simplified human microbiota to identify bacterial metabolites that agonize G protein-coupled receptors (GPCRs). These results indicate that diverse aspects of human health are potentially modulated by structurally simple metabolites arising from primary bacterial metabolism.
Respiratory viral infections are frequent in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) and can potentially progress to lower respiratory tract infection ...(LRTI). The intestinal microbiota contributes to resistance against viral and bacterial pathogens in the lung. However, whether intestinal microbiota composition and associated changes in microbe-derived metabolites contribute to the risk of LRTI following upper respiratory tract viral infection remains unexplored in the setting of allo-HCT. Fecal samples from 360 allo-HCT patients were collected at the time of stem cell engraftment and subjected to deep, 16S ribosomal RNA gene sequencing to determine microbiota composition, and short-chain fatty acid levels were determined in a nested subset of fecal samples. The development of respiratory viral infections and LRTI was determined for 180 days following allo-HCT. Clinical and microbiota risk factors for LRTI were subsequently evaluated using survival analysis. Respiratory viral infection occurred in 149 (41.4%) patients. Of those, 47 (31.5%) developed LRTI. Patients with higher abundances of butyrate-producing bacteria were fivefold less likely to develop viral LRTI, independent of other factors (adjusted hazard ratio = 0.22, 95% confidence interval 0.04-0.69). Higher representation of butyrate-producing bacteria in the fecal microbiota is associated with increased resistance against respiratory viral infection with LRTI in allo-HCT patients.
•Butyrate-producing bacteria abundance is correlated with protection against viral LRTI following allo-HCT.
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Bone marrow transplantation (BMT) offers curative potential for patients with high-risk hematologic malignancies, but the post-transplantation period is characterized by profound immunodeficiency. ...Recent studies indicate that the intestinal microbiota not only regulates mucosal immunity, but can also contribute to systemic immunity and hematopoiesis. Using antibiotic-mediated microbiota depletion in a syngeneic BMT mouse model, here we describe a role for the intestinal flora in hematopoietic recovery after BMT. Depletion of the intestinal microbiota resulted in impaired recovery of lymphocyte and neutrophil counts, while recovery of the hematopoietic stem and progenitor compartments and the erythroid lineage were largely unaffected. Depletion of the intestinal microbiota also reduced dietary energy uptake and visceral fat stores. Caloric supplementation through sucrose in the drinking water improved post-BMT hematopoietic recovery in mice with a depleted intestinal flora. Taken together, we show that the intestinal microbiota contribute to post-BMT hematopoietic reconstitution in mice through improved dietary energy uptake.
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•Intestinal microbiota depletion impairs hematopoiesis after bone marrow transplantation•Intestinal flora depletion decreases energy harvest and reduces visceral adipose tissue•Caloric supplementation rescues impaired hematopoiesis in microbiota-depleted mice•The effects of intestinal flora disruption are dose dependent
Intestinal bacteria can exert effects on systemic hematopoiesis. Staffas et al. show that the intestinal flora contributes to hematopoietic recovery after bone marrow transplantation (BMT) through improved dietary energy uptake. The findings suggest possible clinical intervention strategies for improved BMT outcomes.
BACKGROUND:Tranexamic acid (TXA) is an antifibrinolytic drug. Topical administration of TXA during total knee arthroplasty (TKA) is favored for certain patients because of concerns about thrombotic ...complications, despite a lack of supporting literature. We compared local and systemic levels of thrombogenic markers, interleukin (IL)-6, and TXA between patients who received intravenous (IV) TXA and those who received topical TXA.
METHODS:Seventy-six patients scheduled for TKA were enrolled in this randomized double-blinded study. The IV group received 1.0 g of IV TXA before tourniquet inflation and again 3 hours later; a topical placebo was administered 5 minutes before final tourniquet release. The topical group received an IV placebo before tourniquet inflation and again 3 hours later; 3.0 g of TXA was administered topically 5 minutes before final tourniquet release. Peripheral and wound blood samples were collected to measure levels of plasmin-anti-plasmin (PAP, a measure of fibrinolysis), prothrombin fragment 1.2 (PF1.2, a marker of thrombin generation), IL-6, and TXA.
RESULTS:At 1 hour after tourniquet release, systemic PAP levels were comparable between the IV group (after a single dose of IV TXA) and the topical group. At 4 hours after tourniquet release, the IV group had lower systemic PAP levels than the topical group (mean and standard deviation, 1,117.8 ± 478.9 µg/L versus 1,280.7 ± 646.5 µg/L; p = 0.049), indicative of higher antifibrinolytic activity after the second dose. There was no difference in PF1.2 levels between groups, indicating that there was no increase in thrombin generation. The IV group had higher TXA levels at all time points (p < 0.001). Four hours after tourniquet release, wound blood IL-6 and TXA levels were higher than systemic levels in both groups (p < 0.001). Therapeutic systemic TXA levels (mean, 7.2 ± 7.4 mg/L) were noted in the topical group. Calculated blood loss and the length of the hospital stay were lower in the IV group (p = 0.026 and p = 0.025).
CONCLUSIONS:Given that therapeutic levels were reached with topical TXA and the lack of a major difference in the mechanism of action, coagulation, and fibrinolytic profile between topical TXA and a single dose of IV TXA, it may be a simpler protocol for institutions to adopt the use of a single dose of IV TXA when safety is a concern.
LEVEL OF EVIDENCE:Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
The transient nucleolus plays a central role in the up‐regulated synthesis of ribosomal RNA (rRNA) to sustain ribosome biogenesis, a hallmark of aberrant cell growth. This function, in conjunction ...with its unique pathohistological features in malignant cells and its ability to mediate apoptosis, renders this sub‐nuclear structure a potential target for chemotherapeutic agents. In this Minireview, structurally and functionally diverse small molecules are discussed that have been reported to either interact with the nucleolus directly or perturb its function indirectly by acting on its dynamic components. These molecules include all major classes of nucleic‐acid‐targeted agents, antimetabolites, kinase inhibitors, anti‐inflammatory drugs, natural product antibiotics, oligopeptides, as well as nanoparticles. Together, these molecules are invaluable probes of structure and function of the nucleolus. They also provide a unique opportunity to develop novel strategies for more selective and therefore better‐tolerated chemotherapeutic intervention. In this regard, inhibition of RNA polymerase‐I‐mediated rRNA synthesis appears to be a promising mechanism for killing cancer cells. The recent development of molecules targeted at G‐quadruplex‐forming rRNA gene sequences, which are currently undergoing clinical trials, seems to attest to the success of this approach.
Getting to the core: The cell's nucleolus is emerging as a promising anticancer target. Herein we review a broad range of molecular entities that have been shown to interact with the nucleolus. Molecules that interfere with this sub‐nuclear structure have the potential to trigger cancer cell death by mechanisms such as inhibition of ribosomal RNA transcription, thereby producing a selective therapeutic effect while sparing normal tissue.
Platinum–acridine hybrid agents show low‐nanomolar potency in chemoresistant non‐small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these ...agents and improve their pharmacological properties, a modular build–click–screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7‐Aminobenzcacridine was identified as a promising scaffold in a hybrid agent (P1–B1) that maintained submicromolar activity in several of the DNA‐repair proficient and p53‐mutant cancer models, while showing improved tolerability in mice by 32‐fold compared to the parent platinum–acridine (P1–A1). The distribution and DNA/RNA adduct levels produced by the acridine‐ and benzcacridine‐based analogues in NCI‐H460 cells (confocal microscopy, ICP‐MS), and their ability to bind G‐quadruplex forming DNA sequences (CD spectroscopy, HR‐ESMS) were studied. P1–B1 emerges as a less genotoxic, more tolerable, and potentially more target‐selective hybrid agent than P1–A1.
A promising hybrid based on 7‐aminobenzcacridine (P1–B1), which displays less genotoxicity, excellent tolerance, and potentially better target‐selectivity than the parent platinum–acridine (P1–A1), has been identified from a small library of 20 hybrid agents containing truncated and extended chromophores of varying basicities. P1–B1 maintained submicromolar activity in several of the DNA‐repair proficient and p53‐mutant cancer models.
Using a versatile synthetic approach, a new class of potential ester prodrugs of highly potent, but systemically too toxic, platinum–acridine anticancer agents was generated. The new hybrids contain ...a hydroxyl group, which has been masked with a cleavable lipophilic acyl moiety. Both butanoic (butyric) and bulkier 2‐propanepentanoic (valproic) esters were introduced. The goals of this design were to improve the drug‐like properties (e.g., logD) and to reduce the systemic toxicity of the pharmacophore. Two distinct pathways by which the target compounds undergo effective ester hydrolysis, the proposed activating step, have been confirmed: platinum‐assisted, self‐immolative ester cleavage in a low‐chloride environment (LC‐ESMS, NMR spectroscopy) and enzymatic cleavage by human carboxylesterase‐2 (hCES‐2) (LC‐ESMS). The valproic acid ester derivatives are the first example of a metal‐containing agent cleavable by the prodrug‐converting enzyme. They show excellent chemical stability and reduced systemic toxicity. Preliminary results from screening in lung adenocarcinoma cell lines (A549, NCI‐H1435) suggest that the mechanism of the valproic esters may involve intracellular deesterification.
New class: Using a versatile synthetic approach, a new class of potential ester prodrugs of highly potent, but systemically too toxic, platinum–acridine anticancer agents was generated. The new hybrids such as depicted contain a hydroxyl group, which has been masked with a cleavable lipophilic acyl moiety. Both butanoic (butyric) and bulkier 2‐propanepentanoic (valproic) esters were introduced.
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