Biology subjects

Burrows, A.

Publications and source records attributed to Burrows, A..

6 recordsLinked to original sources

bioRxiv2025

Gut Microbe-Derived N-Acyl Serinol Lipids Shape Host Postprandial Metabolic Homeostasis

Although strong evidence links the gut microbiome to metabolic disease, the mechanisms linking microbiota to hormonal and metabolic responses to food are not well understood. After a meal, gut bacteria produce a wide array of small molecule, protein, and lipid metabolites originating from bacterial sources. Annotating physiological function to select gut microbe-derived metabolites is critical to understanding diet-microbe-host interactions, and to developing microbiome-inspired therapies to improve human health. Here, we have investigated the role of a poorly annotated class of gut microbiome-derived lipids called N-acyl amides in postprandial metabolic physiology. Here we show both bacterial overproduction and provision of exogenous N-acyl amides reorganize host hormone-driven metabolic transition after a meal. Moreover, N-acyl amides exert broad effects on the meal- and circadian-related reorganization of gene expression, metabolic hormones, and gut microbiome composition. Collectively, these results demonstrate that microbiota-derived N-acyl amides play a physiologic role in postprandial metabolic homeostasis in the host.

physiology↗

bioRxiv2025

Gut Microbe-Derived Trimethylamine Shapes Circadian Rhythms Through the Host Receptor TAAR5

Elevated levels of the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) are associated with cardiometabolic disease risk. However, the mechanism(s) linking TMAO production to human disease are incompletely understood. Initiation of the metaorganismal TMAO pathway begins when dietary choline and related metabolites are converted to trimethylamine (TMA) by gut bacteria. Gut microbe-derived TMA can then be further oxidized by host flavin-containing monooxygenases to generate TMAO. Previously, we showed that drugs lowering both TMA and TMAO protect mice against obesity via rewiring of host circadian rhythms. Although most mechanistic studies in the literature have focused on the metabolic end product TMAO, here we have instead tested whether the primary metabolite TMA alters host metabolic homeostasis and circadian rhythms via trace amine-associated receptor 5 (TAAR5). Remarkably, mice lacking the host TMA receptor (Taar5-/-) have altered circadian rhythms in gene expression, metabolic hormones, gut microbiome composition, and diverse behaviors. Also, mice genetically lacking bacterial TMA production or host TMA oxidation have altered circadian rhythms. These results provide new insights into diet-microbe-host interactions relevant to cardiometabolic disease, and implicate gut bacterial production of TMA and the host receptor that senses TMA (TAAR5) in the physiologic regulation of circadian rhythms in mice. HIGHLIGHTSO_LIMice lacking the host TMA receptor (Taar5-/-) have altered circadian rhythms. C_LIO_LITaar5-/- mice have altered innate behaviors in a time of day dependent manner. C_LIO_LIThe normal circadian oscillations in the gut microbiome are dysregulated in Taar5-/- mice. C_LIO_LIGenetic deletion of bacterial TMA production or host TMA oxidation shapes circadian rhythms. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=137 HEIGHT=200 SRC="FIGDIR/small/647082v2_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1608forg.highwire.dtl.DTLVardef@6a809aorg.highwire.dtl.DTLVardef@2131f7org.highwire.dtl.DTLVardef@1575559_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2022

Ifit2 regulates murine-coronavirus spread to the spinal cord white matter and its associated myelin pathology

Ifit2, an interferon-induced protein with tetratricopeptide repeats 2, plays a critical role in restricting neurotropic murine {beta}-coronavirus RSA59 infection. RSA59 intracranial injection of Ifit2 deficient (-/-) compared to wild type (WT) mice results in impaired acute microglial activation, associated with reduced CX3CR1 expression, which consecutively limits migration of peripheral lymphocytes into the brain, leading to impaired virus control followed by severe morbidity and mortality. While the protective role of Ifit2 is established for acute viral encephalitis, less is known about its influence on demyelination during the chronic phase of RSA59 infection. Our current study demonstrates that Ifit2 deficiency causes extensive RSA59 viral spread throughout both the spinal cord grey and white matter and is associated with impaired CD4+ T cell infiltration. Cervical lymph nodes of RSA59 infected Ifit2-/- mice showed reduced activation of CD4+ T cells and impaired IFN{gamma} expression during acute encephalomyelitis. Furthermore, blood-brain-barrier integrity was preserved in the absence of Ifit2 as evidenced by integral, tight junction protein ZO-1 expression surrounding the meninges and blood vessels and decreased Texas red dye uptake. In contrast to WT mice exhibiting only sparse myelin loss, the chronic disease phase in Ifit2-/- mice was associated with severe demyelination and persistent viral load, even at low infection doses. Overall, our study highlights that Ifit2 provides antiviral functions by promoting acute neuroinflammation and thereby aiding virus control and limiting severe demyelination. Author SummaryThe role of interferons in providing protective immunity against viral spread and pathogenesis is well known. Interferons execute their function by inducing certain genes collectively called as interferon stimulated genes (ISGs) among which Interferon-induced protein with tetratricopeptide repeats 2, Ifit2, is known for restricting neurotropic viral replication and spread in the brain. So far, not much has been investigated about its role in viral spread to the spinal cord and its associated myelin pathology. Towards this our study using neurotropic murine-{beta}-coronavirus and Ifit2 deficient mice demonstrate that Ifit2 deficiency causes extensive viral spread throughout grey and white matter of spinal cord accompanied by impaired microglial activation and CD4+ T cell infiltration. Furthermore, infected Ifit2 deficient mice showed impaired activation of T cells in cervical lymph node and Blood-Brain-Barrier was relatively intact. Ifit2 deficient mice developed viral induced severe chronic neuroinflammatory demyelination accompanied by the presence of ameboid shaped phagocytotic microglia/macrophages.

neuroscience↗

bioRxiv2022

IFN-induced protein with tetratricopeptide repeats 2 (Ifit2) limits autoimmune inflammation by regulating myeloid cell activation and metabolic activity

Besides anti-viral functions, Type I IFN expresses potent anti-inflammatory properties and is being widely used to treat certain autoimmune conditions, such as multiple sclerosis (MS). In murine model of MS, experimental autoimmune encephalomyelitis (EAE), administration of IFN{beta} effectively attenuates the disease development. However, the precise mechanisms underlying the treatment remain elusive. In this study, we report that IFN-induced protein with tetratricopeptide repeats 2 (Ifit2), a type I and type III IFN-stimulated gene, plays a previously unrecognized immune regulatory role during autoimmune neuroinflammation. Mice deficient in Ifit2 display greater susceptibility to EAE and escalated immune cell infiltration in the central nervous system. Ifit2 deficiency is also associated with microglial activation and increased myeloid cell infiltration. Unexpectedly, myelin debris clearance and the subsequent remyelination is impaired in Ifit2-/- CNS tissues. Clearing myelin debris is an important property of reparative M2 type myeloid cells to promote remyelination. Indeed, we observed that bone marrow derived macrophages, CNS infiltrating myeloid cells, and microglia from Ifit2-/- mice express cytokine and metabolic genes associated with proinflammatory M1 type subsets. Taken together, our findings uncover a novel regulatory function of Ifit2 in autoimmune inflammation in part by modulating myeloid cell function and metabolic activity.

immunology↗

bioRxiv2020

Gut Microbe-Targeted Choline Trimethylamine Lyase Inhibition Improves Obesity Via Rewiring of Host Circadian Rhythms

Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (ob/ob). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake, but is instead associated with beneficial remodeling of the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism, and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have untapped potential as anti-obesity therapeutics.

physiology↗

bioRxiv2020

Stability of extemporaneously compounded amiloride nasal spray

Anxiety disorders (AD) are the most common mental illnesses affecting an estimated 40 million adults in the United States. Amiloride, a diuretic agent, has shown efficacy in treating AD in preclinical models by inhibiting the acid-sensing ion channels (ASIC). By delivering amiloride via nasal route, rapid onset of action can be achieved due to direct "nose-to-brain" access. Therefore, this study reports the formulation, physical, chemical, and microbiological stability of an extemporaneously prepared amiloride 2 mg/mL nasal spray. The amiloride nasal spray was prepared by adding 100 mg of amiloride hydrochloride to 50 mL of sterile water for injection in a sterile reagent bottle. A stability-indicating high-performance liquid chromatography (HPLC) method was developed and validated. Forced-degradation studies were performed to confirm the ability of the HPLC method to identify the degradation products from amiloride distinctively. The physical stability of the amiloride nasal spray was assessed by pH, clarity, and viscosity assessments. For chemical stability studies, samples of nasal sprays stored at room temperature were collected at time-points 0, 3 hr., 24 hr., and 7 days and were assayed in triplicate using the stability-indicating HPLC method. Microbiological stability of the nasal spray solution was evaluated for up to 7 days based on the sterility test outlined in United States Pharmacopoeia (USP) chapter 71. The stability-indicting HPLC method identified the degradation products of amiloride without interference from amiloride. All tested solutions retained over 90% of the initial amiloride concentration for the 7-day study period. There were no changes in color, pH, and viscosity in any sample. The nasal spray solutions were sterile for up to 7 days in all samples tested. An extemporaneously prepared nasal spray solution of amiloride hydrochloride (2 mg/mL) was physically, chemically, and microbiologically stable for 7 days when stored at room temperature.

pharmacology and toxicology↗