Biology subjects

Scott, S. A.

Publications and source records attributed to Scott, S. A..

5 recordsLinked to original sources

bioRxiv2026

A class of metallohydrolases expands bile salt hydrolase activity in the gut

Abstract/Summary ParagraphBile acids are steroidal metabolites produced by host and microbial metabolism that shape gut microbiome ecology and influence host physiology1,2. Bile acid structural diversification requires gut microbial bile salt hydrolase (BSH) activities, which cleave the amide bond of liver-derived bile acid amidates (BAAs)3. Beyond this gatekeeping metabolic function, BSHs expand the bile acid pool via their amine N-acyltransferase activity to produce numerous microbially derived BAAs that signal via host receptors and are further metabolized4,5. To date, all BSH activity has been attributed to a family of N-terminal nucleophile (Ntn) cysteine hydrolases. However, numerous gut anaerobic bacteria possess BSH activity but do not encode bsh genes from the Ntn family. Here, we describe a previously unknown class of metal-dependent BSHs (mBSHs) broadly distributed in the gut microbiome. These metalloenzymes have a distinct active site architecture from the canonical Ntn superfamily of cysteine hydolase BSHs (cBSHs) and are selective for taurine-conjugated BAAs. The discovery of this heretofore unappreciated class of BSHs overturns the paradigm that this important, conserved biochemical activity of the gut microbiota is provided exclusively by canonical cysteine hydrolases, greatly expands the known landscape of bile acid metabolism, and reveals a previously unrecognized link connecting host-microbiota bile acid co-metabolism with microbial taurine utilization pathways.

biochemistry↗

bioRxiv2024

Chemoproteomic profiling of substrate specificity in gut microbiota-associated bile salt hydrolases

The gut microbiome possesses numerous biochemical enzymes that biosynthesize metabolites that impact human health. Bile acids comprise a diverse collection of metabolites that have important roles in metabolism and immunity. The gut microbiota-associated enzyme that is responsible for the gateway reaction in bile acid metabolism is bile salt hydrolase (BSH), which controls the hosts overall bile acid pool. Despite the critical role of these enzymes, the ability to profile their activities and substrate preferences remains challenging due to the complexity of the gut microbiota, whose metaproteome includes an immense diversity of protein classes. Using a systems biochemistry approach employing activity-based probes, we have identified gut microbiota-associated BSHs that exhibit distinct substrate preferences, revealing that different microbes contribute to the diversity of the host bile acid pool. We envision that this chemoproteomic approach will reveal how secondary bile acid metabolism controlled by BSHs contributes to the etiology of various inflammatory diseases.

microbiology↗

bioRxiv2023

Dopamine receptor D2 confers colonization resistance via gut microbial metabolites

Abstract/Summary ParagraphThe gut microbiome plays major roles in modulating host physiology. One such function is colonization resistance, or the ability of the microbial collective to protect the host against enteric pathogens1-3, including enterohemorrhagic Escherichia coli (EHEC) serotype O157:H7, an attaching and effacing (AE) food-borne pathogen that causes severe gastroenteritis, enterocolitis, bloody diarrhea, and acute renal failure (hemolytic uremic syndrome)4,5. Although gut microbes can provide colonization resistance by outcompeting some pathogens or modulating host defense provided by the gut barrier and intestinal immune cells, this phenomenon remains poorly understood. Emerging evidence suggests that small-molecule metabolites produced by the gut microbiota may mediate this process6. Here, we show that tryptophan (Trp)-derived metabolites produced by the gut bacteria protect the host against Citrobacter rodentium, a murine AE pathogen widely used as a model for EHEC infection7,8, by activation of the host neurotransmitter dopamine receptor D2 (DRD2) within the intestinal epithelium. We further find that these Trp metabolites act through DRD2 to decrease expression of a host actin regulatory protein involved in C. rodentium and EHEC attachment to the gut epithelium via formation of actin pedestals. Previously identified mechanisms of colonization resistance either directly affect the pathogen by competitive exclusion or indirectly by modulation of host defense mechanisms9,10, so our results delineate a noncanonical colonization resistance pathway against AE pathogens featuring an unconventional role for DRD2 outside the nervous system in controlling actin cytoskeletal organization within the gut epithelium. Our findings may inspire prophylactic and therapeutic approaches for improving gut health and treating gastrointestinal infections, which afflict millions globally.

microbiology↗

bioRxiv2022

Aldy 4: An efficient genotyper and star-allele caller for pharmacogenomics

High-throughput sequencing provides sufficient means for determining genotypes of clinically important pharmacogenes that can be used to tailor medical decisions to individual patients. However, pharmacogene genotyping, also known as star-allele calling, is a challenging problem that requires accurate copy number calling, structural variation discovery, variant calling and phasing within each pharmacogene copy present in the sample. Here we introduce Aldy 4, a fast and efficient tool for genotyping pharmacogenes that utilizes combinatorial optimization for accurate star-allele calling across different sequencing technologies. Aldy 4 adds support for long reads and ships with a novel phasing model and improved copy number and variant calling models. We compare Aldy 4 against the current state-of-the-art star-allele callers on a large and diverse set of samples and genes sequenced by various sequencing technologies, such as whole-genome and targeted Illumina sequencing, barcoded 10X Genomics and PacBio HiFi. We show that Aldy 4 is the most accurate star-allele caller with near-perfect accuracy in all evaluated contexts. We hope that Aldy remains an invaluable tool in the clinical toolbox even with the advent of long-read sequencing technologies. AvailabilityAldy 4 is available at https://github.com/0xTCG/aldy.

bioinformatics↗

bioRxiv2022

Temporal origin of mouse claustrum and development of its cortical projections

The claustrum is known for its extensive connectivity with many other forebrain regions, but its elongated shape and deep location have made further study difficult. We have sought to understand when mouse claustrum neurons are born, where they are located in developing brains and when they develop their widespread connections to cortex. We established that a well-characterised parvalbumin-plexus, which identifies the claustrum in adults, is only present from postnatal day (P)21. A myeloarchitectonic outline of the claustrum can be derived from a triangular fibre arrangement from P15. A dense patch of Nurr1+ cells is present at its core, and is already evident at birth. BrdU-birthdating of forebrain progenitors reveals that the majority of claustrum neurons are born during a narrow time window centred on embryonic day (E)12.5, which is later than the adjacent subplate and endopiriform nucleus. Retrograde tracing revealed that claustrum projections to anterior cingulate (ACA) and retrosplenial cortex (RSP) follow distinct developmental trajectories. Claustrum-ACA connectivity matures rapidly, and reaches adult-like innervation density by P10, whereas claustrum-RSP innervation emerges later over a protracted time window. This work establishes the timeline of claustrum development, and provides a framework for understanding how the claustrum is built and develops its unique connectivity.

neuroscience↗