Biology subjects

Holton, M.

Publications and source records attributed to Holton, M..

8 recordsLinked to original sources

bioRxiv2026

Culturomics-Guided Precision FMT Enables Stable Antibiotic-Independent Engraftment via Metabolic Niche Targeting

The gut microbiome's functional architecture can be conceptualized as a network of metabolic niches, yet clinical approaches to fecal microbiota transplantation (FMT) do not leverage niche-level information to guide engraftment. Here, we present a culturomics-based framework that profiles the metabolic niche landscape of individual microbiomes to enable targeted, antibiotic-independent FMT. Using a panel of 60 diverse media conditions, we show that gut communities from genetically identical mice harboring distinct microbiomes exhibit reproducible, vendor-specific niche-occupancy profiles, with each condition selecting for compositionally distinct niche-associated communities (NACs). We demonstrate that antibiotic pretreatment prior to FMT compromises community resilience, yielding communities that lose donor taxa more rapidly and recover less taxonomic diversity after secondary perturbation compared to untreated recipients. By comparing donor and recipient niche profiles, we identify vacant metabolic niches in recipient microbiomes and show that NACs targeting these vacancies achieve stable engraftment persisting for over 72 days without antibiotic pretreatment, whereas NACs targeting occupied niches fail to colonize. Furthermore, complex NACs not only fill vacant niches but reshape the surrounding native community, while simpler NACs engraft with minimal collateral impact. This culturomics-guided framework provides a scalable, mechanistic approach for rational donor-recipient matching that could advance personalized microbiome-based therapies.

microbiology↗

bioRxiv2026

Metagenome-scale Modeling to Assess Microbiome Metabolic Complementarity for Precision Microbiota Transplantation Therapies

Fecal microbiota transplantation (FMT) holds therapeutic promise beyond recurrent Clostridioides difficile infection, but clinical outcomes remain unpredictable, in part because existing computational models do not fully capture the metabolic compatibility between donor and recipient communities. Here, we present a metagenome-scale metabolic modeling framework that quantifies metabolic niche complementarity between donor and recipient microbiomes to predict transplantation outcomes. Using MICOM-derived community metabolic models, we show that donor taxa whose metabolic flux profiles are more dissimilar from the recipient community engraft at significantly higher rates in both murine and human FMT cohorts. In a human IBS trial, metabolic models accurately predicted post-FMT community composition via leave-one-out cross-validation and recapitulated disease-associated alterations in short-chain fatty acid, sulfur, and gas metabolism. We then performed 2,548 in silico FMT simulations between IBS-D/M patients and donors from the OpenBiome biobank to demonstrate a platform for personalized donor screening. This screen identified super-donors characterized by high taxonomic diversity, broad metabolic niche coverage, and community interaction networks dominated by cross-feeding rather than competition, as quantified by a flux-derived ecological network balance index that strongly predicted engraftment potential. This framework provides a mechanistic, scalable tool for rational donor-recipient matching that could guide personalized microbiome-based therapies.

microbiology↗

bioRxiv2025

Single Cell RNA-sequencing of BCG naive and recurrent non-muscle invasive bladder cancer reveals a CD6/ALCAM mediated immune-suppressive pathway

Non-muscle invasive bladder cancer (NMIBC) represents 70-80% patients with newly diagnosed bladder cancer, and Bacillus Calmette-Guerin (BCG) remains a cornerstone treatment for intermediate-and high-risk NMIBC to prevent disease recurrence and progression. However, many patients experience recurrence after induction BCG, posing significant challenges in the management of the disease. We conducted single cell RNA sequencing on freshly collected NMIBC samples, distinguishing between those naive to BCG treatment and those that recurred post-BCG treatment. We observed a clear activation of inflammatory pathways across cell types during recurrence, but these were not associated with canonical immune checkpoint or T cell exhaustion phenotypes. Analysis of cell-to-cell communication revealed enhanced interactions between T cells and urothelial cells in BCG-recurrence, predominantly modulated by CD6 and ALCAM. Furthermore, we found CD6hi T cells to be immunosuppressed and enriched in recurrent samples, suggesting a potential role for CD6 as an immune evasion signal in NMIBC. SIGNIFICANCEThese findings uncover a novel mechanism responsible for bladder cancer recurrence after BCG treatment. Enhanced T cell-urothelial cell communication in recurrent tumors mediated by CD6 and ALCAM leads to an immunosuppressed state. Thus, CD6 may have potential as a therapeutic target to augment BCG response in non-muscle invasive bladder cancer.

cancer biology↗

bioRxiv2022

Integrative Analysis of Checkpoint Blockade Response in Advanced Non-Small Cell Lung Cancer

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). While our understanding of the biology underlying immune checkpoint blockade in NSCLC is still incomplete, studies to date have established predictive roles for PD-L1 tumor expression and tumor mutational burden (TMB). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up 2 Cancer - Mark Foundation (SU2C-MARK) Cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including: 1) favorable (e.g., ATM altered), and unfavorable (e.g., TERT amplified) genomic subgroups, 2) distinct immune infiltration signatures associated with wound healing (unfavorable) and immune activation (favorable), and 3) a novel de-differentiated tumor-intrinsic subtype characterized by expression of endodermal lineage genes, immune activation, and enhanced response rate. Taken together, results from this cohort extend our understanding of NSCLC-specific predictors, providing a rich set of molecular and immunologic hypotheses with which to further our understanding of the biology of checkpoint blockade in NSCLC.

genomics↗

bioRxiv2021

Animal lifestyle changes acceptable mass limits for attached tags

O_LIAnimal-attached devices have transformed our understanding of vertebrate ecology. To minimize tag-related harm for these studies, researchers have long advocated that tag masses should not exceed 3% of the animals body mass. However, this proposition ignores tag forces generated as a result of animal movement. C_LIO_LIUsing data from collar-attached accelerometers on diverse free-ranging terrestrial animals, we detail a tag-based acceleration method (TbAM) in which we quantify animal athleticism in terms of fractions of animal movement time devoted to different collar-recorded accelerations. The varying accelerations are converted to forces imposed on the animals based on the acceleration and tag mass and allow derivation of defined force limits, including those amounting to 3% of the animals mass, for specified fractions of any animals active time. C_LIO_LIWe demonstrate how species athleticism is the principal determinant of tag forces, whereas body mass is of little importance. Forces exerted by 3% tags were mostly equivalent to 4-19% of the animals masses during moving, with a maximum of 54% in a hunting cheetah. Cumulative frequency curves of tag acceleration for periods when animals were active, all showed a characteristic sigmoid pattern, which was displaced further to the right as higher acceleration activities accounted for an increasing proportion of any animals time. Specifying that tags should exert forces that are less than 3% of the animals body mass for 95% of the time led to corrected tag masses constituting between 1.6% and 2.98% of our study animals masses, with values depending on animal athleticism. C_LIO_LIRecognition that animal athleticism affects tag forces of their carriers fundamentally changes how acceptable tag mass limits should be determined by ethics bodies. In order to have a scientifically robust acceptable threshold to limit the forces experienced by an animal carrier, we suggest practitioners derive a similar cumulative acceleration profile for their study species and use a minimum of the 95% limits on the plot (although higher limits may be more appropriate). C_LI

zoology↗

bioRxiv2020

Forces experienced by instrumented animals depend on lifestyle

Animal-attached devices have transformed our understanding of vertebrate ecology. However, to be acceptable, researchers must minimize tag-related harm. The long-standing recommendation that tag masses should not exceed 3% of the animals body mass ignores tag forces generated by movement. We used collar-attached accelerometers on four free-ranging carnivores, spanning two orders of magnitude in mass, to reveal that during movement, forces exerted by 3% tags were generally equivalent to 4-19% of the animals masses, with a record of 54% in a hunting cheetah. Controlled studies on domestic dogs revealed how the tag forces are dictated by animal gait and speed but appear largely invariant of body mass. This fundamentally changes how acceptable tag mass limits should be determined, requiring cognizance of animal athleticism. One Sentence SummaryThere can be no universal rule for collar-tag masses as a percentage of carrier mass since tag forces depend on lifestyle.

ecology↗

bioRxiv2020

Path tortuosity changes the transport cost paradigm in terrestrial animals

Animal movement paths are variously tortuous, with high turn rates predicted to be energetically costly, especially at high speeds. Animals travel most efficiently at the speed that gives the lowest cost of transport (COT), a well-defined point for movement in fluid media. However, theoretically, land animals should travel at their maximum speed to minimize COT, which they do not, instead travelling at walking pace. We measured oxygen consumption in humans to demonstrate that the energetic costs of turning increase disproportionately with both speed and angular velocity. This resulted in the minimum COT speed occurring at very low speeds, which reduced with increased path tortuosity. Data on turn rates from six free-ranging terrestrial species underpinned this because all individuals turned faster at the slowest speeds across the full speed range. The optimum movement speed for minimum COT in land animals thus depends on the environment and behavior since both affect track tortuosity.

ecology↗

bioRxiv2018

Human cytomegalovirus genomes sequenced directly from clinical material: variation, multiple-strain infection, recombination and mutation

The genomic characteristics of human cytomegalovirus (HCMV) strains sequenced directly from clinical pathology samples were investigated, focusing on variation, multiple-strain infection, recombination and natural mutation. A total of 207 datasets generated in this and previous studies using target enrichment and high-throughput sequencing were analysed, in the process facilitating the determination of genome sequences for 91 strains. Key findings were that (i) it is important to monitor the quality of sequencing libraries in investigating diversity, (ii) many recombinant strains have been transmitted during HCMV evolution, and some have apparently survived for thousands of years without further recombination, (iii) mutants with non-functional genes (pseudogenes) have been circulating and recombining for long periods and can cause congenital infection and resulting clinical sequelae, and (iv) intrahost diversity in single-strain infections is much less than that in multiple-strain infections. Future population-based studies are likely to continue illuminating the evolution, epidemiology and pathogenesis of HCMV.

microbiology↗