Biology subjects

Staley, C.

Publications and source records attributed to Staley, C..

5 recordsLinked to original sources

bioRxiv2026

Shotgun metagenomic and untargeted metabolomic analysis of gut microbiome associated with peripheral artery disease

Background: While the human gut microbiome is a potentially important and modifiable risk factor for cardiovascular diseases, the links between the gut microbiome and peripheral artery disease (PAD) and its clinical subgroups (claudication and chronic limb-threatening ischemia; CLTI) are not well understood. Methods: We used shotgun metagenomics and untargeted metabolomics to analyze the fecal samples of people with PAD and age- and sex-matched non-PAD controls collected in a cross-sectional manner. We used functional prediction pathways, a network analysis, and weighted gene co-expression network analysis of metagenomic, metabolomics, and clinical data to better understand PAD-associated dysbiosis. Results: Alpha and beta diversity were similar between the PAD (n=78) and non-PAD (n=20) groups. Differentially abundant species were dominated by those belonging to the Lachnospiraceae, Ruminococcaceae and Enterobacteriaceae families. Fecal butyrate levels were reduced between the non-PAD and PAD groups, but differences were not statistically significant. There was significantly reduced alpha diversity in the samples of the CLTI compared to claudication subgroup. Abundance of multiple butyrate producers were greater in the claudication group compared to CLTI. Network analysis revealed 5 meta-modules, each with specific associations to PAD presentation and metabolomic profiles, and species that are both top module hubs and differentially abundant between groups. Community interconnectedness appears to increase in claudication, followed by community disintegration in CLTI. Conclusions: This metagenomic-metabolomic analysis of the gut microbiome of individuals with PAD, highlights the importance of studying functional capacity, diversity, and connectivity between species. Microbial modules may allow an integrative view of the microbial ecology relevant to presence and progression of PAD.

microbiology↗

bioRxiv2025

Isoflavones impair response to anti-PD1 therapy in murine breast cancer models, irrespective of dietary fiber and fecal short chain fatty acid levels

BackgroundFermentable dietary fibers, also called microbiota-accessible carbohydrates (MAC), and the consequent increase in fecal short-chain fatty acids (SCFAs) are linked to improved responsiveness to immune checkpoint blockade (ICB) therapy in human and mouse studies. However, experimental diets high in MAC also often contain estrogenic isoflavones, which may counter fibers beneficial effects by causing immunosuppression. MethodsWe studied the effects of feeding female C57BL/6Tac mice low-MAC (AIN93G), low-MAC supplemented with isoflavone genistein, high-MAC (5V5M) or high-MAC isoflavone (high-MACi; 5058D) diet on their gut microbiome and response to anti-PD1 therapy against E0771 allografted triple negative breast cancer (TNBC) and 7,12-dimethylbenz[a]anthracene (DMBA)-initiated estrogen receptor positive (ER+) mammary tumors. We also determined whether blocking ER with tamoxifen (TAM) impacted responsiveness to anti-PD1 therapy in mice fed different diets. The effect of diet and treatments on immune cell signaling pathways was investigated using NanoString PanCancer Immune Profiling Panel. ResultsHigh-MAC and high-MACi diets increased fecal microbial alpha-diversity and the abundances of SCFA producing families Lachnospiraceae, and Oscillospiraceae as well as fecal SCFA levels, compared with low-MAC diet. E0771 tumors responded to anti-PD1 in mice fed high-MAC, while mice fed high-MACi did not respond. Low-MAC fed mice with single E0771 allograft also responded to anti-PD1, but genistein supplementation eliminated responsiveness. E0771 tumors in high-MAC fed mice contained elevated levels of exhausted CD8+ T cells, which were decreased after anti-PD1 therapy. Opposite effects were seen in mice fed high-MACi diet. Mice with DMBA-initiated ER+ mammary tumors did not respond to anti-PD1. TAM converted TNBC and ER+ tumors to become sensitive to anti-PD1 therapy in mice fed high-MACi or low-MAC diets, respectively. Genes in TH17 differentiation pathways were linked to TAM-induced improved anti-PD1 response both in TNBC and ER+ mammary tumors. ConclusionsOur results highlight the role of diet in impacting the effectiveness of ICB therapies. We found that increased SCFA levels alone are not predictive of response to anti-PD1, but if tumor expresses ER or if diet contains ER activating compounds, such as isoflavones, blocking ER+ might convert unresponsive tumors responsive to anti-PD1. Word count: 339 What is already known on this topicDietary fiber is proposed to improve response to checkpoint inhibitor therapy against melanoma, but this has been challenged by a recent preclinical study in which different mouse tumor models were used. None of the studies have been done in breast cancer or preclinical breast cancer models. What this study addsOur study showed, using triple negative breast cancer (TNBC) and estrogen receptor positive (ER+) breast cancer models, that indeed high levels of microbiota accessible carbohydrates (MACs) in diet did not alone determine responsiveness to anti-PD1 therapy, but diet high in plant isoflavones/ hormones impaired anti-PD1 effectiveness, regardless of whether diet contained high fiber levels or not. We also found that the adverse effects of isoflavones were counteracted by tamoxifen, partial estrogen receptor antagonist. How this study might affect research, practice or policyOur findings could indicate that breast cancer patients, both those with TNBC and ER+ disease, should not consume diets high in isoflavones when treated with anti-PD1.

cancer biology↗

bioRxiv2023

Hepatic lipid-associated macrophages mediate the protective effects of bariatric surgery against NASH

For patients with obesity and metabolic syndrome, bariatric procedures such as vertical sleeve gastrectomy (VSG) have a clear benefit in ameliorating metabolic dysfunction-associated steatohepatitis (MASH). While the effects of bariatric surgeries have been mainly attributed to nutrient restriction and malabsorption, whether immuno-modulatory mechanisms are involved remains unclear. Here we report that VSG ameliorates MASH progression in a weight loss- independent manner. Single-cell RNA sequencing revealed that hepatic lipid-associated macrophages (LAMs) expressing the triggering receptor expressed on myeloid cells 2 (TREM2) increase their lysosomal activity and repress inflammation in response to VSG. Remarkably, TREM2 deficiency in mice ablates the reparative effects of VSG, suggesting that TREM2 is required for MASH resolution. Mechanistically, TREM2 prevents the inflammatory activation of macrophages and is required for their efferocytotic function. Overall, our findings indicate that bariatric surgery improves MASH through a reparative process driven by hepatic LAMs, providing insights into the mechanisms of disease reversal that may result in new therapies and improved surgical interventions.

physiology↗

bioRxiv2022

Fecal Microbiota Restoration Modulates the Microbiome in Inflammation-Driven Colorectal Cancer

Chronic inflammation of the colon (colitis) is a known risk factor for inflammatory-driven colorectal cancers (idCRC), and intestinal microbiota has been implicated in the etiology of id-CRC. Manipulation of the microbiome is a clinically viable therapeutic approach to limiting id-CRC. To understand the microbiome changes that occur over time in id-CRC, we used a mouse model of idCRC with the treatment of azoxymethane (AOM) and dextran sodium sulfate (DSS) and measured the microbiome over time using 16S rRNA amplicon sequencing. We included cohorts where the microbiome was restored using cage bedding swapping and where the microbiome was depleted using antibiotics to compare to untreated animals. We identified consistent increases in Akkermansia in mice receiving horizontal microbiome transfer (HMT), while the control cohort had consistent longitudinal increases in Anaeroplasma and Alistipes. Additionally, fecal lipocalin-2 (Lcn-2) concentrations were elevated in unrestored animals compared to restored and antibiotic-treated counterparts following HMT. These observations suggest a potential role for Akkermansia, Anaeroplasma, and Alistipes in regulating colonic inflammation in id-CRC.

microbiology↗

bioRxiv2019

Population structure determined by comparative amplicon gene sequencing in biofilm and planktonic bacterial communities from pesticide-contaminated water

Molecular and bioinformatics tools for research are very important for biodiversity characterization in contaminated environments due the presence of a high percentage of nonculturable microorganisms. The wide use of pesticides in agriculture exposes microbiomes to stressful and selective conditions that demand survival strategies such as biofilm formation. The purpose of this work was to evaluate the bacterial population structure in planktonic and biofilm communities of water that was used for washing the packaging of herbicides and stored for six months in tanks. This substance is highly contaminated waste. Samples of water and biofilms from tanks and biofilms developed for short times in flasks were used for DNA isolation and 16S rRNA gene sequencing. The physicochemical conditions imposed by water used for washing the containers were inadequate for killing the bacterial genera identified according to water and wastewater standards. The variation in population structure and diversity was lower in the planktonic samples than in the biofilm samples, indicating a possible combination of genetic drift and subsequent selection of individuals surviving under stressful water conditions, such as heating and contact with agrochemicals, over a six-month period. The biofilm formation in water tanks contaminated with pesticides enabled the survival of bacterial genera harboring the essential processes for adaptation to these environments; the presence of these processes was determined according to descriptions obtained from the genomic databases. This study suggests the potential of bacterial genera identified in biofilms obtained from tanks to adapt to contaminated environments through their metabolic complexity. Thus, herbicide biodegradation kinetics can be accessed through a culturable collection obtained from these communities.

microbiology↗