Biology subjects

Antony, L.

Publications and source records attributed to Antony, L..

10 recordsLinked to original sources

bioRxiv2026

PDE4 Inhibitor Apremilast Rebalances Inflammatory Responses to Pseudomonas aeruginosa Infection in CF Rats

CFTR modulator therapies have transformed CF care, yet chronic airway inflammation persists in many people with cystic fibrosis (pwCF) even after long-term highly effective modulator therapy (HEMT). Because of the adverse side effects or the incompatibility with CFTR modulators, the use of traditional anti-inflammatory therapies is very limited in CF. Hence, new therapeutic strategies that rebalance inflammation without worsening infection with immunosuppression are needed. We evaluated the selective phosphodiesterase 4 (PDE4) inhibitor apremilast (Apr) for its ability to modulate dysregulated inflammation in humanized CF (G551D) rats acutely challenged with Pseudomonas aeruginosa. Apr is an approved anti-inflammatory therapeutic strategy for several chronic inflammatory conditions, but it has not been well studied in CF. In the humanized CF (G551D) rats, a short prophylactic Apr regimen significantly preserved lung function and reduced lung injury, accompanied by broad modulation of inflammatory responses, notably within Th1 and Th17 axes. Importantly, Apr did not cause a significant increase in bacterial burden. Just as importantly, Apr did not reduce CFTR mRNA or protein in vivo, and it increased G551D-CFTR phosphorylation critical for channel gating in vitro, supporting mechanistic compatibility with HEMT. These findings suggest Apr as a potential adjunct to CFTR modulators to rebalance airway inflammation while preserving host defense.

immunology↗

bioRxiv2025

Robust Colonization of Nasal Microbiota Across the Respiratory Tract and the Gut Modulates Innate Immune Response in a Germ-Free Pig Model

The use of antibiotics in swine production has contributed to improved health and growth rates but also led to significant challenges, including the emergence of antibiotic-resistant bacteria and disruptions in the microbiome. This study employs a germ-free pig model to investigate the transplantation of the nasal microbiome into the respiratory tract, exploring its potential to colonize multiple body sites and its impact on host immunity. Using germ-free piglets inoculated with nasal microbiota from healthy donors, we examined the dynamics of microbial community formation across the respiratory and gastrointestinal tracts and assessed the effects of antibiotic intervention. Our findings reveal that specific taxa, predominantly from the phyla Proteobacteria and Firmicutes, cross colonized both respiratory as well as gastrointestinal tract. This cross- colonization highlights the adaptability of nasal microbiota and suggests a significant role in modulating host immunity through the gut-lung axis. The administration of the antibiotic tulathromycin on day 11 post-inoculation altered both nasal and gut microbiota compositions, reducing microbial diversity and impacting immune gene expression and cytokine profiles. These results underscore the complex interactions within the gut-lung axis and emphasize the implications of antibiotic use on microbial health and host immunity. Understanding these interactions provides crucial insights into alternative strategies for managing health in swine production without relying on antibiotics. Our study advocates for a reevaluation of antibiotic practices and supports the development of microbiome-centered interventions in swine health management.

microbiology↗

bioRxiv2024

LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate cancer

Progression to lethal metastatic castration-resistant prostate cancer (mCRPC) is driven in part by epigenetic modulators such as LSD1 (KDM1A), a lysine-specific demethylase. Yet, mCRPC is increasingly recognized as a highly heterogeneous disease whose classification into subtypes is defined by the extent of androgen receptor (AR) and/or neuroendocrine (NE) characteristics. Meanwhile, the role of LSD1 in driving the different subtypes of mCRPC has remained unclear. Here, we assess the necessity of LSD1 in driving progression of mCRPC subtypes including AR+/NE- (ARPC), AR-/NE+ (NEPC), AR+/NE+ (amphicrine; AMPC), and AR-/NE- (double-negative; DNPC) through the use of LSD1 inhibitors in clinical development. LSD1 inhibition (LSD1i) was observed to be highly effective in restricting growth of NEPC, and efficacy was associated with TP53 loss-of-function. Mice bearing NEPC patient-derived xenografts treated with the LSD1 inhibitors, bomedemstat (MK-3543) or iadademstat (ORY-1001), exhibited suppression of the NE transcriptional profile, including ASCL1. LSD1i also induced expression and activity of YAP1, a non-NE transcription factor canonically silenced in NEPC (YAPOFF cancer), thereby switching NEPC from a YAPOFF to a YAPON cancer class. Therapeutically-induced YAPON NEPC tumors exhibited cell cycle arrest and repression of proliferative transcriptional programs. Importantly, the LSD1i-mediated YAPON state induced sensitivity to an inhibitor of YAP/TEAD function, IAG933, which extended antitumor efficacy against NEPC. Altogether, these findings indicate that patients diagnosed with NEPC may obtain greater relative benefit from LSD1-targeted therapies compared to those with other mCRPC subtypes and that dual inhibition of LSD1 and YAP/TEAD function demonstrates a promising treatment strategy potentially extending to other YAPOFF cancers. SignificanceAcross prostate cancer subtypes, NEPC is exceptionally responsive to LSD1 inhibition and this response is enhanced in combination with a YAP/TEAD disruptor which may improve patient selection and outcomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=171 HEIGHT=200 SRC="FIGDIR/small/576106v2_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@77332eorg.highwire.dtl.DTLVardef@1c127d0org.highwire.dtl.DTLVardef@1cec77org.highwire.dtl.DTLVardef@e87ed7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Enhancing Recovery from Gut Microbiome Dysbiosis and Alleviating DSS-Induced Colitis in Mice with a Consortium of Rare Short-Chain Fatty Acid-Producing Bacteria

The human gut microbiota is a complex community comprising hundreds of species, with a few present in high abundance and the vast majority in low abundance. The biological functions and effects of these low-abundant species on their hosts are not yet fully understood. In this study, we assembled a bacterial consortium (SC-4) consisting of B. paravirosa, C. comes, M. indica, and A. butyriciproducens, which are low-abundant, short-chain fatty acid (SCFA)-producing bacteria isolated from healthy human gut, and tested its effect on host health using germfree and human microbiota-associated colitis mouse models. The selection also favored these four bacteria being reduced in abundance in either Ulcerative Colitis (UC) or Crohns disease (CD) metagenome samples. Our findings demonstrate that SC-4 can colonize germ-free (GF) mice, increasing mucin thickness by activating MUC-1 and MUC-2 genes, thereby protecting GF mice from Dextran Sodium Sulfate (DSS)-induced colitis. Moreover, SC-4 aided in the recovery of human microbiota-associated mice from DSS-induced colitis, and intriguingly, its administration enhanced the alpha diversity of the gut microbiome, shifting the community composition closer to control levels. The results showed enhanced phenotypes across all measures when the mice were supplemented with Inulin as a dietary fiber source alongside SC-4 administration. We also showed a functional redundancy existing in the gut microbiome, resulting in the low abundant SCFA producers acting as a form of insurance, which in turn accelerates recovery from the dysbiotic state upon the administration of SC-4. SC-4 colonization also upregulated iNOS gene expression, further supporting its ability to produce an increasing number of goblet cells. Collectively, our results provide evidence that low-abundant SCFA-producing species in the gut may offer a novel therapeutic approach to IBD.

microbiology↗

bioRxiv2023

Alcohol-Induced Mucociliary Dysfunction: Role of Defective CFTR Channel Function

Excessive alcohol use is thought to increase the risk of respiratory infections by impairing mucociliary clearance (MCC). In this study, we investigate the hypothesis that alcohol reduces the function of CFTR, the protein that is defective in individuals with cystic fibrosis, thus altering mucus properties to impair MCC and the airways defense against inhaled pathogens. MethodsSprague Dawley rats with wild type CFTR (+/+), matched for age and sex, were administered either a Lieber-DeCarli alcohol diet or a control diet with the same number of calories for eight weeks. CFTR activity was measured using nasal potential difference (NPD) assay and Ussing chamber electrophysiology of tracheal tissue samples. In vivo MCC was determined by measuring the radiographic clearance of inhaled Tc99 particles and the depth of the airway periciliary liquid (PCL) and mucus transport rate in excised trachea using micro-optical coherence tomography ({micro}OCT). The levels of rat lung MUC5b and CFTR were estimated by protein and mRNA analysis. ResultsAlcohol diet was found to decrease CFTR ion transport in the nasal and tracheal epithelium in vivo and ex vivo. This decrease in activity was also reflected in partially reduced full-length CFTR protein levels but not, in mRNA copies, in the lungs of rats. Furthermore, alcohol-fed rats showed a significant decrease in MCC after 8 weeks of alcohol consumption. The trachea from these rats also showed reduced PCL depth, indicating a decrease in mucosal surface hydration that was reflected in delayed mucus transport. Diminished MCC rate was also likely due to the elevated MUC5b expression in alcohol-fed rat lungs. ConclusionsExcessive alcohol use can decrease the expression and activity of CFTR channels, leading to reduced airway surface hydration and impaired mucus clearance. This suggests that CFTR dysfunction plays a role in the compromised lung defense against respiratory pathogens in individuals who drink alcohol excessively. What is the current scientific knowledge on this subject?Excessive alcohol is associated with delayed mucociliary clearance (MCC) and an increased risk of respiratory infections among heavy drinkers. What does this study add to the field?Chronic alcohol use reduces CFTR activity and airway surface hydration explaining the mechanisms underlying mucociliary dysfunction. Acquired CFTR dysfunction may be a suitable target to improve host immunity in those affected by prolonged alcohol use.

pharmacology and toxicology↗

bioRxiv2022

Identification of a microbial sub-community from the feral chicken gut that reduces Salmonella colonization and improves gut health in a gnotobiotic chicken model.

A complex microbial community in the gut generally prevent the colonization of enteric pathogens such as Salmonella. Because of the high complexity, several species or combination of species in the gut can confer colonization resistance. To gain a better understanding of the colonization resistance against Salmonella enterica, we isolated a library of 1,300 bacterial strains from feral chicken gut microbiota which represented a total of 51 species. Using a co-culture assay, we screened the representative species from this library and identified 30 species that inhibited Salmonella enterica Typhimurium. To improve the Salmonella inhibition capacity, from a pool of fast-growing species, we formulated 66 bacterial blends, each of which composed of 10 species. Bacterial blends were more efficient in inhibiting Salmonella as compared to individual species. The blend that showed maximum inhibition (Mix10) also inhibited other serotypes of Salmonella frequently found in poultry. The in vivo effect of Mix10 was examined in a gnotobiotic and conventional chicken model. The Mix10 consortium reduced Salmonella colonization, intestinal tissue damage and inflammation in both models. Cell free supernatant of Mix10 did not show Salmonella inhibition, indicating that Mix10 inhibits Salmonella through either nutritional competition or reinforcement of host immunity. Out of ten species, three species in Mix10 did not colonize while three species constituted more than 70% of the community. Two of these species represents previously uncultured bacteria. Our approach could be used as a high-throughput screening system to identify additional bacterial sub-communities that confer colonization resistance against enteric pathogens and its effect on the host. ImportanceSalmonella colonization in chicken and human infections originating from Salmonella- contaminated poultry is a significant problem. Poultry has been identified as the most common food linked to enteric pathogen outbreaks in the United States. Since multi-drug resistant Salmonella often colonize chicken and cause human infections, methods to control Salmonella colonization in poultry are needed. The method we describe here could form the basis of developing gut microbiota-derived bacterial blends as a microbial ecosystem therapeutic against Salmonella.

microbiology↗

bioRxiv2019

Identifying Clostridioides difficile-inhibiting gut commensals using culturomics, phenotyping, and combinatorial community assembly

A major function of the gut microbiota is to provide colonization resistance, wherein pathogens are inhibited or suppressed below infectious level. However, the fraction of gut microbiota required for colonization resistance remains unclear. We used culturomics to isolate a gut microbiota culture collection comprising 1590 isolates belonging to 102 species. Estimated by metagenomic sequencing of fecal samples used for culture, this culture collection represents 50.73% of taxonomic diversity and 70% functional capacity. Using whole genome sequencing we characterized species representatives from this collection, and predicted their phenotypic traits, further characterizing isolates by defining nutrient utilization profile and short chain fatty acid (SCFA) production. When screened using a co-culture assay, 66 species in our culture collection inhibited C. difficile. Several phenotypes, particularly, growth rate, production of SCFAs, and the utilization of mannitol, sorbitol or succinate correlated with C. difficile inhibition. We used a combinatorial community assembly approach to formulate defined bacterial mixes inhibitory to C. difficile. When 256 combinations were tested, we found both species composition and blend size to be important in inhibition. Our results show that the interaction of bacteria with each other in a mix and with other members of gut commensals must be investigated for designing defined bacterial mixes for inhibiting C. difficile in vivo.\n\nIMPORTANCEAntibiotic treatment causes instability of gut microbiota and the loss of colonization resistance, allowing pathogens such as C. difficile to colonize, causing recurrent infection and mortality. Although fecal microbiome transplantation has shown to be an effective treatment for C. difficile infection (CDI), a more desirable approach would be the use of a defined mix of inhibitory gut bacteria. C. difficile-inhibiting species and bacterial combinations we identify herein improve our understanding of the ecological interactions controlling colonization resistance against C. difficile, and could aid the design of defined bacteriotherapy as a non-antibiotic alternative against CDI.

microbiology↗

bioRxiv2019

The Gut Microbiota composition of Feral and Tamworth Pigs determined using High-Throughput Culturomics and Metagenomics Reveals Compositional Variations When Compared to the Commercial Breeds

Bacterial communities in the hindguts of pigs have a profound impact on health and disease. Yet very limited studies have been performed outside intensive swine farms to determine pig gut microbiome composition in natural populations. Feral pigs represent a unique situation where the microbiome structure can be observed outside the realm of modern agriculture. Additionally, Tamworth pigs that freely forage were included to characterize the microbiome structure of this rare breed. In this study, gut microbiome of feral and Tamworth pigs were determined using metagenomics and culturomics. Tamworth pigs are highly dominated by Bacteroidetes primarily composed of the genus Prevotella whereas feral samples were more diverse with almost equal proportions of Firmicutes and Bacteroidetes. In total, 46 distinct species were successfully isolated from 1000 colonies selected. The combination of metagenomics and culture techniques facilitated a greater retrieval of annotated genes than either method alone. Furthermore, the naturally raised Tamworth pig microbiome contained more number of antibiotic resistance genes when compared to feral pig microbiome. The single medium based pig microbiota library we report is a resource to better understand pig gut microbial ecology and function by assembling simple to complex microbiota communities in bioreactors or germfree animal models.

microbiology↗

bioRxiv2019

Sellimonas caecigallum sp. nov., description and genome sequence of a new member of the Sellimonas genus isolated from the cecum of feral chicken

An obligately anaerobic, non-motile, Gram-positive coccobacillus strain SW451 was isolated from pooled cecum contents of feral chickens. Comparative analysis based on 16s rRNA sequence showed that strain SW451 had 95.24% nucleotide sequence similarity to Sellimonas intestinalis BR31T, the closest species with a valid taxonomy. The genome of SW451 is 2.67 Mbp with 45.23 mol% of G+C content. The major cellular fatty acids were C16: 0, C14: 0 and C16: 0 DMA. Based on taxonogenomic, physiological, and biochemical analysis, the strain SW451 represents a new species of the genus Sellimonas, for which the name Sellimonas caecigallum sp. nov. is proposed. The type strain of Sellimonas caecigallum is SW451 (=DSM 109473T)

microbiology↗

bioRxiv2019

Olsenella lakotia SW165 sp. nov., an acetate producing obligate anaerobe with a GC rich genome

A Gram-positive and obligately anaerobic bacterium was isolated from cecal content of feral chickens in Brookings, South Dakota, USA. The microorganism grew at 37-45{degrees} C and pH 6-7.5. This strain produced acetic acid as the primary metabolic end product. Major fatty acids were C12:0, C14:0, C14:0 DMA and summed feature 1 (C13:1 at 12-13 and C14:0 aldehyde). Phylogenetic analyses based on 16S rRNA gene sequence suggested that strain SW165 belongs to the family Atopobiaceae with the closest relatives being Olsenella profusa DSM 13989T (96.33% similarity), Olsenella umbonate DSM 26220T (96.18%) and Olsenella uli DSM 7084T (96.03%). Genome sequencing revealed a genome size of 2.43 Mbp with a G+C content of 67.59 mol%, which is the highest G+C content among members of the genus Olsenella. Phylogenetic and phenotypic comparison indicated that strain SW165 represents a novel species of the genus Olsenella, for which the name Olsenella lakotia sp. nov. is proposed. The type strain is SW165 (=DSM 107283T).

microbiology↗