Biology subjects

Bergin, I. L.

Publications and source records attributed to Bergin, I. L..

11 recordsLinked to original sources

bioRxiv2026

High-fat diet rewires gut host-microbiota relationship to derive worse outcomes following Clostridioides difficile infection

AbstractClostridioides difficile is a leading cause of hospital-acquired enteric infections, with outcomes ranging from mild diarrhea to life-threatening pseudomembranous colitis and death. Dietary modulations can influence the course of antibiotic-induced C. difficile infection (CDI), and high-fat diets are associated with increased mortality. Here, we profiled host innate immune cells, cecal microbial composition, and the host transcriptome of normal diet (ND) and high-fat diet (HFD)-fed C57BL/6 male and female mice following experimental CDI during the acute and recovery phases. HFD-fed male mice exhibited delayed disease onset but increased mortality following CDI. During acute infection, HFD-fed males showed increased monocyte infiltration and expansion of CD103CD11b- and CD103-CD11b dendritic cell subsets; transcriptomic modules were enriched for antigen presentation and signatures consistent with T cell activation, coincident with enrichment of Escherichia and Lactococcus. In contrast, during recovery, HFD-fed males and females displayed sustained neutrophil and monocyte infiltration, depletion of eosinophils (prominent in males), tissue-resident Tim4/CD206 macrophage subsets and ILC3s, increased expression of Tlr4 and endothelial activation markers, downregulation of metabolic pathways, and failure to restore cecal microbial diversity. Collectively, these data indicate that high-fat feeding disrupts resolution programs after CDI and promotes progression to severe disease, with the most pronounced susceptibility in males.

microbiology↗

bioRxiv2025

VGLL3-centered network connects placental, vascular, and immune defects in preeclampsia

Preeclampsia affects approximately 1 in 10 pregnancies, leading to severe complications and long-term health risks for both mother and offspring. While the etiology remains unclear, preeclampsia has been linked to both autoimmunity and the timing of menarche. Through human single-cell and spatial analyses, coupled with in vitro, in vivo, and ex vivo models, we demonstrate that VGLL3, a transcription co-regulator in the Hippo pathway, is upregulated in preeclamptic placentas. VGLL3 promotes immune activation, impairs trophoblast differentiation, and induces endothelial dysfunction, all of which contribute to pregnancy-related hypertension, fetal growth restriction, and offspring mortality. Our data reveal that VGLL3 acts upstream of preeclampsia-associated processes, including the production of sFLT1, a key biomarker of the disease. Notably, targeting VGLL3--either by genetic deletion in mouse placentas or through therapeutic inhibition in human placentas--protects against preeclampsia and alleviates disease pathology. These findings position VGLL3 as a promising novel therapeutic target for preeclampsia.

immunology↗

bioRxiv2025

Miniature bioreactor arrays for modeling functional and structural dysbiosis in inflammatory bowel disease

Alterations in the gut microbiota, known as gut dysbiosis, are associated with inflammatory bowel disease (IBD). There is a need for model systems that can recapitulate the IBD gut microbiome to better understand the mechanistic impact of differences in microbiota composition and its functional consequences in a controlled laboratory setting. To this end, we introduced fecal samples from patients with Crohns disease (CD) and ulcerative colitis (UC), as well as from healthy control subjects, to miniature bioreactor arrays (MBRAs) and analyzed the microbial communities over time. We then performed two functional assessments. First, we evaluated the colitogenic potential of the CD microbiotas in genetically susceptible germ-free IL-10-deficient mice and found that colitogenic capacity was preserved in a bioreactor-cultivated CD microbiota. Second, we tested impaired colonization resistance against Clostridioides difficile in UC microbiotas using the MBRA system and found that UC microbiotas were innately susceptible to C. difficile colonization while healthy microbiotas were resistant, consistent with what is seen clinically. Overall, our results demonstrate that IBD microbiotas perform comparably to healthy donor microbiotas in the MBRA system, successfully recapitulating microbial structure while preserving IBD-specific functional characteristics. These findings establish a foundation for further mechanistic research into the IBD microbiota using MBRAs.

microbiology↗

bioRxiv2022

Intestinal inflammation reversibly alters the microbiota to drive susceptibility to Clostridioides difficile colonization in a mouse model of colitis

Susceptibility to Clostridioides difficile infection (CDI) typically follows the administration of antibiotics. Patients with inflammatory bowel disease (IBD) have increased incidence of CDI, even in the absence of antibiotic treatment. However, the mechanisms underlying this susceptibility are not well understood. To explore the intersection between CDI and IBD, we recently described a mouse model where colitis triggered by the murine gut bacterium, Helicobacter hepaticus, in IL-10-/- mice led to susceptibility to C. difficile colonization without antibiotic administration. The current work disentangles the relative contributions of inflammation and gut microbiota in colonization resistance to C. difficile in this model. We show that inflammation drives changes in microbiota composition, which leads to CDI susceptibility. Decreasing inflammation with an anti-p40 monoclonal antibody promotes a shift of the microbiota back toward a colonization-resistant state. Transferring microbiota from susceptible and resistant mice to germ-free animals transfers the susceptibility phenotype, supporting the primacy of the microbiota in colonization resistance. These findings shine light on the complex interactions between the host, microbiota, and C. difficile in the context of intestinal inflammation, and may form a basis for the development of strategies to prevent or treat CDI in IBD patients. ImportancePatients with inflammatory bowel disease (IBD) have an increased risk of developing C. difficile infection (CDI), even in the absence of antibiotic treatment. Yet, mechanisms regulating C. difficile colonization in IBD patients remain unclear. Here, we use an antibiotic-independent mouse model to demonstrate that intestinal inflammation alters microbiota composition to permit C. difficile colonization in mice with colitis. Notably, treating inflammation with an anti-p40 monoclonal antibody, a clinically relevant IBD therapeutic, restores microbiota-mediated colonization resistance to the pathogen. Through microbiota transfer experiments in germ-free mice, we confirm that the microbiota shaped in the setting of IBD is the primary driver of susceptibility to C. diffiicile colonization. Collectively, our findings provide insight into CDI pathogenesis in the context of intestinal inflammation, which may inform methods to manage infection in IBD patients. More broadly, this work advances our understanding of mechanisms by which the host-microbiota interface modulates colonization resistance to C. difficile.

microbiology↗

bioRxiv2022

The gut bacterial community potentiates Clostridioides difficile infection severity

The severity of Clostridioides difficile infections (CDI) has increased over the last few decades. Patient age, white blood cell count, creatinine levels as well as C. difficile ribotype and toxin genes have been associated with disease severity. However, it is unclear whether there is an association between members of the gut microbiota and disease severity. The gut microbiota is known to interact with C. difficile during infection. Perturbations to the gut microbiota are necessary for C. difficile to colonize the gut. The gut microbiota can inhibit C. difficile colonization through bile acid metabolism, nutrient consumption and bacteriocin production. Here we sought to demonstrate that members of the gut bacterial communities can also contribute to disease severity. We derived diverse gut communities by colonizing germ-free mice with different human fecal communities. The mice were then infected with a single C. difficile ribotype 027 clinical isolate which resulted in moribundity and histopathologic differences. The variation in severity was associated with the human fecal community that the mice received. Generally, bacterial populations with pathogenic potential, such as Escherichia, Helicobacter, and Klebsiella, were associated with more severe outcomes. Bacterial groups associated with fiber degradation, bile acid metabolism and lantibiotic production, such as Anaerostipes and Coprobacillus, were associated with less severe outcomes. These data indicate that, in addition to the host and C. difficile, populations of gut bacteria can influence CDI disease severity. ImportanceClostridioides difficile colonization can be asymptomatic or develop into an infection, ranging in severity from mild diarrhea to toxic megacolon, sepsis, and death. Models that predict severity and guide treatment decisions are based on clinical factors and C. difficile characteristics. Although the gut microbiome plays a role in protecting against CDI, its effect on CDI disease severity is unclear and has not been incorporated into disease severity models. We demonstrated that variation in the microbiome of mice colonized with human feces yielded a range of disease outcomes. These results revealed groups of bacteria associated with both severe and mild C. difficile infection outcomes. Gut bacterial community data from patients with CDI could improve our ability to identify patients at risk of developing more severe disease and improve interventions which target C. difficile and the gut bacteria to reduce host damage.

microbiology↗

bioRxiv2021

An osmotic laxative renders mice susceptible to prolonged Clostridioides difficile colonization and hinders clearance

Antibiotics are a major risk factor for Clostridioides difficile infections (CDIs) because of their impact on the microbiota. However, non-antibiotic medications such as the ubiquitous osmotic laxative polyethylene glycol (PEG) 3350 also alter the microbiota. Clinicians also hypothesize that PEG helps clear C. difficile. But whether PEG impacts CDI susceptibility and clearance is unclear. To examine how PEG impacts susceptibility, we treated C57Bl/6 mice with 5-day and 1-day doses of 15% PEG in the drinking water and then challenged the mice with C. difficile 630. We used clindamycin-treated mice as a control because they consistently clear C. difficile within 10 days post-challenge. PEG treatment alone was sufficient to render mice susceptible and 5-day PEG-treated mice remained colonized for up to 30 days post-challenge. In contrast, 1-day PEG treated mice were transiently colonized, clearing C. difficile within 7 days post-challenge. To examine how PEG treatment impacts clearance, we administered a 1-day PEG treatment to clindamycin-treated, C. difficile-challenged mice. Administering PEG to mice after C. difficile challenge prolonged colonization up to 30 days post-challenge. When we trained a random forest model with community data from 5 days post-challenge, we were able to predict which mice would exhibit prolonged colonization (AUROC = 0.90). Examining the dynamics of these bacterial populations during the post-challenge period revealed patterns in the relative abundances of Bacteroides, Enterobacteriaceae, Porphyromonadaceae, Lachnospiraceae, and Akkermansia that were associated with prolonged C. difficile colonization in PEG-treated mice. Thus, the osmotic laxative, PEG, rendered mice susceptible to C. difficile colonization and hindered clearance. ImportanceDiarrheal samples from patients taking laxatives are typically rejected for Clostridiodes difficile testing. However, there are similarities between the bacterial communities from people with diarrhea or C. difficile infections (CDI) including lower diversity compared to communities from healthy patients. This observation led us to hypothesize that diarrhea may be an indicator of C. difficile susceptibility. We explored how osmotic laxatives disrupt the microbiotas colonization resistance to C. difficile by administering a laxative to mice either before or after C. difficile challenge. Our findings suggest that osmotic laxatives disrupt colonization resistance to C. difficile, and prevent clearance among mice already colonized with C. difficile. Considering that most hospitals recommend not performing C. difficile testing on patients taking laxatives and laxatives are prescribed prior to administering fecal microbiota transplants via colonoscopy to patients with recurrent CDIs, further studies are needed to evaluate if laxatives impact microbiota colonization resistance in humans.

microbiology↗

bioRxiv2021

Protection from lethal Clostridioides difficile infection via intraspecies competition for co-germinant

Clostridioides difficile, a Gram-positive, spore-forming bacterium, is the primary cause of infectious nosocomial diarrhea. Antibiotics are a major risk factor for C. difficile infection (CDI) as they disrupt the gut microbial community, enabling increased germination of spores and growth of vegetative C. difficile. To date the only single-species bacterial preparation that has demonstrated efficacy in reducing recurrent CDI in humans is non-toxigenic C. difficile. Using multiple infection models we determined that pre-colonization with a less virulent strain is sufficient to protect from challenge with a lethal strain of C. difficile, surprisingly even in the absence of adaptive immunity. Additionally, we showed that protection is dependent on high levels of colonization by the less virulent strain and that it is mediated by exclusion of the invading strain. Our results suggest that reduction of amino acids, specifically glycine following colonization by the first strain of C. difficile is sufficient to decrease germination of the second strain thereby limiting colonization by the lethal strain. ImportanceAntibiotic-associated colitis is often caused by infection with the bacterium Clostridioides difficile. In this study we found that reduction of the amino acid glycine by pre-colonization with a less virulent strain of C. difficile is sufficient to decrease germination of a second strain. This finding demonstrates that the axis of competition for nutrients can include multiple life stages. This work is important, as it is the first to identify a possible mechanism through which pre-colonization with C. difficile, a current clinical therapy, provides protection from reinfection. Furthermore, our work suggests that targeting nutrients utilized by all life stages could be an improved strategy for bacterial therapeutics that aim to restore colonization resistance in the gut.

microbiology↗

bioRxiv2020

Intestinal inflammation and altered gut microbiota associated with inflammatory bowel disease renders mice susceptible to Clostridioides difficile colonization and infection

Clostridioides difficile has emerged as a noteworthy pathogen in patients with inflammatory bowel disease (IBD). Concurrent IBD and CDI is associated with increased morbidity and mortality compared to CDI alone. IBD is associated with alterations of the gut microbiota, an important mediator of colonization resistance to C. difficile. Here, we describe and utilize a mouse model to explore the role of intestinal inflammation in susceptibility to C. difficile colonization and subsequent disease severity in animals with underlying IBD. Helicobacter hepaticus, a normal member of the mouse gut microbiota, was used to trigger inflammation in the distal intestine akin to human IBD in mice that lack intact IL-10 signaling. Development of IBD resulted in a distinct intestinal microbiota community compared to non-IBD controls. We demonstrate that in this murine model, IBD was sufficient to render mice susceptible to C. difficile colonization. Mice with IBD were persistently colonized by C. difficile, while genetically identical non-IBD controls were resistant to C. difficile colonization. Concomitant IBD and CDI was associated with significantly worse disease than unaccompanied IBD. IL-10-deficient mice maintained gut microbial diversity and colonization resistance to C. difficile in experiments utilizing an isogenic mutant of H. hepaticus that does not trigger intestinal inflammation. These studies in mice demonstrate that the IBD-induced microbiota is sufficient for C. difficile colonization and that this mouse model requires intestinal inflammation for inducing susceptibility to CDI in the absence of other perturbations, such as antibiotic treatment. IMPORTANCEThe incidence of CDI continues to increase significantly among patients with IBD, independent of antibiotic use, yet the relationship between IBD and increased risk for CDI remains to be understood. However, antibiotic-induced perturbations of the gut microbiota may mask mechanisms specific to IBD-induced C. difficile susceptibility and infection. Our study sought to describe and utilize a mouse model to specifically explore the relationship between the IBD-induced gut microbial community and susceptibility to C. difficile colonization and CDI development. We demonstrate that IBD is sufficient for C. difficile colonization and infection in mice and results in significantly worse disease than IBD alone, representing a murine model that recapitulates human IBD and CDI comorbidity. Furthermore, this model requires IBD-induced inflammation to sculpt a microbiota permissible to C. difficile colonization. Use of this model will aid in developing new clinical approaches to predict, diagnose, and treat C. difficile infection in the IBD population.

microbiology↗

bioRxiv2020

Aging dampens the intestinal innate immune response during Clostridioides difficile infection and is associated with altered intestinal eosinophil mobilization

Clostridioides (formerly Clostridium) difficile is the most common cause of hospital-acquired infection, and advanced age is a risk factor for C. difficile infection. Disruption of the intestinal microbiota and immune responses contribute to host susceptibility and severity of C. difficile infection. However, the impact of aging on the cellular immune response associated with C. difficile infection in the setting of advanced age remains to be well described. This study explores the effect of age on cellular immune responses in C. difficile infection as well as disease severity. Young adult mice (2-3 months old) and aged mice (22-28 months old) were rendered susceptible to C. difficile infection with cefoperazone and then infected with C. difficile strains of varying disease-causing potential. Aged mice infected with C. difficile develop more severe clinical disease, compared to young mice. Tissue-specific CD45+ immune cell responses occurred at the time of peak disease severity in the cecum and colon of all mice infected with a high-virulence strain of C. difficile; however, significant deficits in intestinal neutrophils and eosinophils were detected in aged mice. Interestingly, while C. difficile infection in young mice was associated with a robust increase in cecal and colonic eosinophils, there was a complete lack of an intestinal eosinophil response in aged counterparts accompanied by a simultaneous increase in blood eosinophils with severe disease. These findings demonstrate that age-related alterations in immune responses are associated with significantly worse C. difficile infection and support a key role for intestinal eosinophils in mitigating C. difficile-mediated disease severity.

immunology↗

bioRxiv2019

Effects of the copper IUD on composition of the vaginal microbiota in the olive baboon

ObjectivesAssess the impact of transcervical insertion, use, and removal of copper intrauterine devices (Cu-IUD) on baboon physiology (e.g. weight, menstruation) and vaginal microbiota.\n\nStudy designVaginal swabs were taken before insertion (pre-IUD), during IUD use (IUD), and after removal (post-IUD) and microbiota assessed by 16S rRNA-encoding gene sequence analysis.\n\nResultsNo animals showed physical changes or discomfort during pre-IUD, IUD, or post-IUD phases. There were no changes to the microbiome associated with insertion or use of Cu-IUD over 16 weeks, although removal resulted in perturbation to community structure.\n\nConclusionsBaboons tolerate Cu-IUD insertion with minimal device-associated changes to their vaginal microbiome throughout use and have no significant changes to their physiology or menstrual cycle during any phase.\n\nImplicationsA baboon model of Cu-IUD may allow investigations into the intersection of Cu-IUDs, reproductive tract disorders and pathogens that would not be possible in human studies.

microbiology↗

bioRxiv2019

Outbreak of murine infection with Clostridium difficile associated with the administration of a pre- and peri-natal methyl-donor diet

Between October 2016 and June 2017, a C57BL/6J mouse colony that was undergoing a pre- and peri-natal methyl-donor supplementation diet intervention to study the impact of parental nutrition on offspring susceptibility to disease was found to suffer from an epizootic of unexpected deaths. Necropsy revealed the presence of severe colitis, and further investigation linked these outbreak deaths to a Clostridium difficile strain of ribotype 027 we term 16N203. C. difficile infection (CDI) is associated with antibiotic use in humans. Current murine models of CDI rely on antibiotic pretreatment to establish clinical phenotypes. In this report, the C. difficile outbreak occurs in F1 mice linked to alterations in the parental diet. The diagnosis of CDI in the affected mice was confirmed by cecal/colonic histopathology, presence of C. difficile bacteria in fecal/colonic culture, and detection of C. difficile toxins. F1 mice from parents fed the methyl-supplementation diet also had significantly reduced survival (p<0.0001) than F1 mice from parents fed the control diet. When we tested the 16N203 outbreak strain in an established mouse model of antibiotic-induced CDI, we confirmed that this strain is pathogenic. Our serendipitous observations from this spontaneous outbreak of C. difficile in association with a pre- and perinatal methyl-donor diet suggest the important role diet may play in host defense and CDI risk factors.\n\nImportanceClostridium difficile infection (CDI) has become the leading cause of infectious diarrhea in hospitals worldwide, owing its preeminence to the emergence of hyperendemic strains, such as ribotype 027 (RT027). A major CDI risk factor is antibiotic exposure which alters gut microbiota, resulting in the loss of colonization resistance. Current murine models of CDI also depend on pretreatment of antibiotics of animals to establish disease. The outbreak we report here is unique in that the CDI occurred in mice with no antibiotic exposure and is associated to a pre- and peri-natal methyl-supplementation donor diet intervention study. Our investigation subsequently reveals that the outbreak strain we term 16N203 is an RT027 strain, and this isolated strain is also pathogenic in an established murine model of CDI (with antibiotics). Our report of this spontaneous outbreak offers additional insight into the importance of environmental factors, such as diet, and CDI susceptibility.

epidemiology↗