Biology subjects

Vendrov, K. C.

Publications and source records attributed to Vendrov, K. C..

9 recordsLinked to original sources

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↗

bioRxiv2024

Host origin of microbiota drives functional recovery and Clostridioides difficile clearance in mice

Colonization resistance provided by the gut microbiota is essential for resisting both initial Clostridioides difficile infection (CDI) and potential recurrent infection (rCDI). Although fecal microbiota transplantation (FMT) has been successful in treating rCDI by restoring microbial composition and function, mechanisms underlying efficacy of standardized stool-derived products remain poorly understood. Using a combination of 16S rRNA gene-based and metagenomic sequencing alongside metabolomics, we investigated microbiome recovery following FMT from human and murine donor sources in a mouse model of rCDI. We found that a human-derived microbiota was less effective in clearing C. difficile compared to a mouse-derived microbiota, despite successful microbial engraftment and recovery of bacterial functional potential. Metabolomic analysis revealed deficits in secondary metabolites, suggesting a functional remodeling between human microbes in their new host environment. Collectively, our data revealed additional environmental, ecological, or host factors involved in FMT-based recovery from rCDI. ImportanceClostridioides difficile is a significant healthcare-associated pathogen, with recurrent infections presenting a major treatment challenge due to further disruption of the microbiota after antibiotic administration. Despite the success of fecal microbiota transplantation (FMT) for the treatment of recurrent infection, the mechanisms mediating its efficacy remain largely underexplored. This study reveals that effectiveness of FMT may be compromised by a mismatch between donor microbes and the recipient environment, leading to deficits in key microbial metabolites. These findings highlight additional factors to consider when assessing the efficacy of microbial-based therapeutics for CDI and other conditions.

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↗

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

Dietary xanthan gum alters antibiotic efficacy against the murine gut microbiota and attenuates Clostridioides difficile colonization

Dietary fiber provides a variety of microbiota-mediated benefits ranging from anti-inflammatory metabolites to pathogen colonization resistance. A healthy gut microbiota protects against Clostridioides difficile colonization. Manipulation of these microbes through diet may increase colonization resistance to improve clinical outcomes. The primary objective of this study was to identify how the dietary fiber xanthan gum affects the microbiota and C. difficile colonization.\n\nWe added 5% xanthan gum to the diet of C57Bl/6 mice and examined its effect on the microbiota through 16S rRNA-gene amplicon sequencing and short-chain fatty acid analysis. Following either cefoperazone or an antibiotic cocktail administration, we challenged mice with C. difficile and measured colonization by monitoring colony-forming units.\n\nXanthan gum administration associates with increases in fiber degrading taxa and short-chain fatty acid concentrations. However, by maintaining both the diversity and absolute abundance of the microbiota during antibiotic treatment, the protective effects of xanthan gum administration on the microbiota were more prominent than the enrichment of these fiber degrading taxa. As a result, mice that were on the xanthan gum diet experienced limited to no C. difficile colonization.\n\nXanthan gum administration alters mouse susceptibility to C. difficile colonization by maintaining the microbiota during antibiotic treatment. While antibiotic-xanthan gum interactions are not well understood, xanthan gum has previously been used to bind drugs and alter their pharmacokinetics. Thus, xanthan gum may alter the activity of the oral antibiotics used to make the microbiota susceptible. Future research should further characterize how this and other common dietary fibers interact with drugs.\n\nIMPORTANCEA healthy gut bacterial community benefits the host by breaking down dietary nutrients and protecting against pathogens. Clostridioides difficile capitalizes on the absence of this community to cause diarrhea and inflammation. Thus, a major clinical goal is to find ways to increase resistance to C. difficile colonization by either supplementing with bacteria that promote resistance or a diet to enrich for those already present in the gut. In this study, we describe an interaction between xanthan gum, a human dietary additive, and the microbiota resulting in an altered gut environment that is protective against C. difficile colonization.

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↗

bioRxiv2019

The gut microbiota is associated with clearance of Clostridium difficile infection independent of adaptive immunity

Clostridium (Clostridioides) difficile, a Gram-positive, anaerobic bacterium is the leading single cause of nosocomial infections in the United States. A major risk factor for C. difficile infection (CDI) is prior exposure to antibiotics as they increase susceptibility to CDI by altering the membership of the microbial community enabling colonization. The importance of the gut microbiota in providing protection from CDI is underscored by the reported 80-90% success rate of fecal microbial transplants in treating recurrent infection. Adaptive immunity, specifically humoral immunity, is also sufficient to protect from both acute and recurrent CDI. However, the role of the adaptive immune system in mediating clearance of C. difficile has yet to be resolved. Using murine models of CDI, we found that adaptive immunity is dispensable for clearance of C. difficile. However, Random Forest analysis using only 2 members of the resident bacterial community correctly identified animals that would go on to clear the infection with 66.7% accuracy. These findings indicate that the indigenous gut microbiota independent of adaptive immunity facilitates clearance of C. difficile from the murine gastrointestinal tract.\n\nImportanceC. difficile infection is a major cause of morbidity and mortality in hospitalized patients in the United States. Currently the role of the adaptive immune response in modulating levels of C. difficile colonization is unresolved. This work suggests that the indigenous gut microbiota is a main factor that promotes clearance of C. difficile from the GI tract. Our results show that clearance of C. difficile can occur without contributions from the adaptive immune response. This study also has implications for the design of preclinical studies testing the efficacy of vaccines on clearance of bacterial pathogens as inherent differences in the baseline community structure of animals may bias findings.

microbiology↗