Browsing by Subject "Intestines"
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Item Changes in the Gut Metabolic Landscape Drive Inflammation-Associated Dysbiosis and Host Responses(2020-12-01T06:00:00.000Z) Hughes, Elizabeth Rose; Sperandio, Vanessa; Pfeiffer, Julie K.; Alto, Neal; Winter, Sebastian E.Intestinal inflammation is frequently associated with alterations in composition of gut microbial communities, termed dysbiosis. Inflammation-associated dysbiosis is characterized by an expansion of facultative anaerobic bacteria in the Proteobacteria phylum, such as Escherichia coli. A dysbiotic microbiota has been linked to increased disease severity in the context of inflammatory bowel disease. However, the mechanisms responsible for inflammation-associated dysbiosis and its impact on disease are incompletely understood. Utilizing bioinformatic analyses of gut microbiota composition and mechanistic studies with Escherichia coli as a model organism in murine models, we uncovered two metabolic pathways that are unique to intestinal inflammation and responsible for changes in microbiota composition. Aerobic respiration coupled with formate oxidation, and utilization of molecular hydrogen fuel expansion of Escherichia coli populations during intestinal inflammation. The impact of oxygen leakage into the gut lumen on obligate anaerobic bacterial metabolism was additionally investigated. In vitro metabolite measurements and use of bacterial genetics indicated formate production increased in Bacteroides exposed to low oxygen levels. Formate measurements and exogenous delivery of formate in mice suggested that intestinal formate levels increase during inflammation and may exacerbate disease. However, further study is required. In conclusion, we identified key changes that occur during non-infectious inflammation in the gut metabolic landscape, illustrating the importance of understanding bacterial metabolism in order to understand host-microbiota interactions.Item Gastrointestinal Influences on Poliovirus Replication, Dissemination and Pathogenesis in Mice(2011-12-12) Kuss, Sharon Kay; Pfeiffer, Julie K.Enteric viruses are transmitted between individuals by fecal-oral spread. After oral acquisition, enteric viruses encounter a complex environment within the gastrointestinal (GI) tract, including pH changes, mucus, resident bacteria and a variety of epithelial and immune cell types. Little is known about how factors within and comprising the GI tract influence viral replication, dissemination and pathogenesis. In order to assess the influence of the intestinal environment on enteric viruses, poliovirus was used as a model enteric virus. Following infection within the GI tract, poliovirus has the capacity to spread to the central nervous system (CNS). Poliovirus infection of the CNS is uncommon, but it can result in acute flaccid paralysis known as poliomyelitis in humans. Poliomyelitis can be mimicked in mice susceptible to poliovirus. Initial studies were performed in mice to examine poliovirus infection within and dissemination from the GI tract to extra-intestinal tissues, including blood and the CNS. By monitoring spread of a marked poliovirus population in susceptible mice, many host barriers to intra-host viral trafficking were identified. Type I interferon responses and intestinal epithelial cell integrity are host barriers that were found to restrict poliovirus. Infecting cells within the GI tract was also difficult for poliovirus, which further limited dissemination from the intestine to the blood and CNS. Bottlenecks were imposed on poliovirus while trafficking through and disseminating from the GI tract, possibly providing an explanation for the low incidence of poliomyelitis disease onset in humans following poliovirus infection. Because the GI tract was a substantial barrier to poliovirus, studies were undertaken to characterize factors that limit poliovirus dissemination from the GI tract. The naturally-residing microbiota are amongst many other factors present within the GI tract that may influence poliovirus infection. Although suspected to limit poliovirus, intestinal microbiota augmented poliovirus infection in mice and cell culture by enhancing viral infectivity. The studies described herein demonstrate how host complexity imparts detrimental and beneficial influences on poliovirus acquired by the natural fecal-oral route.Item The microbiome and spondyloarthritis(2015-10-30) Reimold, AndreasItem Regulation of Body Composition by the Microbiota and the Circadian Clock(2017-11-21) Wang, Yuhao; Green, Carla B.; Liu, Yi; Wan, Yihong; Hooper, Lora V.The intestinal microbiota has been identified as an environmental factor that markedly impacts energy storage and body fat accumulation, yet the underlying mechanisms remain unclear. In this dissertation, I show that the microbiota regulates body composition through the circadian transcription factor NFIL3 in intestinal epithelial cells. First, epithelial NFIL3 promotes lipid absorption and export in the intestine by regulating a circadian expression program of epithelial lipid metabolic genes. Second, Nfil3 transcription oscillates diurnally in intestinal epithelial cells and the amplitude of the circadian oscillation is controlled by the microbiota through group 3 innate lymphoid cells (ILC3), STAT3, and the epithelial cell circadian clock. These findings provide mechanistic insight into how the intestinal microbiota regulates body composition and establish NFIL3 as an essential molecular link among the microbiota, the circadian clock, and host metabolism.Item Transcriptional Regulation of Intestinal Stem Cell Lineage in Drosophila(2017-04-17) Lan, Qing; Jiang, Jin; Kraus, W. Lee; Sadek, Hesham A.; Jiang, HuaqiThe question of how somatic stem cells respond to tissue needs is always intriguing, since aberrant somatic stem cell behaviors may lead to adult tissue degeneration or tumorigenesis. Here, this thesis focuses on the transcriptional regulation of a somatic stem cell lineage: the intestinal stem cell in Drosophila adult gut. The Drosophila adult gut is a dynamic organ. It is maintained by hundreds of somatic gut stem cell evenly distributed throughout the gut epithelium. These multi-potent somatic stem cells undergo self-renewal and differentiation to replenish two mature gut cell types: the absorptive enterocytes and secretory entero-endocrine cells. Through an RNAi screen targeting transcription factors required for stem cell-mediated acute gut regeneration, two novel transcription factors, the FoxA family Fork head (Fkh) and SoxE family sox100b (dSox9), were uncovered and functionally characterized in this thesis. During gut regeneration, transcription factor Fkh and dSox9 are required for stem cell proliferation. During gut homeostasis, Fkh maintains stemness and prevents progenitor from precocious differentiation; dSox9 controls lineage differentiation through Jak-Stat pathway. To further probe mechanisms underlying gut stem cell physiology, ChIP-Seq technique was applied to map chromatin binding sites of gut stem cell regulators (HA tagged) in stem/progenitor cells of dissected fly guts, including transcription factors (FoxA family/Fkh, SoxE family/dSox9, bHLH family/Da), niche pathway downstream factors (Jak-Stat pathway/Stat92E, BMP pathway/Mad, Notch pathway/Su(H), JNK pathway/Kay), and transcriptional regulators (Mediator/Med20, p300/Nej). A set of shared ChIP-Seq peak regions likely functions as enhancers to drive gene expression in gut stem/progenitor cells. This thesis leads to the speculation of a transcriptional network that maintains gut stem/progenitor cell normal physiology in adult Drosophila.Item Unexpected Factors That Influence Coxsackievirus B3 Replication in Mouse Intestine(2017-04-14) Wang, Yao; Kahn, Jeffrey; Pfeiffer, Julie K.; Hooper, Lora V.; Ye, JinCoxsackievirus is a human pathogen that frequently infect humans. Although many infections are asymptomatic, there can be severe outcomes, including heart inflammation and pancreas inflammation. Most studies with coxsackieviruses and other viruses use laboratory-adapted viral strains because of their efficient replication in cell culture. I used a cell culture-adapted strain of coxsackievirus B3 (CVB3), CVB3-Nancy, to examine viral replication and pathogenesis in orally inoculated mice. Using HeLa cell plaque assays with agar overlays, I noticed that some fecal viruses generated plaques >100 times as large as inoculum viruses. These large-plaque variants emerged following viral replication in several different tissues. I identified a single amino acid change, N63Y, in the VP3 capsid protein that was sufficient to confer the large-plaque phenotype. Wild-type CVB3 and N63Y mutant CVB3 had similar plaque sizes when agarose was used in the overlay instead of agar. I determined that sulfated glycans in agar inhibited plaque formation by wild-type CVB3 but not by N63Y mutant CVB3. Furthermore, N63Y mutant CVB3 bound heparin, a sulfated glycan, less efficiently than wild-type CVB3 did. While N63Y mutant CVB3 had a growth defect in cultured cells and reduced attachment, it had enhanced replication and pathogenesis in mice. Infection with N63Y mutant CVB3 induced more severe hepatic damage than infection with wild-type CVB3, likely because N63Y mutant CVB3 disseminates more efficiently to the liver. This work reinforce the idea that culture-adapted laboratory virus strains can have reduced fitness in vivo. N63Y mutant CVB3 may be useful as a platform to understand viral adaptation and pathogenesis in animal studies. I also explored other factors that influence CVB3 infection in mouse intestine. First, a sex bias for severe sequelae from coxsackievirus infections has been observed in humans. We sought to examine if the phenomenon can be seen in mice and to further understand the mechanisms. Here we orally infected mice with CVB3 and confirmed that CVB3 replication in the intestine is sex-dependent. CVB3 replicated efficiently in male mice intestine, but not female mice. Overall these data suggest that sex and the immune response play an important role in CVB3 replication in the intestine and should be considered in light of the sex bias observed in human disease. Previously, our lab has shown that intestinal microbiota promote replication and pathogenesis of several viruses, including poliovirus (PV), reovirus and CVB3. With that finding, we wanted to examine how microbiota enhance CVB3 infection. Bacteria in the colon produce millimolar quantities of butyrate and other short-chain fatty acids (SCFAs) through fermentation of dietary fiber. SCFAs are among the most abundant molecules in the distal gastrointestinal tract. To determine whether bacterial-derived SCFAs such as butyrate impact CVB3 replication in the intestine, I antibiotic treated mice and then supplied them with tributyrin, a form of butyrate that is absorbed in the distal gastrointestinal tract. I found that CVB3 replication and pathogenesis was restored in antibiotic-treated mice that received tributyrin. These results suggest that butyrate is sufficient to promote CVB3 replication. My preliminary data demonstrate that oral delivery of a histone deacetylase (HDAC) inhibitor, Vorinostat, is sufficient to restore CVB3 replication in antibiotic-treated mice, suggesting that the HDAC activity of butyrate may promote CVB3 infection. Taken all together, I identified several unexpected factors that may influence CVB3 replication in mouse intestine although much remains open for exploration.Item [UT Southwestern Medical Center News](2011-05-09) Shear, Kristen Holland