Browsing by Subject "Dysbiosis"

Now showing 1 - 8 of 8
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    A Dysbiotic Microbiome Promotes Head and Neck Squamous Cell Carcinoma
    (Springer Nature, 2022) Frank, Daniel N.; Qiu, Yue; Cao, Yu; Zhang, Shuguang; Lu, Ling; Kofonow, Jennifer M.; Robertson, Charles E.; Liu, Yanqiu; Wang, Haibo; Levens, Cassandra L.; Kuhn, Kristi A.; Song, John; Ramakrishnan, Vijay R.; Lu, Shi-Long; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Recent studies have reported dysbiotic oral microbiota and tumor-resident bacteria in human head and neck squamous cell carcinoma (HNSCC). We aimed to identify and validate oral microbial signatures in treatment-naïve HNSCC patients compared with healthy control subjects. We confirm earlier reports that the relative abundances of Lactobacillus spp. and Neisseria spp. are elevated and diminished, respectively, in human HNSCC. In parallel, we examined the disease-modifying effects of microbiota in HNSCC, through both antibiotic depletion of microbiota in an induced HNSCC mouse model (4-Nitroquinoline 1-oxide, 4NQO) and reconstitution of tumor-associated microbiota in a germ-free orthotopic mouse model. We demonstrate that depletion of microbiota delays oral tumorigenesis, while microbiota transfer from mice with oral cancer accelerates tumorigenesis. Enrichment of Lactobacillus spp. was also observed in murine HNSCC, and activation of the aryl-hydrocarbon receptor was documented in both murine and human tumors. Together, our findings support the hypothesis that dysbiosis promotes HNSCC development.
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    A review of gut failure as a cause and consequence of critical illness
    (Springer Nature, 2025-02-26) Soranno, Danielle E.; Coopersmith, Craig M.; Brinkworth, Jessica F.; Factora, Faith N. F.; Muntean, Julia H.; Mythen, Monty G.; Raphael, Jacob; Shaw, Andrew D.; Vachharajani, Vidula; Messer, Jeannette S.; Pediatrics, School of Medicine
    In critical illness, all elements of gut function are perturbed. Dysbiosis develops as the gut microbial community loses taxonomic diversity and new virulence factors appear. Intestinal permeability increases, allowing for translocation of bacteria and/or bacterial products. Epithelial function is altered at a cellular level and homeostasis of the epithelial monolayer is compromised by increased intestinal epithelial cell death and decreased proliferation. Gut immunity is impaired with simultaneous activation of maladaptive pro- and anti-inflammatory signals leading to both tissue damage and susceptibility to infections. Additionally, splanchnic vasoconstriction leads to decreased blood flow with local ischemic changes. Together, these interrelated elements of gastrointestinal dysfunction drive and then perpetuate multi-organ dysfunction syndrome. Despite the clear importance of maintaining gut homeostasis, there are very few reliable measures of gut function in critical illness. Further, while multiple therapeutic strategies have been proposed, most have not been shown to conclusively demonstrate benefit, and care is still largely supportive. The key role of the gut in critical illness was the subject of the tenth Perioperative Quality Initiative meeting, a conference to summarize the current state of the literature and identify key knowledge gaps for future study. This review is the product of that conference.
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    FRI009 Microbiome Affects Host Metabolic Homeostasis Via Differential Regulation Of Gene Expression In The Endocrine System
    (The Endocrine Society, 2023-10-05) Milhouse, Wynne; Ren, Hongxia; Pediatrics, School of Medicine
    Dysbiosis has been implicated in many metabolic disorders, but the exact role of microbiota is not completely understood. To address this question, we used germ-free (GF) and conventional (CON) mouse models to examine the expression of genes critical for endocrine regulation of metabolic homeostasis. Samples of the mediobasal hypothalamus (MBH) were obtained from 18 germ-free and 18 conventional C57BL/6 mice (n=9 males, 9 females). Each gene transcript was quantified using quantitative real-time polymerase chain reaction (qRT-PCR). We also collected the serum from both cohorts and measured ad libitum insulin and leptin concentrations by enzyme-linked immunosorbent assay (ELISA). Our results showed that, in the MBH, GF mice had increased expression of neuropeptides involved in feeding regulation, i.e., Neuropeptide Y (Npy) and Proopiomelanocortin (Pomc), compared to CON mice (p < 0.0001). Furthermore, CON mice had increased expression of a negative regulator of leptin signaling, Suppressor of cytokine signaling 3 (Socs3), in the MBH. Consistently, serum leptin in CON male mice was higher than that of male GF mice (p < 0.001). In the gut samples, the GF cohort demonstrated increased expression of gut hormones that promote satiety, such as Peptide yy (Pyy) and Cholecystokinin (Cck), respectively (p < 0.05 and p < 0.0001). The absence of a microbiome had differing effects on the expression of incretin hormones and the G protein-coupled receptors (GPCRs) that stimulate their secretion. In the jejunum, ileum, and colon of CON mice, expression of Glucagon-like peptide 1 (Glp-1) was increased compared to that of GF mice (p < 0.001, p < 0.05, and p < 0.0001, respectively). Conversely, Glucose-dependent insulinotropic polypeptide (Gip) showed increased expression in the duodenum of male and female GF mice (p < 0.0001). G protein-coupled receptor 119 (Gpr119) and G protein-coupled receptor 120 (Gpr120) showed increased expression only in the colon of female GF mice (p < 0.0001 and p < 0.01, respectively). Germ-free and conventional mice demonstrated comparable ad libitum insulin concentrations. We conclude that the increased expression of Pomc, Gip, Cck, and Pyy and the increased leptin sensitivity in GF mice contribute to the lean phenotype observed in these mice. The additional increase in Npy and decrease in Glp-1 likely play a compensatory role in regulating energy consumption and expenditure. Thus, the microbiome may impinge upon diverse effectors of the neuroendocrine and enteroendocrine systems to regulate host metabolism, influencing energy consumption and expenditure in the development of obesity.
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    Multi-modal Single-Cell Analysis Reveals Brain Immune Landscape Plasticity during Aging and Gut Microbiota Dysbiosis
    (Elsevier, 2020-12-01) Golomb, Samantha M.; Guldner, Ian H.; Zhao, Anqi; Wang, Qingfei; Palakurthi, Bhavana; Aleksandrovic, Emilija A.; Lopez, Jacqueline A.; Lee, Shaun W.; Yang, Kai; Zhang, Siyuan; Medicine, School of Medicine
    Phenotypic and functional plasticity of brain immune cells contribute to brain tissue homeostasis and disease. Immune cell plasticity is profoundly influenced by tissue microenvironment cues and systemic factors. Aging and gut microbiota dysbiosis that reshape brain immune cell plasticity and homeostasis has not been fully delineated. Using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), we analyze compositional and transcriptional changes of the brain immune landscape in response to aging and gut dysbiosis. Discordance between canonical surface-marker-defined immune cell types and their transcriptomes suggest transcriptional plasticity among immune cells. Ly6C+ monocytes predominate a pro-inflammatory signature in the aged brain, while innate lymphoid cells (ILCs) shift toward an ILC2-like profile. Aging increases ILC-like cells expressing a T memory stemness (Tscm) signature, which is reduced through antibiotics-induced gut dysbiosis. Systemic changes due to aging and gut dysbiosis increase propensity for neuroinflammation, providing insights into gut dysbiosis in age-related neurological diseases.
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    Oral inflammation and microbiome dysbiosis exacerbate chronic graft-versus-host disease
    (American Society of Hematology, 2025) Kambara, Yui; Fujiwara, Hideaki; Yamamoto, Akira; Gotoh, Kazuyoshi; Tsuji, Shuma; Kunihiro, Mari; Oyama, Tadashi; Terao, Toshiki; Sato, Ayame; Tanaka, Takehiro; Peltier, Daniel; Seike, Keisuke; Nishimori, Hisakazu; Asada, Noboru; Ennishi, Daisuke; Fujii, Keiko; Fujii, Nobuharu; Matsuoka, Ken-Ichi; Soga, Yoshihiko; Reddy, Pavan; Maeda, Yoshinobu; Pediatrics, School of Medicine
    The oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in graft-versus-host disease (GVHD) pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients after hematopoietic cell transplantation (HCT) associated with increased chronic GVHD (cGVHD), even in patients receiving posttransplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures exacerbated cGVHD and increased bacterial load in the oral cavity and gut, with Enterococcaceae significantly increasing in both organs. In this model, the migration of Enterococcaceae to cervical lymph nodes both before and after transplantation activated antigen-presenting cells, thereby promoting the expansion of donor-derived inflammatory T cells. Based on these results, we hypothesize that pathogenic bacteria increase in the oral cavity might not only exacerbate local inflammation but also enhance systemic inflammation throughout the HCT course. Additionally, these bacteria translocated to the gut and formed ectopic colonies, further amplifying systemic inflammation. Furthermore, interventions targeting the oral microbiome mitigated murine cGVHD. Collectively, our findings highlight the importance of oral dysbiosis in cGVHD and suggest that modulation of the oral microbiome during transplantation may be an effective approach for preventing or treating cGVHD.
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    Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice
    (American Diabetes Association, 2018-09) Beli, Eleni; Yan, Yuanqing; Moldovan, Leni; Vieira, Cristiano P.; Gao, Ruli; Duan, Yaqian; Prasad, Ram; Bhatwadekar, Ashay; White, Fletcher A.; Townsend, Steven D.; Chan, Luisa; Ryan, Caitlin N.; Morton, Daniel; Moldovan, Emil G.; Chu, Fang-I; Oudit, Gavin Y.; Derendorf, Hartmut; Adorini, Luciano; Wang, Xiaoxin X.; Evans-Molina, Carmella; Mirmira, Raghavendra G.; Boulton, Michael E.; Yoder, Mervin C.; Li, Qiuhong; Levi, Moshe; Busik, Julia V.; Grant, Maria B.; Pediatrics, School of Medicine
    Intermittent fasting (IF) protects against the development of metabolic diseases and cancer, but whether it can prevent diabetic microvascular complications is not known. In db/db mice, we examined the impact of long-term IF on diabetic retinopathy (DR). Despite no change in glycated hemoglobin, db/db mice on the IF regimen displayed significantly longer survival and a reduction in DR end points, including acellular capillaries and leukocyte infiltration. We hypothesized that IF-mediated changes in the gut microbiota would produce beneficial metabolites and prevent the development of DR. Microbiome analysis revealed increased levels of Firmicutes and decreased Bacteroidetes and Verrucomicrobia. Compared with db/db mice on ad libitum feeding, changes in the microbiome of the db/db mice on IF were associated with increases in gut mucin, goblet cell number, villi length, and reductions in plasma peptidoglycan. Consistent with the known modulatory effects of Firmicutes on bile acid (BA) metabolism, measurement of BAs demonstrated a significant increase of tauroursodeoxycholate (TUDCA), a neuroprotective BA, in db/db on IF but not in db/db on AL feeding. TGR5, the TUDCA receptor, was found in the retinal primary ganglion cells. Expression of TGR5 did not change with IF or diabetes. However, IF reduced retinal TNF-α mRNA, which is a downstream target of TGR5 activation. Pharmacological activation of TGR5 using INT-767 prevented DR in a second diabetic mouse model. These findings support the concept that IF prevents DR by restructuring the microbiota toward species producing TUDCA and subsequent retinal protection by TGR5 activation.
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    Volatile Organic Compound Assessment as a Screening Tool for Early Detection of Gastrointestinal Diseases
    (MDPI, 2023-07-17) Dalis, Costa; Mesfin, Fikir M.; Manohar, Krishna; Liu, Jianyun; Shelley, W. Christopher; Brokaw, John P.; Markel, Troy A.; Surgery, School of Medicine
    Gastrointestinal (GI) diseases have a high prevalence throughout the United States. Screening and diagnostic modalities are often expensive and invasive, and therefore, people do not utilize them effectively. Lack of proper screening and diagnostic assessment may lead to delays in diagnosis, more advanced disease at the time of diagnosis, and higher morbidity and mortality rates. Research on the intestinal microbiome has demonstrated that dysbiosis, or unfavorable alteration of organismal composition, precedes the onset of clinical symptoms for various GI diseases. GI disease diagnostic research has led to a shift towards non-invasive methods for GI screening, including chemical-detection tests that measure changes in volatile organic compounds (VOCs), which are the byproducts of bacterial metabolism that result in the distinct smell of stool. Many of these tools are expensive, immobile benchtop instruments that require highly trained individuals to interpret the results. These attributes make them difficult to implement in clinical settings. Alternatively, electronic noses (E-noses) are relatively cheaper, handheld devices that utilize multi-sensor arrays and pattern recognition technology to analyze VOCs. The purpose of this review is to (1) highlight how dysbiosis impacts intestinal diseases and how VOC metabolites can be utilized to detect alterations in the microbiome, (2) summarize the available VOC analytical platforms that can be used to detect aberrancies in intestinal health, (3) define the current technological advancements and limitations of E-nose technology, and finally, (4) review the literature surrounding several intestinal diseases in which headspace VOCs can be used to detect or predict disease.