Browsing by Subject "Gut dysbiosis"

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    Acyloxyacyl hydrolase is a host determinant of gut microbiome-mediated pelvic pain
    (The American Physiological Society, 2021) Rahman-Enyart, Afrida; Yang, Wenbin; Yaggie, Ryan E.; White, Bryan A.; Welge, Michael; Auvil, Loretta; Berry, Matthew; Bushell, Colleen; Rosen, John M.; Rudick, Charles N.; Schaeffer, Anthony J.; Klumpp, David J.; Pharmacology and Toxicology, School of Medicine
    Dysbiosis of gut microbiota is associated with many pathologies, yet host factors modulating microbiota remain unclear. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition of chronic pelvic pain often with comorbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in patients with IC/BPS. We identified the locus encoding acyloxyacyl hydrolase, Aoah, as a modulator of pelvic pain severity in a murine IC/BPS model. AOAH-deficient mice spontaneously develop rodent correlates of pelvic pain, increased responses to induced pelvic pain models, voiding dysfunction, and anxious/depressive behaviors. Here, we report that AOAH-deficient mice exhibit dysbiosis of gastrointestinal (GI) microbiota. AOAH-deficient mice exhibit an enlarged cecum, a phenotype long associated with germ-free rodents, and a "leaky gut" phenotype. AOAH-deficient ceca showed altered gene expression consistent with inflammation, Wnt signaling, and urologic disease. 16S sequencing of stool revealed altered microbiota in AOAH-deficient mice, and GC-MS identified altered metabolomes. Cohousing AOAH-deficient mice with wild-type mice resulted in converged microbiota and altered predicted metagenomes. Cohousing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAH-deficient mice with stool slurry of wild-type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAH-deficient mice. Oral gavage of AOAH-deficient mice with anaerobes cultured from IC/BPS stool resulted in exacerbation of pelvic allodynia. Together, these data indicate that AOAH is a host determinant of normal gut microbiota, and dysbiosis associated with AOAH deficiency contributes to pelvic pain. These findings suggest that the gut microbiome is a potential therapeutic target for IC/BPS.
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    Does the Gut Microbiome Play a Role in Obesity in Type 1 Diabetes? Unanswered Questions and Review of the Literature
    (Frontiers Media, 2022-07-08) Ismail, Heba M.; Evans-Molina, Carmella; Pediatrics, School of Medicine
    Evidence suggests that type 1 diabetes (T1D) risk and progression are associated with gut bacterial imbalances. Children with either T1D or islet antibody positivity exhibit gut dysbiosis (microbial imbalance) characterized by lower gram-positive to gram-negative gut bacterial ratios compared to healthy individuals, leading to a pro-inflammatory milieu. In addition, specific gut microbiome changes, including increased virulence factors, elevated phage, prophage, and motility genes, and higher amplitude stress responses, have been identified in individuals who have or are progressing towards T1D. Additionally, gut microbiome differences are associated with and thought to contribute to obesity, a comorbidity that is increasingly prevalent among persons with T1D. Obesity in T1D is problematic because individuals with obesity progress faster to T1D, have reduced insulin sensitivity compared to their lean counterparts, and have higher risk of complications. Animal and human studies suggest higher relative abundance of bacterial taxa associated with changes in bile acid and short chain fatty acid biosynthesis in obesity. However, it is unknown to what extent the gut microbiome plays a role in obesity in T1D and these worse outcomes. In this review, we aim to evaluate potential gut microbiome changes and associations in individuals with T1D who are obese, highlighting the specific gut microbiome changes associated with obesity and with T1D development. We will identify commonalities and differences in microbiome changes and examine potential microbiota-host interactions and the metabolic pathways involved. Finally, we will explore interventions that may be of benefit to this population, in order to modify disease and improve outcomes.
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    Hepatic Autophagy Deficiency Remodels Gut Microbiota for Adaptive Protection via FGF15-FGFR4 Signaling
    (Elsevier, 2021) Yan, Shengmin; Khambu, Bilon; Chen, Xiaoyun; Dong, Zheng; Guo, Grace; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
    Background & aims: The functions of the liver and the intestine are closely tied in both physiological and pathologic conditions. The gut microbiota (GM) often cause deleterious effects during hepatic pathogenesis. Autophagy is essential for liver homeostasis, but the impact of hepatic autophagy function on liver-gut interaction remains unknown. Here we investigated the effect of hepatic autophagy deficiency (Atg5Δhep) on GM and in turn the effect of GM on the liver pathology. Methods: Fecal microbiota were analyzed by 16S sequencing. Antibiotics were used to modulate GM. Cholestyramine was used to reduce the enterohepatic bile acid (BA) level. The functional role of fibroblast growth factor 15 (FGF15) and ileal farnesoid X receptor (FXR) was examined in mice overexpressing FGF15 gene or in mice given a fibroblast growth factor receptor-4 (FGFR4) inhibitor. Results: Atg5Δhep causes liver injury and alterations of intestinal BA composition, with a lower proportion of tauro-conjugated BAs and a higher proportion of unconjugated BAs. The composition of GM is significantly changed with an increase in BA-metabolizing bacteria, leading to an increased expression of ileal FGF15 driven by FXR that has a higher affinity to unconjugated BAs. Notably, antibiotics or cholestyramine treatment decreased FGF15 expression and exacerbated liver injury. Consistently, inhibition of FGF15 signaling in the liver enhances liver injury. Conclusions: Deficiency of autophagy function in the liver can affect intestinal environment, leading to gut dysbiosis. Surprisingly, such changes provide an adaptive protection against the liver injury through the FGF15-FGFR4 signaling. Antibiotics use in the condition of liver injury may thus have unexpected adverse consequences via the gut-liver axis.