Antibody deficiency is the most frequently diagnosed form of primary immunodeficiency in humans. Common variable immunodeficiency (CVID) is the most severe form of antibody deficiency and is characterized as hypogammaglobulinemia (low IgG) with an accompanying deficit in IgA and/or IgM titers. In both humans and laboratory mouse models, IgA deficiency has been associated with alterations to the composition and function of symbiotic microbial communities (a.k.a. the microbiota) in the gut, and emerging data from CVID patients indicate that a similar association exists. Up to 50% of CVID patients will develop gastrointestinal symptoms, and the major complication of CVID is CVID enteropathy. CVID enteropathy most often presents as chronic diarrhea and weight loss due to an underlying intestinal malabsorption. The pathophysiological mechanism driving CVID enteropathy is not known but pathological alterations to the microbiota ('dysbiosis') could be a key factor. Bile acids (BAs) are secreted into the gut where they play a crucial role in the emulsification of dietary lipids that facilitates their absorption. The microbiome plays a central role in shaping BA composition in the gut. Thus, dysbiosis caused by gut antibody deficiency may drive CVID enteropathy and associated metabolic disease by influencing BA metabolism in the gut. The objective of Specific Aim #1 is to test that intestinal malabsorption is an IgA-dependent phenotype using adoptive transfer models in antibody deficient recipients. The objective of Specific Aim #2 is to specifically test that bacterial bile salt hydrolase (bsh) activity results in enhanced BA deconjugation that drives malabsorption in antibody deficient mice. Mono-colonization experiments in germfree Ig-deficient mice using WT and bsh-null mutant strain of commensal bacteria will be used to address this hypothesis. The objective of Specific Aim #3 is to determine the impact of altered BA pools on host metabolism using a mixture of in vitro and in vivo models. Collectively, these experiments are the first to address the role of mucosal IgA deficiency in the context of CVID on the regulation of bacterial BA metabolism and its effect on host health. Several approaches will be utilized to assess the feasibility of treating malabsorption and chronic inflammation through dietary manipulation of the microbiome.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103641-08
Application #
10220550
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Krasnova, Irina N
Project Start
2020-06-01
Project End
2023-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of South Carolina at Columbia
Department
Type
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
Miranda, Kathryn; Yang, Xiaoming; Bam, Marpe et al. (2018) MicroRNA-30 modulates metabolic inflammation by regulating Notch signaling in adipose tissue macrophages. Int J Obes (Lond) 42:1140-1150
Alhasson, Firas; Seth, Ratanesh Kumar; Sarkar, Sutapa et al. (2018) High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pathology in nonalcoholic fatty liver disease. Redox Biol 17:1-15
Bam, Marpe; Yang, Xiaoming; Sen, Souvik et al. (2018) Characterization of Dysregulated miRNA in Peripheral Blood Mononuclear Cells from Ischemic Stroke Patients. Mol Neurobiol 55:1419-1429
Elliott, David M; Singh, Narendra; Nagarkatti, Mitzi et al. (2018) Cannabidiol Attenuates Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis Through Induction of Myeloid-Derived Suppressor Cells. Front Immunol 9:1782
Liese, Angela D; Ma, Xiaonan; Ma, Xiaoguang et al. (2018) Dietary quality and markers of inflammation: No association in youth with type 1 diabetes. J Diabetes Complications 32:179-184
Alghetaa, Hasan; Mohammed, Amira; Sultan, Muthanna et al. (2018) Resveratrol protects mice against SEB-induced acute lung injury and mortality by miR-193a modulation that targets TGF-? signalling. J Cell Mol Med 22:2644-2655
Zhang, Tao; Zhou, Juhua; Man, Gene Chi Wai et al. (2018) MDSCs drive the process of endometriosis by enhancing angiogenesis and are a new potential therapeutic target. Eur J Immunol 48:1059-1073
Seth, Ratanesh Kumar; Kimono, Diana; Alhasson, Firas et al. (2018) Increased butyrate priming in the gut stalls microbiome associated-gastrointestinal inflammation and hepatic metabolic reprogramming in a mouse model of Gulf War Illness. Toxicol Appl Pharmacol 350:64-77
Finnell, Julie E; Muniz, Brandon L; Padi, Akhila R et al. (2018) Essential Role of Ovarian Hormones in Susceptibility to the Consequences of Witnessing Social Defeat in Female Rats. Biol Psychiatry 84:372-382
Dubey, Seema; Yoon, Hyunho; Cohen, Mark Steven et al. (2018) Withaferin A Associated Differential Regulation of Inflammatory Cytokines. Front Immunol 9:195

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