Publications by authors named "Justin L McCarville"

Colorectal cancer (CRC) is driven by genomic alterations in concert with dietary influences, with the gut microbiome implicated as an effector in disease development and progression. While meta-analyses have provided mechanistic insight into patients with CRC, study heterogeneity has limited causal associations. Using multi-omics studies on genetically controlled cohorts of mice, we identify diet as the major driver of microbial and metabolomic differences, with reductions in α diversity and widespread changes in cecal metabolites seen in high-fat diet (HFD)-fed mice.

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  • - Disease tolerance is a vital survival strategy that minimizes physical damage from infections without directly killing the pathogens, and this tolerance shifts as an organism ages.
  • - Research using a polymicrobial sepsis model revealed distinct health responses in young and old mice after infection, highlighting different disease courses related to their age.
  • - Young mice utilized a protective mechanism involving FoxO1 that helped them survive, while the same mechanism contributed to heart issues and death in older mice, underscoring the need for age-specific therapy in infections.
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  • Hosts utilize both aggressive and cooperative strategies to defend against infections, with Leptin playing a key role in resistance mechanisms but its impact on cooperation with pathogens not fully understood.
  • In a study on mice infected with Yersinia pseudotuberculosis, a lack of Leptin signaling resulted in increased cooperation between the host and pathogen, leading to protection against infection, though it wasn't due to resistance or changes in energy metabolism.
  • The findings suggest that in certain situations, it may be more advantageous for hosts to tolerate organ damage caused by infection rather than solely focusing on preventing damage or killing the pathogen.
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  • The link between infectious diseases and allergies is still not well understood.
  • Agaronyan et al. (2022) research reveals that the bacteria Pseudomonas aeruginosa can alter the immune system, leading to an increase in type 2 immune responses.
  • This immune shift may change how the body reacts to harmless substances, triggering allergic reactions.
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Metabolism of tryptophan by the gut microbiota into derivatives that activate the aryl hydrocarbon receptor (AhR) contributes to intestinal homeostasis. Many chronic inflammatory conditions, including celiac disease involving a loss of tolerance to dietary gluten, are influenced by cues from the gut microbiota. We investigated whether AhR ligand production by the gut microbiota could influence gluten immunopathology in nonobese diabetic (NOD) mice expressing DQ8, a celiac disease susceptibility gene.

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  • Metabolism drives interactions between microorganisms and their multicellular hosts, influencing energy needs and biosynthetic processes.
  • Recent research highlights how metabolites from microbiota play key regulatory roles in host functions like immunity, inflammation, and infection defense.
  • Understanding this metabolic communication could lead to new treatments for diseases caused by microbes, enhancing our grasp of both beneficial and harmful microbial interactions.
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  • Disease tolerance helps maintain host health during infections without necessarily eliminating the pathogen.
  • A study by Luan et al. (2019) highlights GDF15 as a key regulator for disease tolerance against bacterial and viral infections.
  • GDF15 works by facilitating communication between different organs through the sympathetic and metabolic systems, ultimately protecting the heart from damage.
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Microbe-host interactions are generally homeostatic, but when dysfunctional, they can incite food sensitivities and chronic diseases. Celiac disease (CeD) is a food sensitivity characterized by a breakdown of oral tolerance to gluten proteins in genetically predisposed individuals, although the underlying mechanisms are incompletely understood. Here we show that duodenal biopsies from patients with active CeD have increased proteolytic activity against gluten substrates that correlates with increased Proteobacteria abundance, including Pseudomonas.

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Background & Aims: Wheat-related disorders, a spectrum of conditions induced by the ingestion of gluten-containing cereals, have been increasing in prevalence. Patients with celiac disease have gluten-specific immune responses, but the contribution of non-gluten proteins to symptoms in patients with celiac disease or other wheat-related disorders is controversial.

Methods: C57BL/6 (control), Myd88, Ticam1, and Il15 mice were placed on diets that lacked wheat or gluten, with or without wheat amylase trypsin inhibitors (ATIs), for 1 week.

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  • The study reveals that monomethyl branched-chain fatty acids (mmBCFAs) are produced not just from diet, but are also synthesized from branched-chain amino acids (BCAAs) in mitochondria, primarily in brown fat tissue.* ! -
  • It shows that the enzyme carnitine acetyltransferase (CrAT) is crucial for exporting mmBCFAs to the cytosol for further elongation by fatty acid synthase (FASN), which typically makes straight-chain fatty acids.* ! -
  • The synthesis of mmBCFAs is affected by conditions like hypoxia, particularly in obese adipose tissue, leading to lower levels of these fatty acids in obese animals, indicating a connection
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Background: Changes in hygiene and dietary habits, including increased consumption of foods high in fat, simple sugars, and salt that are known to impact the composition and function of the intestinal microbiota, may explain the increase in prevalence of chronic inflammatory diseases. High salt consumption has been shown to worsen autoimmune encephalomyelitis and colitis in mouse models through p38/MAPK signaling pathway. However, the effect of high salt diet (HSD) on gut microbiota and on intestinal immune homeostasis, and their roles in determining vulnerability to intestinal inflammatory stimuli are unknown.

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Celiac disease is triggered by partially digested gluten proteins. Enzyme therapies that complete protein digestion in vivo could support a gluten-free diet, but the barrier to completeness is high. Current options require enzyme amounts on the same order as the protein meal itself.

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Background & Aims: Partially degraded gluten peptides from cereals trigger celiac disease (CD), an autoimmune enteropathy occurring in genetically susceptible persons. Susceptibility genes are necessary but not sufficient to induce CD, and additional environmental factors related to unfavorable alterations in the microbiota have been proposed. We investigated gluten metabolism by opportunistic pathogens and commensal duodenal bacteria and characterized the capacity of the produced peptides to activate gluten-specific T-cells from CD patients.

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The gut microbiota contributes to the maintenance of health and, when disrupted, may drive gastrointestinal and extragastrointestinal disease. This can occur through direct pathways such as interaction with the epithelial barrier and mucosal immune system or indirectly via production of metabolites. There is no current curative therapy for chronic inflammatory conditions such as inflammatory bowel disease, which are complex multifactorial disorders involving genetic predisposition, and environmental triggers.

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Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. Innate immunity contributes to the pathogenesis of CD, but the mechanisms remain poorly understood. Although previous in vitro work suggests that gliadin peptide p31-43 acts as an innate immune trigger, the underlying pathways are unclear and have not been explored in vivo.

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Polymorphisms in the PTPN11 gene encoding for the tyrosine phosphatase SHP-2 were described in patients with ulcerative colitis. We have recently demonstrated that mice with an intestinal epithelial cell-specific deletion of SHP-2 (SHP-2(IEC-KO) ) develop severe colitis 1 month after birth. However, the mechanisms by which SHP-2 deletion induces colonic inflammation remain to be elucidated.

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Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. The recent increase in CD incidence suggests that additional environmental factors, such as intestinal microbiota alterations, are involved in its pathogenesis. However, there is no direct evidence of modulation of gluten-induced immunopathology by the microbiota.

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  • Celiac disease is an autoimmune condition caused by gluten intake, leading to immune reactions against gluten and transglutaminase 2.
  • The only established treatment today is a strict gluten-free diet, though several new therapies are being researched, including vaccines and drugs aimed at mitigating symptoms while eating gluten.
  • Current research focuses on improving gut barrier function, altering immune responses, and interacting with environmental factors like the gut microbiome to manage the disease more effectively.
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Celiac disease (CD) is an autoimmune disorder in individuals that carry DQ2 or DQ8 MHC class II haplotypes, triggered by the ingestion of gluten. There is no current treatment other than a gluten-free diet (GFD). We have previously shown that the BL-7010 copolymer poly(hydroxyethyl methacrylate-co-styrene sulfonate) (P(HEMA-co-SS)) binds with higher efficiency to gliadin than to other proteins present in the small intestine, ameliorating gliadin-induced pathology in the HLA-HCD4/DQ8 model of gluten sensitivity.

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  • The study investigated the impact of long-duration spaceflight on immune functions in two types of mice: wild type (Wt) and transgenic mice over-expressing pleiotrophin (PTN-Tg).
  • Conducted aboard the International Space Station using the Mouse Drawer System (MDS), the research measured immune markers such as interleukin-2 (IL-2) and transforming growth factor-beta1 (TGF-β1) in various tissues after 91 days in space.
  • Results indicated significant differences in immune responses between spaceflight mice and ground controls, including reduced levels of TGF-β1 and IL-2 in both mouse types, suggesting unique immune challenges associated with space travel.
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