Ulcerative colitis (UC) is driven by disruptions in host-microbiota homeostasis, however current treatments exclusively target host inflammatory pathways. To understand how host-microbiota interactions become disrupted in UC, we collected and analyzed six fecal or serum based –omic datasets (metaproteomic, metabolomic, metagenomic, metapeptidomic, and amplicon sequencing profiles of fecal samples and proteomic profiles of serum samples) from 40 UC patients at a single inflammatory bowel disease centre, as well as various clinical, endoscopic, and histologic measures of disease activity. A validation cohort of 210 samples (73 UC, 117 Crohn’s disease (CD), 20 healthy controls) was collected and analyzed separately and independently. Data integration across both cohorts showed that a subset of the clinically active UC patients had an over-abundance of proteases that originated from the bacterium, Bacteroides vulgatus . To test whether B. vulgatus proteases contribute to UC disease activity, we first profiled B. vulgatus proteases found in patients and bacterial cultures. Use of a broad-spectrum protease inhibitor improved B. vulgatus -induced barrier dysfunction in vitro , and prevented colitis in B. vulgatus monocolonized, IL-10 deficient mice. Furthermore, transplantation of feces from UC patients with a high abundance of B. vulgatus proteases into germ-free mice induced colitis dependent on protease activity. These results, stemming from a multi-omics approach, improve understanding of functional microbiota alterations that drive UC and provides a resource for identifying other pathways that could be inhibited as a strategy to treat this disease.

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Accumulating evidence indicates that obesity with its associated metabolic dysregulation, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Caloric restriction can ameliorate the harmful metabolic effects of obesity and inhibit cancer progression but is difficult to implement and maintain outside of the clinic. In this study, we aim to test a time-restricted feeding (TRF) approach on mouse models of obesity-driven postmenopausal breast cancer. We show that TRF abrogates the obesity-enhanced mammary tumor growth in two orthotopic models in the absence of calorie restriction or weight loss. TRF also reduces breast cancer metastasis to the lung. Furthermore, TRF delays tumor initiation in a transgenic model of mammary tumorigenesis prior to the onset of obesity. Notably, TRF increases whole-body insulin sensitivity, reduces hyperinsulinemia, restores diurnal gene expression rhythms in the tumor, and attenuates tumor growth and insulin signaling. Importantly, inhibition of insulin secretion with diazoxide mimics TRF whereas artificial elevation of insulin through insulin pumps implantation reverses the effect of TRF, suggesting that TRF acts through modulating hyperinsulinemia. Our data suggest that TRF is likely to be effective in breast cancer prevention and therapy.

Mounting evidence suggests a role for mitochondrial dysfunction in the pathogenesis of many diseases including type 2 diabetes, aging and ovarian failure. Because of the central role of mitochondria in energy production, heme biosynthesis, calcium buffering, steroidogenesis, and apoptosis signaling within cells, understanding the molecular mechanisms behind mitochondrial dysregulation and its potential implications in disease is critical. This review will take a journey through the past and summarize what is known about mitochondrial dysfunction in various disorders focusing on metabolic alterations and reproductive abnormalities. Evidence is presented from studies in different human populations, and rodents with genetic manipulations of pathways known to affect mitochondrial function.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Serine-arginine rich splicing factor 3 (SRSF3) plays a critical role in hepatocyte function and its loss in mice promotes chronic liver damage and leads to HCC. Hepatocyte-specific SRSF3 knockout mice (SKO mice) also overexpress insulin-like growth factor 2 (IGF2). In the present study, double deletion of Igf2 and Srsf3 (DKO mice) prevents hepatic fibrosis and inflammation, and completely prevents tumor formation, and is associated with decreased proliferation, apoptosis and DNA damage, and restored DNA repair enzyme expression. This is confirmed in vitro, where IGF2 treatment of HepG2 hepatoma cells decreases DNA repair enzyme expression and causes DNA damage. Tumors from the SKO mice also show mutational signatures consistent with homologous recombination and mismatch repair defects. Analysis of frozen human samples shows that SRSF3 protein is decreased sixfold in HCC compared to normal liver tissue but SRSF3 mRNA is increased. Looking at public TCGA data, HCC patients having high SRSF3 mRNA expression show poor survival, as do patients with alterations in known SRSF3-dependent splicing events. The results indicate that IGF2 overexpression in conjunction with reduced SRSF3 splicing activity could be a major cause of DNA damage and driver of liver cancer.

Mice lacking peroxisome-proliferator activated receptor-γ (PPARγ) in neurons do not become leptin resistant when placed on a high-fat diet (HFD). In male mice, this results in decreased food intake and increased energy expenditure, causing reduced body weight, but this difference in body weight is not observed in female mice. In addition, estrous cycles are disturbed and the ovaries present with hemorrhagic follicles. We observed that PPARγ was more highly expressed in astrocytes than neurons, so we created an inducible, conditional knockout of PPARγ in astrocytes (AKO). The AKO mice had impaired glucose tolerance and hepatic steatosis that did not worsen with HFD. Expression of gluconeogenic genes was elevated in the mouse livers, as was expression of several genes involved in lipogenesis, lipid transport, and storage. The AKO mice also had a reproductive phenotype with fewer estrous cycles, elevated plasma testosterone levels, reduced corpora lutea formation, and alterations in hypothalamic and ovarian gene expression. Thus, the phenotypes of the AKO mice were very different from those seen in the neuronal knockout mice, suggesting distinct roles for PPARγ in these two cell types.

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Group B Streptococcus (GBS, S. agalactiae) is a human commensal and occasional pathogen that remains a leading cause of neonatal sepsis and meningitis with increasing disease burden in adult populations. Although programs for universal screening in pregnancy to guide intrapartum prophylaxis have reduced GBS invasive disease burden resulting from mother-to-newborn transfer during birth, better knowledge of disease mechanisms may elucidate new strategies to reduce antibiotic exposure. In our efforts to expand the knowledge base required for targeted anti-virulence therapies, we identified a GBS homolog for a recently identified virulence determinant of group A Streptococcus, S protein, and evaluated its role in GBS pathogenesis. A GBS S protein deletion mutant, Δess, showed altered cell-surface properties compared to the WT parent strain, including defective retention of its surface polysaccharide. Quantitative proteome analysis of enzymatically shaved surface epitopes of the GBS Δess mutant revealed a dysregulated cell surface virulome, with reduced abundance of several protein and glycoprotein components. The Δess mutant showed markedly attenuated virulence in a murine model of GBS systemic infection, with increased proteasome activity detected in the spleens of animals infected with the Δess mutant. These results expand the key roles S protein plays in streptococcal pathogenesis and introduces a new GBS virulence determinant and potential target for therapy development.