Whereas a significant role for intestinal microbiota in affecting the pathogenesis and progression of chronic hepatic diseases is well documented, the contribution of the intestinal flora to acute liver injury has not been extensively addressed. Elucidating the influence of the intestinal microbiota on acute liver inflammation would be important for better understanding the transition from acute injury to chronic liver disease. Using the Concanavalin A (ConA)-induced liver injury model in laboratory mice, we show that the severity of acute hepatic damage varies greatly among genetically identical mice raised in different environments and harboring distinct microbiota. Through reconstitution of germ-free (GF) mice, and the co-housing of conventional mice, we provide direct evidence that manipulation of the intestinal flora alters susceptibility to ConA-induced liver injury. Through deep sequencing of the fecal microbiome, we observe that the relative abundance of Ruminococcaceae, a Gram(+) family within the class Clostridia, but distinct from segmented filamentous bacteria, is positively associated with the degree of liver damage. Searching for the underlying mechanism(s) that regulate susceptibility to ConA, we provide evidence that the extent of liver injury following triggering of the death receptor Fas varies greatly as a function of the microbiota. We demonstrate that the extent of Fas induced liver injury increases in GF mice after microbiota reconstitution, and decreases in conventionally raised mice following reduction of intestinal bacterial load, by antibiotic treatment. We also show that the regulation of sensitivity to Fas induced liver injury is dependent upon the Toll-Like Receptor signaling molecule MyD88.ConclusionThe status and composition of the intestinal microbiota determine the susceptibility to ConA-induced acute liver injury. The microbiota acts as a rheostat, actively modulating the extent of liver damage in response to Fas triggering.

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Human Immunodeficiency Virus-type 1 (HIV-1) binds to CD4 and CCR5 receptors on target cells in the human female reproductive tract. We sought to determine whether reducing levels of messenger RNA (mRNA) transcripts that encode these receptors in female reproductive tract cells could protect mucosal tissue explants from HIV-1 infection. Explants prepared from the endometrium, endocervix, and ectocervix of hysterectomy tissues from HIV-1 sero-negative women were exposed to nanoparticles containing CD4- and CCR5-specific short-interfering RNA (siRNA) sequences. Explants were then exposed two days later to HIV-1, and HIV-1 reverse transcripts were measured five days post-infection. Explants treated with nanoparticles containing CD4- and CCR5-specific siRNA showed reduced levels of CD4 and CCR5 transcripts, and significantly lower levels of HIV-1 reverse transcripts compared to those treated with an irrelevant siRNA. In female reproductive tract explants and in peripheral blood cell cultures, siRNA transfection induced the secretion of IFN-alpha (IFN-α), a potent antiviral cytokine. In female mice, murine-specific Cd4-siRNA nanoparticles instilled within the uterus significantly reduced murine Cd4 transcripts by day 3. Our findings demonstrate that siRNA nanoparticles reduce expression of HIV-1 infectivity receptors in human female reproductive tract tissues and also inhibit HIV-1 infection. Murine studies demonstrate that nanoparticles can penetrate the reproductive tract tissues in vivo and silence gene expression. The induction of IFN-α after siRNA transfection can potentially contribute to the antiviral effect. These findings support the therapeutic development of nanoparticles to deliver siRNA molecules to silence host cell receptors in the female reproductive tract as a novel microbicide to inhibit mucosal HIV-1 transmission.

The risk of developing gallstones can increase during pregnancy.The main purpose of the gallbladder is to store bile, which is released into the small intestine after meals to help with digestion. Bile is made up of cholesterol, bilirubin (a product of red blood cells), and bile salts. Gallstones are formed when these components are not well balanced.Women are at higher risk of gallstones, and that risk increases during pregnancy. Increased hormones during pregnancy can cause higher cholesterol levels and delayed gallbladder emptying, which can lead to formation of gallstones. Nearly 8% of pregnant women form new gallstones by the third trimester, but only about 1% have symptoms. Of those with symptoms, less than 10% develop complications.

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