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Bacteriophage therapy may ease severity of alcoholic hepatitis | National Institutes of Health (NIH)

Bacteriophage therapy may ease severity of alcoholic hepatitis | National Institutes of Health (NIH)

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Bacteriophage therapy may ease severity of alcoholic hepatitis

NIH-funded study in mice merits further investigation as a potential treatment.
A specific strain of a common bacteria found in most people with alcoholic hepatitis correlates with greater liver disease severity and mortality, according to a new study published in Nature. Alcoholic hepatitis is a serious form of alcohol-associated liver disease, and people with it have high levels of the bacterium Enterococcus faecalis (E. faecalis) in their gut.  The study also found that a novel therapeutic approach that specifically targets the E. faecalis strain lessened alcohol-associated liver disease in mice. The research team was funded in part by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), of the National Institutes of Health.
“This is a hopeful advance against a potentially life-threatening disease for which few effective treatments are available,” said NIAAA Director Dr. George F. Koob. “Alcoholic hepatitis has a mortality rate of more than 50% within the first 60 days of diagnosis in severe cases and is a particularly important area of focus for NIAAA. The current findings warrant further investigation as a potential novel treatment for people with alcoholic hepatitis.”
A multitude of bacteria populate the human digestive tract, and this gut microbiota plays important roles in maintaining health. With chronic alcohol misuse, the levels and types of bacteria in the gut microbiota change which contributes along with other factors to alcohol-associated liver diseases such as alcoholic hepatitis.
In analyses of gut microbes from alcohol use disorder (AUD) patients with alcoholic hepatitis, a team of scientists led by Bernd Schnabl, M.D., of the University of California, San Diego, found that fecal samples from patients with alcoholic hepatitis had about 2,700-fold more E. faecalis than samples from non-AUD controls. Further studies of E. faecalis, showed that cytolysin, a toxin secreted by specific E. faecalis strains, killed liver cells and caused liver damage in a mouse model of alcohol-associated liver disease.
“We detected cytolysin-positive E. faecalis (cytolytic E. faecalis) in fecal samples from 30% of patients with alcoholic hepatitis, and in none of the fecal samples from non-AUD controls,” said Dr. Schnabl.  “Importantly, 89% of cytolysin-positive patients with alcoholic hepatitis died within 180 days after admission compared to only about 4% of cytolysin-negative patients.”
In another series of experiments, the researchers studied mice that had been transplanted with feces from the intestines of people with alcoholic hepatitis and that contained cytolytic E. faecalis. They confirmed that transplantation of the bacteria caused severe liver disease in mice. Dr. Schnabl and his colleagues then investigated the therapeutic potential of bacteria-killing viruses known as bacteriophages that specifically target cytolytic E. faecalis.
Using a mouse model of alcohol-associated liver disease, mice were transplanted with stool from cytolysin-positive alcoholic hepatitis patients and treated with a cocktail of bacteriophages targeting the cytolytic E. faecalis strains. The researchers found that mice treated with bacteriophages that target cytolytic E. faecalis had less liver injury and inflammation compared to controls. Administration of E. faecalis-targeting bacteriophage also significantly reduced levels of cytolysin in the liver.
“Taken together, our findings link cytolytic E. faecalis with worse clinical outcomes and mortality in humans with alcoholic hepatitis, and that bacteriophages can specifically target cytolytic E. faecalis in a mouse model of alcohol-induced liver disease,” said Dr. Schnabl.  “A prospective clinical trial is required to validate the human relevance of our findings and to test whether this new therapeutic approach is effective for patients with alcoholic hepatitis.”
About the National Institute on Alcohol Abuse and Alcoholism (NIAAA): The National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, diagnosis, prevention, and treatment of alcohol use disorder. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at www.niaaa.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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Reference

Yi Duan, C Llorente, S Lang, K Brandl, H Chu, L Jiang, RC White, TH Clarke, K Nguyen, M Torralba, Y Shao, J Liu, A Hernandez-Morales, L Lessor, IR Rahman, Y Miyamoto, M Ly, B Gao, W Sun, R Kiesel, F Hutmacher, S Lee, M Ventura-Cots, F Bosques-Padilla, EC Verna, JG Abraldes, RS Brown Jr, V Vargas, J Altamirano, J Caballería, DL Shawcross, SB Ho, A Louvet, MR Lucey, P Mathurin, G Garcia-Tsao, R Bataller, XM Tu, L Eckmann, WA van der Donk, R Young, TD Lawley, P Stärkel, D Pride, DE Fouts and B Schnabl. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature. Published online November 13, 2019. 

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Divergent Antigen-specific Cellular Immune Responses During Asymptomatic Subclinical and Clinical States of Disease in Cows Naturally Infected with... - PubMed - NCBI

Divergent Antigen-specific Cellular Immune Responses During Asymptomatic Subclinical and Clinical States of Disease in Cows Naturally Infected with... - PubMed - NCBI



 2019 Oct 14. pii: IAI.00650-19. doi: 10.1128/IAI.00650-19. [Epub ahead of print]

Divergent Antigen-specific Cellular Immune Responses During Asymptomatic Subclinical and Clinical States of Disease in Cows Naturally Infected with Mycobacterium avium subspparatuberculosis.

Author information


1
USDA-ARS, National Animal Disease Center, Ames, IA 50010 judy.stabel@ars.usda.gov.
2
USDA-ARS, National Animal Disease Center, Ames, IA 50010.

Abstract

Infection of the host with Mycobacterium avium subspparatuberculosis (MAP) results in a chronic and progressive enteritis that traverses both subclinical and clinical stages. The mechanism(s) for the shift from asymptomatic subclinical disease state to advanced clinical disease are not fully understood. In the present study, naturally infected dairy cattle were defined as subclinical and clinical infection groups, along with noninfected control cows of similar parity to study host immune responses in different stages of infection. Both infection groups had higher secretion of IFN-γ, TNF-α, and IL-2 than control cows, whereas only clinical cows had increased secretion of IL-10, IL-12 and IL-18 upon stimulation of PBMCs with antigen. Conversely, secretion of IL-17A was decreased for clinical cows compared to subclinical and control cows. Pro-inflammatory cytokine genes were upregulated only for subclinical cows, whereas increased IL-10 and IL-17 gene expression were observed for both infection groups. Increased CD4+, CD8+ and γδ TCR+ T cells were observed for subclinical cows compared to clinical cows. Although clinical cows expressed antigen-specific immune responses, the profile for subclinical cows was one of a dominant pro-inflammatory response to infection. We reason that a complex coordination of immune responses occurs during MAP infection, with these responses shifting as the host transitions through the different stages of infection and disease (subclinical to clinical). Further understanding of the series of events characterized by Th1/Th2/Th17 responses will provide mechanisms for disease progression and may direct insightful intervention strategies.

PMID:
 
31611273
 
DOI:
 
10.1128/IAI.00650-19

Acute systemic inflammatory response to lipopolysaccharide stimulation in pigs divergently selected for residual feed intake. - PubMed - NCBI

Acute systemic inflammatory response to lipopolysaccharide stimulation in pigs divergently selected for residual feed intake. - PubMed - NCBI



 2019 Oct 11;20(1):728. doi: 10.1186/s12864-019-6127-x.

Acute systemic inflammatory response to lipopolysaccharide stimulation in pigs divergently selected for residual feed intake.

Author information


1
Department of Animal Science, Iowa State University, 2258 Kildee Hall, Ames, IA, 50011, USA.
2
Interdepartmental Immunobiology, Department of Animal Science, Iowa State University, 2258 Kildee Hall, Ames, IA, 50011, USA.
3
Department of Mathematics and Statistics, Old Dominion University, Norfolk, VA, 23529, USA.
4
Department of Animal and Food Sciences, Texas Tech University, Lubbock, TX, 79409, USA.
5
Food Safety and Enteric Pathogens Research Unit, National Animal Disease Center, ARS, USDA, 1920 Dayton Ave, Ames, IA, 50010, USA.
6
Department of Animal Science, Iowa State University, 239 Kildee Hall, Ames, IA, 50011, USA.
7
Department of Animal Science, Iowa State University, 2255 Kildee Hall, Ames, IA, 50011, USA. cktuggle@iastate.edu.

Abstract

BACKGROUND:

It is unclear whether improving feed efficiency by selection for low residual feed intake (RFI) compromises pigs' immunocompetence. Here, we aimed at investigating whether pig lines divergently selected for RFI had different inflammatory responses to lipopolysaccharide (LPS) exposure, regarding to clinical presentations and transcriptomic changes in peripheral blood cells.

RESULTS:

LPS injection induced acute systemic inflammation in both the low-RFI and high-RFI line (n = 8 per line). At 4 h post injection (hpi), the low-RFI line had a significantly lower (p = 0.0075) mean rectal temperature compared to the high-RFI line. However, no significant differences in complete blood count or levels of several plasma cytokines were detected between the two lines. Profiling blood transcriptomes at 0, 2, 6, and 24 hpi by RNA-sequencing revealed that LPS induced dramatic transcriptional changes, with 6296 genes differentially expressed at at least one time point post injection relative to baseline in at least one line (n = 4 per line) (|log2(fold change)| ≥ log2(1.2); q < 0.05). Furthermore, applying the same cutoffs, we detected 334 genes differentially expressed between the two lines at at least one time point, including 33 genes differentially expressed between the two lines at baseline. But no significant line-by-time interaction effects were detected. Genes involved in protein translation, defense response, immune response, and signaling were enriched in different co-expression clusters of genes responsive to LPS stimulation. The two lines were largely similar in their peripheral blood transcriptomic responses to LPS stimulation at the pathway level, although the low-RFI line had a slightly lower level of inflammatory response than the high-RFI line from 2 to 6 hpi and a slightly higher level of inflammatory response than the high-RFI line at 24 hpi.

CONCLUSIONS:

The pig lines divergently selected for RFI had a largely similar response to LPS stimulation. However, the low-RFI line had a relatively lower-level, but longer-lasting, inflammatory response compared to the high-RFI line. Our results suggest selection for feed efficient pigs does not significantly compromise a pig's acute systemic inflammatory response to LPS, although slight differences in intensity and duration may occur.

KEYWORDS:

Lipopolysaccharide; RNA-seq; Residual feed intake; Sus scrofa; Systemic inflammation

PMID:
 
31610780
 
PMCID:
 
PMC6792331
 
DOI:
 
10.1186/s12864-019-6127-x

NfL (Neurofilament Light Chain - PubMed - NCBI

NfL (Neurofilament Light Chain - PubMed - NCBI



Best matches for NfL (Neurofilament Light Chain:



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