Bacterial Infections, PPARγ Pathway and Pioglitazone

Research on Clostridium difficile infection yields promising new drug target

http://www.vtnews.vt.edu/articles/2012/11/113012-vbi-josepclostridium.html

BLACKSBURG, Va., Nov. 30, 2012 – Researchers in the Nutritional Immunology and Molecular Medicine Laboratory at Virginia Bioinformatics Institute have discovered how a common diarrhea-causing bacterium sends the body’s natural defenses into overdrive, actually intensifying illness while fighting infection.

The discovery, recently published in PLOS One, may lead to new drug treatments for Clostridium difficile, a common germ in health care-associated infections often referred to as C. diff. It has been linked to the death of 14,000 Americans annually, according to the Centers for Disease Control and Prevention.

Researchers with the Center for Modeling Immunity to Enteric Pathogens at Virginia Tech applied computational and mathematical modeling in combination with RNA-sequencing and mouse studies to understand an important regulatory pathway during Clostridium difficile infection.

“We have found that tissue damage and disease severity in C. difficile infection is associated with a disruption of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway,” said Josep Bassaganya-Riera, a professor of immunology, director of the Nutritional Immunology and Molecular Medicine Laboratory and the principal investigator with the Center for Modeling Immunity to Enteric Pathogens.

The human intestine must peacefully coexist with trillions of beneficial bacteria while swiftly responding to pathogens such as C. difficile. Sometimes the immune system will go into overdrive when responding to pathogens, causing more damage in an attempt to clear the infection.

Scientists studying mice bowels found the PPARγ pathway keeps the immune response in check, allowing the body to heal while the immune cells that fight infection do their work in a controlled manner. When PPARγ was absent or inactive, disease was more rampant and colonic lesions from C. difficile were much worse.

In addition, researchers found the protective mechanism can be activated and the severity of the C. difficile infection can be reduced by using an existing diabetes drug. More studies will be needed before the drug can be tested against  C. difficile.

“This research demonstrates that the integration of powerful computer simulations of host responses with immunology experimentation not only contributes to a better understanding of the immunoregulatory processes in the gut mucosa during C. difficile infection, but it also advances the discovery of broad-based therapeutic targets in the host for infectious diseases,” said Raquel Hontecillas, an assistant professor of immunology at Virginia Tech, co-director of the Nutritional Immunology and Molecular Medicine Laboratory and leader of the immunology component of the Center for Modeling Immunity to Enteric Pathogens.

This research builds on previous work from the Nutritional Immunology and Molecular Medicine Laboratory, which shows that PPARγ is critical to reducing disease caused by enteric pathogens and regulating autoimmune diseases such as inflammatory bowel disease.

“With continued research, new drugs targeting this pathway will be developed that will have fewer side effects and greater efficacy than those currently on the market,” Bassaganya-Riera said.

C. difficile has become a widespread problem in hospitals with patients who have received heavy doses of multiple antibiotics and it is spreading in the community. Symptoms include persistent diarrhea, fever, gut inflammation, and weight loss. Even though such potentially life-threatening intestinal infections occur among very young, elderly or immune-compromised individuals, C. difficile has increasingly been found in patients who traditionally would not be susceptible to this bacterium.

Current strains of C. difficile have become even more virulent and anti-microbial resistant in recent years which emphasizes the importance of developing broad-based, host-targeted approaches to control the disease as opposed to just relying on anti-microbial therapies that target the bacterium and can stimulate the spread of resistance.

The Center for Modeling Immunity to Enteric Pathogens is funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, under Contract No. HHSN272201000056C. PI: Josep Bassaganya-Riera.

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Further Reading – 2007 Research

Effect of pioglitazone treatment on behavioral symptoms in autistic children

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1781426/

Introduction

Autism is complex neuro-developmental disorder which has a symptomatic diagnosis in patients characterized by disorders in language/communication, behavior, and social interactions. The exact causes for autism are largely unknown, but it has been speculated that immune and inflammatory responses, particularly those of Th2 type, may be involved. Thiazolidinediones (TZDs) are agonists of the peroxisome proliferator activated receptor gamma (PPARγ), a nuclear hormone receptor which modulates insulin sensitivity, and have been shown to induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells.

The TZD pioglitazone (Actos) is an FDA-approved PPARγ agonist used to treat type 2 diabetes, with a good safety profile, currently being tested in clinical trials of other neurological diseases including AD and MS. We therefore tested the safety and therapeutic potential of oral pioglitazone in a small cohort of children with diagnosed autism.

Case description

The rationale and risks of taking pioglitazone were explained to the parents, consent was obtained, and treatment was initiated at either 30 or 60 mg per day p.o. A total of 25 children (average age 7.9 ± 0.7 year old) were enrolled. Safety was assessed by measurements of metabolic profiles and blood pressure; effects on behavioral symptoms were assessed by the Aberrant Behavior Checklist (ABC), which measures hyperactivity, inappropriate speech, irritability, lethargy, and stereotypy, done at baseline and after 3–4 months of treatment.

Discussion and evaluation

In a small cohort of autistic children, daily treatment with 30 or 60 mg p.o. pioglitazone for 3–4 months induced apparent clinical improvement without adverse events. There were no adverse effects noted and behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity). Improved behaviors were inversely correlated with patient age, indicating stronger effects on the younger patients.

Conclusion

Pioglitazone should be considered for further testing of therapeutic potential in autistic patients.

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