Adjusting bacteria in intestines may lead to obesity treatments

Sep. 24, 2013 — A drug that appears to target specific intestinal bacteria in the guts of mice may create a chain reaction that could eventually lead to new treatments for obesity and diabetes in humans, according to a team of researchers.

Mice fed a high-fat diet and provided tempol, an anti-oxidant drug that may help protect people from the effects of radiation, were significantly less obese than those that did not receive the drug, according to Andrew Patterson, assistant professor of molecular toxicology, Penn State, who worked with Frank J. Gonzalez, laboratory metabolism chief, and James B. Mitchell, radiation biology branch chief, both of the National Cancer Institute.

"The two interesting findings are that the mice that received tempol didn't gain as much weight and the tempol somehow impacted the gut microbiome of these mice," said Patterson. "Eventually, we hope that this can lead to a new line of therapeutics to treat obesity and diabetes."

The microbiome is the biological environment of microorganisms within the human body.

The researchers, who reported their findings in the current issue of Nature Communications, said that tempol reduces some members of a bacteria -- a genus of Lactobacillus -- in the guts of mice. When the Lactobacillus levels decreases, a bile acid -- tauro-beta-muricholic acid -- increases. This inhibits FXR -- farnesoid X receptor, which regulates the metabolism of bile acids, fats and glucose in the body, according to the researchers.

"The study suggests that inhibiting FXR in the intestine might be a potential target for anti-obesity drugs," said Gonzalez.

The researchers said that tempol may help treat type 2 diabetes symptoms. In addition to lower weight gain, the tempol-treated mice on a high-fat diet had lower blood glucose and insulin levels.

"Previously, Dr. Mitchell observed a significant difference in weight gain in mice on tempol-containing diet," said Patterson. "He approached us to help figure out what was going on, and it had been an interesting journey wading through the complexities of the microbiome."

Other studies hinted at the relationship between tempol, the gut microbiome and obesity, but did not focus on why the drug seemed to control weigh gain, according to Patterson.

The researchers said these studies are demonstrating how integrated the 100 trillion microbes that make up the human microbiome are with metabolism and health and how the microbiome may provide more pathways to treating other disorders.

"There is a tremendous interest in how the microbiome can be manipulated in a therapeutic way," said Patterson. "And we need to look at these microbiome management techniques in a good, unbiased way."

In the study, the researchers dissolved the tempol in drinking water, or delivered it directly to the mice. Within three weeks, tempol reduced the weight gain for the mice in that group. The mice showed significant reduction in weight gain even after 16 weeks.

To further test the role of FXR in obesity, the researchers placed mice that were genetically modified so that they lack FXR on the same high-fat diet. This group was resistant to the effects of tempol and taura-beta-muricholic acid, which further strengthened the importance of FXR in mediating the anti-obesity effect.

Gonzalez said that there are indications that FXR plays a similar role in human obesity and diabetes.

The researchers must now test the treatments to ensure it is effective in humans, as well as check for any potential side effects, including cancer.

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Bacteria responsible for gum disease facilitates rheumatoid arthritis

Sep. 12, 2013 — Does gum disease indicate future joint problems? Although researchers and clinicians have long known about an association between two prevalent chronic inflammatory diseases -- periodontal disease and rheumatoid arthritis (RA) -- the microbiological mechanisms have remained unclear.

In an article published today in PLoS Pathogens, University of Louisville School of Dentistry Oral Health and Systemic Diseases group researcher Jan Potempa, PhD, DSc, and an international team of scientists from the European Union's Gums and Joints project have uncovered how the bacterium responsible for periodontal disease, Porphyromonas gingivalisworsens RA by leading to earlier onset, faster progression and greater severity of the disease, including increased bone and cartilage destruction.

The scientists found that P. gingivalis produces a unique enzyme, peptidylarginine deiminanse (PAD) which then enhances collagen-induced arthritis (CIA), a form of arthritis similar to RA produced in the lab. PAD changes residues of certain proteins into citrulline, and the body recognizes citullinated proteins as intruders, leading to an immune attack. In RA patients, the subsequent result is chronic inflammation responsible for bone and cartilage destruction within the joints.

Potempa and his team studied another oral bacterium, Prevotella intermedia for the same affect, but learned it did not produce PAD, and did not affect CIA.

"Taken together, our results suggest that bacterial PAD may constitute the mechanistic link between P. gingivalis periodontal infection and rheumatoid arthritis, but this ground-breaking conclusion will need to be verified with further research," he said.

Potempa said he is hopeful these findings will shed new light on the treatment and prevention of RA.

Studies indicate that compared to the general population, people with periodontal disease have an increased prevalence of RA and, periodontal disease is at least two times more prevalent in RA patients. Other research has shown that a P. gingivalis infection in the mouth will precede RA, and the bacterium is the likely culprit for onset and continuation of the autoimmune inflammatory responses that occur in the disease.

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