ANTIOXIDANT (tempol) ALTERS GUT BACTERIA COMPOSITION RESULTING IN REDUCED OBESITY

The identification that the bacteria in our guts play critical roles in whole body metabolic and immune homeostasis has led to an explosion of scientific research in this field (intestinal microbiota) as well as to increased interest in developing food products that can deliver beneficial bacteria (probiotic) to the gut. I have written on this subject before in my blog as well as discussed some of the details of how bacteria play a role in the metabolic processes involved in the development of obesity and type 2 diabetes.

Obesity: Metabolic and Clinical Consequences

A recent paper, published in the journal Nature Communications, demonstrates another highly interesting angle to the roles gut microbiota play in the development of obesity and diabetes:

Microbiome remodelling leads to inhibition of intestinalfarnesoid X receptor signaling and decreased obesity

In this study the investigators expanded on an observation that the antioxidant and radiation protectant molecule, tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl), demonstrated an ability to prevent obesity in mice. Another related study demonstrated that tempol administration was associated with an altered metabolome (products of global metabolism) evidenced by alterations in gut-derived metabolic compounds. Related information has previously shown a correlation between the gut microbiome and their effects on metabolic pathways elsewhere in humans such as bile acid and fatty acid metabolism. The two predominant bacterial phyla in the human gut are Firmicutes and Bacteroidetes and the relative abundance of these two populations have been shown to be altered in obesity.

In the current study the investigators found that tempol administration, in mouse chow, preferentially reduced the levels of bacteria from the genus Lactobacillus (of the Firmicutes phylum). Associated with the reduction in Lactobacillus was a decrease in the level of the bile salt hydrolase (BSH) activity of this strain of bacteria. The reduced BSH activity was associated with an increase in the gut level of the bile acid metabolite tauro-beta-muricholic acid (T-b-MCA). T-b-MCA is a known antagonist of the nuclear receptor: farnesoid X receptor (FXR). FXR is a critical transcriptional co-regulator involved in the control of bile acid, lipid, and glucose homeostasis. For more detailed information on the activities of FXR go to the Farnesoid X Receptors page of my website.

The feeding of tempol to experimental obese mice in this study was correlated to reduced levels of obesity and reduced levels of insulin resistance even when the animal were fed a high-fat diet. The increased insulin sensitivity observed in this study is attributed to the tempol-induced reduction in obesity. Numerous studies in rodents and humans have correlated increased insulin sensitivity to reductions in fat content. Comparative analysis showed that intestine-specific FXR null mice exhibited a reduced level of diet-induced obesity even when fed a high-fat diet. Importantly, relative to the mode of action of tempol, is the fact that this study also showed that tempol administration to the intestine-specific FXR null mice did not further decrease weight gain. This demonstrates that the effects observed as a result of tempol ingestion are due to gut-specific responses to the drug not due to effects in other tissues as a result of the absorption of tempol from the gut.

The take home from this study is that compounds like tempol may find utility in the ongoing battle against obesity in humans. It should be pointed out that there is still much work to be done to be able to fully (or even partially) comprehend how we can manipulate the gut microbiome and what types of manipulations should be made. In this study there was a distinct benefit to reducing the level of the genus Lactobacillus in effecting a positive change in obesity. However, other studies have shown benefits to Lactobacillus. The ingestion of Lactobacillus by laboratory rodents has been associated with reduced anxiety and stress. In addition, most probiotics sold at health food stores are predominantly composed of strains of Lactobacillus.