Pilot Studies Program

Use of ancient medicinal plant rosemary to combat psychostimulant addiction

Substance abuse is a critical problem that shows no signs of abating. While opioid drugs, principally synthetic opioids have received the bulk of national attention, overdose deaths from psychostimulants such as cocaine and methamphetamine have also spiked in recent years. Unfortunately, there are no effective treatments for psychostimulant addiction or psychostimulant overdoses. With little investment from Big Pharma in treatments for substance-use disorders, alternative approaches are needed. Botanical medicines offer an ideal alternative, as they are widely available, inexpensive, and have a variety of beneficial health effects. Furthermore, while botanical medicines are used by over 80% of the world as a critical source of medicine, the mechanisms by which these medicines act are largely unknown, meaning that they have substantial untapped potential. Our collaborator recently identified several compounds from rosemary extract that can act on voltage-sensitive potassium channels (KCNQ) that in turn have beneficial health effects, e.g., through relaxing blood vessels. One of these is carnosic acid, which shows selective activation of KCNQ3/5 channels. Importantly, this is the first small molecule identified to have this selectivity. Crucially, my lab recently discovered that only a specific pathway in the brain, one that regulates cocaine addiction, expresses KCNQ3/5 channels, and furthermore, that carnosic acid administration prevents addiction-related behaviors. In this project, we will test whether other components of rosemary extract, as well as the whole extract itself, have similar anti-addiction effects. We will also perform mechanistic studies to test whether carnosic acid does in fact mediate its anti-addiction effects through KCNQ3/5 channels expressed in the brain cells of interest. These studies will unambiguously define the mechanism of action by which carnosic acid exerts its anti-addiction effects and identify the potential for botanical medicines to treat psychostimulant abuse.

Investigating the role of Bifidobacterium diversity on fiber degradation for development of multi-strain probiotics

High-fiber diets, such as those rich in fruits, vegetables, and whole grains are associated with lower risks of cardiovascular disease, cancer, diabetes, and overall mortality. Fermentation of fiber by gut microorganisms produces short-chain fatty acids (SCFAs), chemicals that have anti-inflammatory and anticarcinogenic effects and in general help to maintain gut barrier health. In addition to recommending a fiber-rich diet, health outcomes might be further improved by the introduction of microorganisms (probiotics) and/or the consumption of particular fibers (prebiotics). Indeed, the gut microbiomes of healthy adults in industrialized countries seem to be relatively limited by their genomic potential, suggesting that the deliberate introduction of fiber-consuming microbes could improve the fermentative capacity of an individual’s gut. Tapping into this potential, however, requires an understanding of how particular bacteria, combined with the chemistry of various fiber types, leads to overall rates of fiber degradation and the resulting metabolic products. In this project, we focus on the diversity of one group of bacteria, Bifidobacterium, that excel at degrading and fermenting fiber. Healthy adults generally carry

multiple species (and strains within species) of Bifidobacterium at any one time, and these strains are known to specialize on different fiber types. This evidence suggests that fiber degradation (and potentially, its impacts on the gut) will be influenced by Bifidobacterium diversity. Despite this, commercially available probiotics tend to include only one strain at a time. To test the effects of Bifidobacterium diversity on fiber degradation, we will apply a newly developed method that uses fiber-coated glass beads to quantify the degradation of one fiber at

a time within a resource rich medium like the human gut. Collectively, the research will lay the groundwork for developing multi-strain probiotics for use in combination with whole fiber interventions.

Priming breast cancer surgical patients for success with high fiber diets to promote microbiome and immune health

A high-fiber diet has been associated with a more diverse and beneficial gut microbiome, which may enhance the immune response and improve treatment outcomes in cancer patients. Fiber intake may be critical for protecting the microbiome community resilience during pharmaceutical interventions such as cancer or antibiotic therapy. However, a typical U.S. diet includes about ~15 grams of fiber per day, less than half the daily recommended allowance. This study aims to investigate whether increasing fiber intake in breast cancer patients through dietary counseling or provided meals is more feasible and whether establishing higher fiber consumption two weeks before the start of treatment primes the microbiome and immune system for a more robust response to therapy. The study will involve 30 breast cancer survivors from UCI, who will be randomly assigned to receive either provided meals or dietary counseling to increase their fiber intake to 20-40 grams per day. Fecal samples will be collected at baseline and following the intervention to determine changes in the microbiome associated with fiber intake and improved immune response. The study’s significance lies in the fact that a high-fiber diet is a simple, safe, and cost-effective way to enhance the immune response and improve treatment outcomes in cancer patients, and the study will provide important insights into the feasibility and efficacy of increasing fiber intake through provided meals or dietary counseling.