Targeting the Gut Microbiome To Understand Age-Related Cognitive Decline

The gut–brain axis acts as a pathway through which the gut microbiota can alter brain systems, and vice versa. Multiple pathways are involved in the gut–brain axis and the axis has been implicated as a causative factor in both gastrointestinal and neurological disorders. Ultimate Medicine, a drug discovery company specializing in in vivo multiomics, has been researching the role of a microbiota-related metabolite, delta-valerobetaine, in neurocognitive ability.

We spoke to Dr. Antal Szalay, CEO of Ultimate Medicine, to learn more about the gut‒brain axis in neurological disease and how Ultimate Medicine is working to design therapeutics to combat age-related cognitive decline.

Katie Brighton (KB): There is mounting data highlighting the role of the gut microbiome in health and disease, could you elaborate on what is meant by the gut‒brain axis and touch on some of the related diseases?

Antal Szalay (AS): You are correct, we are now seeing concrete data to support a link between the gut and brain. As with everyone, I’m sure you have felt an uneasy sensation in your stomach or had a bad feeling in your gut. These feelings coming from your gut is the link to your brain.

Furthermore, new research suggests that your brain has an impact on your gut health, and that your gut health may have an impact on your brain health. The gut–brain axis is a communication pathway that connects your stomach to your brain. The central nervous system (CNS) connects with the gut via sympathetic and parasympathetic nerves. This mode of communication is thought to occur through peptides, such as neuropeptide Y, cholecystokinin, ghrelin, leptin as well as by neurotransmitters like dopamine, serotonin, GABA, acetylcholine and glutamate.

Gut disorders in early life have also been linked to the development of autism spectrum disorder (ASD) in humans. When compared to healthy controls, ASD children exhibit a higher abundance of proteobacteria and Bacteroidetes, and a lower abundance of Firmicutes and Bifidobacteria. Researchers are becoming increasingly interested in learning more about the gut microbiota's function in Parkinson's disease (PD).

In one study, the fecal microbiota of PD patients and age-matched controls revealed that PD patients had greater counts of Enterobacteriaceae and lower counts of Prevotellaceae. Prevotella is recognized for breaking down complex carbohydrates and releasing short-chain fatty acids (SCFAs), thiamine and folate as by-products, all of which help to maintain a healthy gut environment.

We also know that aging changes the gut microbial community, which can cause gastrointestinal problems as well as CNS illnesses, including dementia. Alzheimer's disease (AD) is the most prevalent kind of dementia that affects the elderly. It is marked by beta-amyloid plaques and neurofibrillary tangles, which cause cognitive deficits and memory loss. The function of the gut microbiota in host cognition has been determined in several experimental and clinical research studies and showed that dysbiosis linked with aging leads to neurodegeneration.

KB: Can you highlight for us the importance of multiomics approaches within drug discovery? Are there any challenges associated with these approaches?

AS: The finding of a disease-modifying target is the first step in the drug development process. This crucial stage usually starts with a manual search of scientific literature and biomedical databases to acquire information tying a molecular target to a disease and to assess the target's effectiveness, safety and economic viability. The high-throughput and cheap cost of today's omics technologies, which allow quantitative measurements of a wide range of potential targets (e.g., DNA, RNA, protein and metabolite) has dramatically expanded the amount of scientific data accessible for this difficult endeavor. The challenge is to prioritize disease-relevant targets from current biological data sources, such as omics databases.

KB: Can you tell us more about the experimentation that identified delta-valerobetaine as a metabolite that causes age-related memory loss and explain its role in the gut–brain axis?

AS: Experiments that lead to causative results are systemically extremely complex. We were one of the first to employ a series of fecal transplantation experiments in mice in combination with learning and memory behavioral testing, which formed the basis to identify delta-valerobetaine as an interesting factor in age-related memory decline. This metabolite is microbiome-derived, enters the bloodstream and modulates neuronal network activity in the brain. This is fascinating, because it is a start to understand an influencing factor better that connects the gut and the brain. Like the Nobel laureate Ilya Mechnikov proposed already more than 100 years ago, molecules from the gut-microbiome can influence brain activity.

KB: You’re currently leveraging delta-valerobetaine therapeutically in the company’s UM001 program, could you expand more on what this entails? What are the next steps following the program’s completion?

AS: With our lead program, we are building on our deep understanding of delta-valerobetaine and are now progressing further in the preclinical phase. We see the advancement of this program as almost a proof of concept for our overall approach that will enable us to leverage our discovery platform and generate subsequent candidate programs.

Dr. Antal Szalay was speaking to Katie Brighton, Scientific Copywriter for Technology Networks.