Investigators at the University of Freiburg and Swiss startup Ultimate Medicine have identified a compound produced by the gut microbiome as contributing to age-related cognitive decline by modulating inhibitory synaptic transmission and neural network activity.

Co-author Antal Szalay, who is the founder and CEO and of Ultimate Medicine, told BioWorld that the work has "generated insights and information in contrast to the existing paradigm in the field of cognitive decline... it will contribute to further research in the area, but also provides ample target options for further research, [and] to identify cognitive decline earlier."

Szalay, corresponding author Thomas Blank of the University of Freiburg, and their colleagues reported that they were able to recreate cognitive decline by the application of the serum metabolite delta-valerobetaine, a carnitine metabolite produced by the gut microbiota.

The gut microbiome affects the brain in multiple ways, and in their work, the team first tested whether a fetal microbiome transfer from young into aged mice could affect the cognitive decline that accompanies normal aging, even in the absence of dementia.

They showed that a fecal transplant from young mice, but not from aged mice, could reverse learning deficits in aged mice. To identify the specific metabolites that might be driving the change, they then investigated the metabolome of both the brain and the serum, and identified delta-valerobetaine as a metabolite found in both places that potentially mediated the effects of the microbiome transplant.

They next showed that systemic administration of delta-valerobetaine increased its levels in the brain, and that administering the metabolite before administering memory tests to mice decreased their performance on those tests.

Szalay noted that the findings, which he and his colleagues published in the Dec. 20, 2021, issue of Nature Aging, were "not based on dementia models – these are wild-type mouse models" which displayed cognitive declines that are typical of normal aging, rather than Alzheimer's disease (AD)-like deficits.

In keeping with that distinction, the team showed – somewhat to their surprise – that microglia did not appear to play a role in the effects of delta-valerobetaine. Microglia are brain-specific immune cells that play a prominent role in AD. By clearing away debris, they prevent chronic inflammation, which is an underlying factor in many aspects of age-related cellular decline in the brain and elsewhere.

But the authors found that eliminating microglia from the brain did not prevent delta-valerobetaine from affecting cognition.

Szalay said that the team was surprised by the findings, "but it also [reinforced] our understanding that this is something different" than dementia.

From a translational point of view, Szalay said, "the whole pathway from the gut via serum to the brain opens up different avenues to inhibit this response."

The company is currently raising funds and looking for partners, and plans to complete a preclinical package for its lead candidate UM-001 within the next 18 months.

Better beginnings

Beyond the specifics of UM-001, Szalay said, Ultimate Medicine's approach is aimed at generating "more productive drug development, with only those compounds with a better chance of success moving through preclinical evaluation."

Dementia and neurodegeneration, he said, is a broad and difficult field to address – but the current inability to develop effective medications is also related to the way industry searches for them. Those searches are based on high-throughput methods and reductionistic approaches that substitute quantity for quality to a degree.

The work now published in Nature Aging, on the other hand, is not a high-throughput approach. But the use of wild-type animals instead of the highly artificial and "in a way doubtful" animal models of dementia is difficult to scale but better at reflecting the complexity of what is going on during aging, as is the use of cognitive endpoints.

"We started phenotyping from the beginning," Szalay said.