"The microbiome (the ecosystem of gut microbes) is a powerful master key that can control the biological limits of chronic diseases humanity has yet to conquer, degenerative brain disorders, and aging."
Assistant Professor Kim Ju-won of the School of Medicine at Konkuk University Glocal Campus said this about the metabolites produced by gut microbes.
Recent gut health research has entered a new phase, powered by advances in next-generation sequencing and metabolomics. In the past, only a very small fraction of cultivable microbes could be studied, but now it is possible to precisely track the genomes of the trillions of microbes in the gut and the metabolites they produce.
As it has been revealed that metabolites produced by gut microbes send direct signals to organs throughout the body and suppress harmful substances emitted by senescent cells, the view of gut microbes as an endocrine organ in their own right is also gaining traction.
Kim, a researcher in this field, focuses on elucidating how metabolites such as short-chain fatty acids and phenyl lactic acid (PLA) produced by lactic acid bacteria protect and repair mitochondrial function to extend healthy lifespan. The following is a Q&A.
Gut health is being linked to anti-aging and overall health.
"There are two major reasons. The first is analytical technology. In particular, there has been dramatic progress in next-generation sequencing and metabolomics. Whereas in the past only a very small subset of cultivable microbes could be studied, we can now precisely track the genomes of the trillions of microbes in the gut and the metabolites they produce. We have begun to decode how microbes 'talk' to our body's cells. The second is identifying the specific systemic signaling mechanisms. Gut microbes produce key metabolites, and recent findings show that these metabolites travel throughout the body, send direct signals to major organs, and suppress harmful substances emitted by senescent cells. It amounts to a paradigm shift to an 'invisible endocrine organ' that regulates our body's metabolism and the pace of aging."
What microbiome research are you conducting now?
"Our lab focuses on discovering key active substances among metabolites that can slow human aging and prevent disease, and clarifying how they work. The representative substances we are focusing on now are short-chain fatty acids. These metabolites protect and repair mitochondria, the energy powerhouses of cells. When cells age and are under stress, mitochondrial function declines and faulty proteins accumulate, but when metabolites like short-chain fatty acids reach cells, they act as a switch that activates an emergency repair system. We are proving, at the molecular level, which specific microbes produce which substances (metabolites) and how they slow our body's aging clock. Once we fully understand this link, it will open enormous possibilities not only to use beneficial lactic acid bacteria but also to purify the metabolites those microbes produce themselves and develop them into anti-aging new drugs or personalized therapies."
You said prior research confirmed that PLA secreted by gut microbes extends the lifespan of Caenorhabditis elegans (hereafter worm).
"This research is meaningful in that a single metabolite produced by beneficial bacteria acted as a switch that slows aging. It proved the causal relationship that PLA secreted by microbes extends healthy lifespan in living organisms. The worm is a tiny 1-millimeter-long creature, but it shares with humans key genetic and aging-related metabolic pathways, making it a standard model in the biology of aging. When PLA was administered to these worms, not only was lifespan extended, but activity remained robust and declines in muscle function were delayed. It acted as a 'longevity signaling molecule' that awakens the mitochondrial defense system in cells and increases stress resistance. This can be interpreted to mean that, in situations where the same lactic acid bacteria produce varying degrees of effect in the gut, a metabolite with proven efficacy can overcome differences in gut environments and enable the development of therapies that deliver anti-aging benefits to anyone."
Isn't it difficult to apply worm experiment results directly to humans?
"The principles and mechanisms are highly likely to apply to humans, but there are many hurdles to clear to reach actual therapeutics or commercialization. Animal models like worms or lab mice should be viewed as a first step to opening new possibilities. Lab animals share the same genes and eat only controlled diets in identical environments. Humans, however, all have different genetic backgrounds, and environmental factors vary widely. Microbiomes also differ by individual, so we do not know how the immune or metabolic systems will respond in the human body when the same substance is administered. We must also verify whether a metabolite effective in animal models can withstand digestive enzymes, pass through the gut, travel through the bloodstream, and reach target organs or senescent cells in humans. The appropriate concentration for human body size must also be determined."
What are the obstacles to translating microbiome research into actual health supplements or therapeutics?
"The biggest barrier is that an individual's microbiome is completely different, like a fingerprint. With chemically synthesized drugs, nearly identical molecular structures act similarly regardless of who takes them, yielding similar effects, but with microbiome therapeutics or health supplements, the moment they are administered they begin complex interactions with the tens of trillions of existing microbial communities each person has. Beneficial bacteria that become a miracle therapy for one person may fail even to colonize and die off in another person's gut environment, or even trigger harmful reactions. Because the variation in efficacy is so large across individuals, it is extremely difficult to create standardized products that work for everyone."
How far does the microbiome influence the human body?
"Microbiome research is already extending beyond the gut to the entire body. There are ongoing efforts to treat neurological disorders such as depression or dementia via the 'gut-brain axis,' work on the 'gut-vagina axis' that addresses the balance between the gut and the vagina, and research clarifying relationships with the skin, liver, and muscles. The extent to which we can perfectly elucidate the mechanism of 'systems biology integrated aging,' which simultaneously controls the rate of organ and cellular aging throughout the body by modulating the microbiome, will determine the limits of microbiome research."
What is the outlook for the field?
"The ultimate aim of this research is 'healthy human aging.' The microbiome is the powerful master key that can control the biological limits of chronic diseases humanity has yet to conquer, degenerative brain disorders, and aging. The field's prospects hinge on advancing multi-omics that integratively analyzes the genomic data of trillions of microbes, human genetic data, and metabolite data. Once this technology is complete, ultra-personalized precision medicine will be possible, and that will be when the microbiome enters its heyday."
Microbes on youthful skin produce substances that slow aging
"We identified key substances associated with a youthful and healthy skin environment."
Amorepacific R&I Center conducted an integrated analysis of skin microbes and skin-surface metabolites and identified PLA, a metabolite that appears at relatively higher levels in youthful skin. The research findings were published online in April in the international microbiology journal International Microbiology. The research team analyzed skin microbes and skin-surface metabolites in Korean women's skin. In cell experiments, PLA was found to promote collagen production, which plays a key role in maintaining skin elasticity, while inhibiting the activity of collagen-degrading enzymes. The results show that substances produced by skin microbes can directly influence skin aging. The team plans to use these results for future personalized skin diagnostics and the development of microbiome-based functional materials.
Seo Byung-hwi, chief technology officer (CTO) of Amorepacific, said, "This study is highly meaningful in that it identified key substances associated with a youthful and healthy skin environment," and added, "We plan to continue research on next-generation longevity solutions that help skin maintain a healthy environment on its own."