Have you ever felt that nagging sense that aging isn’t just about wrinkles and gray hair, but something deeper, more unseen, happening within your body? What if a surprising new discovery revealed that your gut—that complex inner world of bacteria—holds a key to understanding not just aging, but even the earliest inklings of blood cancer? Groundbreaking research from Cincinnati Children’s and an international team has uncovered a stunning connection that could fundamentally change how we view the silent progression of leukemia, particularly in older adults. Their findings, published in the prestigious journal Nature, pinpoint a tiny, often overlooked molecule made by certain gut bacteria as a potential trigger, pushing hidden, pre-leukemic cells closer to becoming full-blown cancer.
For years, scientists have puzzled over what fuels the growth of these “pre-leukemic” cells, a common age-related condition called clonal hematopoiesis of indeterminate potential, or CHIP. While CHIP doesn’t automatically mean cancer, it significantly raises the risk of developing leukemia and other serious health problems as we get older. This new study lays out, for the very first time, a step-by-step explanation of how this hidden threat might be fed from within our own bodies, starting with our gut.
The Gut-Bloodstream Connection
This isn’t about what you ate for dinner last night. It’s about a subtle yet profound change in the lining of our intestines that can happen as we age, or when our gut isn’t healthy due to certain conditions. This change allows tiny byproducts from specific bacteria to “leak” into the bloodstream.
One particular molecule, called ADP-heptose, comes from common Gram-negative bacteria—a type of bacteria found in your gut. When ADP-heptose gets into the bloodstream, it acts like a signal, essentially telling these dormant pre-leukemic cells to multiply rapidly. This accelerated growth pushes them further along the path toward becoming full-blown leukemia.
Daniel Starczynowski, PhD, who led the study and directs the Advanced Leukemia Therapies and Research Center at Cincinnati Children’s, highlighted the significance: “This study significantly advances our understanding about how blood cancers develop and progress, especially in older adults. The exciting news is that we also may have a way to intervene early—before these pre-leukemic cells evolve into more aggressive disease. We look forward to conducting further studies to pursue this new approach.”
Unpacking the Research: How the Discovery Unfolded
To uncover this intricate link, the research team conducted a series of sophisticated experiments using both lab mice and human blood samples.
Mapping the Mouse Connection: The journey began by studying how gut issues affect pre-leukemic cells in mice. Researchers used mice with a specific genetic change that made their blood-forming cells prone to becoming pre-leukemic. They observed that when the intestinal lining of these mice was damaged—similar to what happens with age or certain gut diseases—the pre-leukemic cells multiplied significantly. When these same mice were given antibiotics, the expansion stopped, which pointed strongly to gut bacteria playing a direct role.
To dig deeper, the scientists transferred gut bacteria from mice with damaged intestines or from older mice into healthy mice with the pre-leukemic gene. In both cases, the transferred gut bacteria encouraged the pre-leukemic cells to grow. This observation solidified the idea that the specific mix of gut bacteria, especially those found in aging or injured guts, is a crucial factor. The team then zeroed in on Gram-negative bacteria, finding that targeting them with specific antibiotics halted the pre-leukemic cell growth, while antibiotics for other bacteria did not. This was a critical clue, showing that products from Gram-negative bacteria were the actual drivers.
Pinpointing the Culprit Molecule: The next step was to identify the specific molecule from these bacteria. They found elevated levels of ADP-heptose, a known byproduct of Gram-negative bacteria, circulating in the blood of older mice and those with gut damage. Crucially, they also found significantly higher levels of ADP-heptose in the blood of older humans and individuals already diagnosed with CHIP or myelodysplastic syndromes (MDS), a type of pre-leukemia. Healthy young people, by contrast, had hardly any ADP-heptose in their blood.
To confirm ADP-heptose’s direct impact, researchers gave it to mice with pre-leukemic genes. The outcome was clear: ADP-heptose treatment dramatically increased the number of pre-leukemic cells, but it had no effect on healthy blood cells. This result showed that ADP-heptose specifically targets and boosts the growth of these abnormal cells. Similar findings were seen with other common pre-leukemic genetic changes.
Connecting to Human Health: To ensure these findings were relevant to humans, the researchers used actual human pre-leukemic bone marrow cells from MDS patients. When these human cells were placed into special mice and then treated with ADP-heptose, the pre-leukemic cells expanded. Healthy human bone marrow cells, however, remained unaffected. This provided strong evidence that the mechanism discovered in mice also applies to human disease. The team further identified the exact cellular pathway involved: ADP-heptose binds to a protein called ALPK1, which then triggers a chain reaction that essentially “turns on” a growth signal for these pre-leukemic cells.
The Groundbreaking Implication
This research marks a significant turning point in our understanding of how pre-leukemia develops, especially as we age. It powerfully demonstrates that the health of our gut and the balance of its microbial residents can directly influence the risk of blood cancers like leukemia. Identifying ADP-heptose and its precise signaling pathway not only solves a critical piece of the aging and disease puzzle but also provides a tangible target for future treatments. Imagine a day when we could potentially prevent the progression of CHIP to full-blown leukemia by simply adjusting factors related to our gut health. This discovery opens the door to truly proactive approaches against cancer before it fully takes hold.
Paper Summary
Methodology
The study employed mouse models with pre-leukemic mutations, introducing intestinal damage via chemical treatments or observing aged mice. They assessed pre-leukemic cell expansion and the impact of broad-spectrum and targeted antibiotics. Fecal microbiota transplants from aged or gut-damaged mice were used to investigate bacterial influence. Human plasma samples from healthy young and old individuals, and patients with CHIP, MDS, and inflammatory bowel disease (IBD) were analyzed for ADP-heptose levels. Human MDS cells were also engrafted into mice to study ADP-heptose effects. Key techniques included mass spectrometry, flow cytometry, and 16S rRNA gene sequencing.
Results
Researchers found that age-related or induced intestinal alterations led to increased gut permeability and elevated circulating ADP-heptose, a byproduct of Gram-negative bacteria. This molecule was significantly higher in older humans and those with CHIP or MDS. ADP-heptose directly promoted the expansion of pre-leukemic cells in mouse models and human xenografts. Mechanistically, ADP-heptose activates ALPK1, triggering a signaling pathway that gives pre-leukemic cells a growth advantage.
Limitations
While establishing a strong mechanistic link in models and human samples, the study is foundational. Further research is needed to translate these findings into direct clinical interventions that modulate ADP-heptose levels in humans to prevent leukemia progression. Specific dietary changes or pre-/pro-biotic interventions for CHIP based on these findings have not yet been determined.
Funding and Disclosures
The research received funding from the National Institutes of Health, the National Institute of Environmental Health Sciences, Cincinnati Children’s Hospital Research Foundation, Edwards P. Evans Foundation, and Cancer Free Kids. Daniel Starczynowski, the corresponding author, disclosed serving on the scientific advisory board at Kurome Therapeutics with equity in the company.
Publication Information
The study, titled “Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1”, was published online on April 23, 2025, in the journal Nature. The full list of authors is Puneet Agarwal, Avery Sampson, Kathleen Hueneman, Kwangmin Choi, Niels Asger Jakobsen, Emma Uible, Chiharu Ishikawa, Jennifer Yeung, Lyndsey Bolanos, Xueheng Zhao, Kenneth D. Setchell, David B. Haslam, Jessica Galloway-Pena, John C. Byrd, Paresh Vyas, and Daniel T. Starczynowski. The article’s DOI is https://doi.org/10.1038/s41586-025-08938-8.