In collaboration with an international team, researchers at Cincinnati Children’s have made a groundbreaking discovery linking gut health to blood cancer risk. This connection, detailed in a study published on 23 April 2025 in the journal Nature, sheds light on how changes in the gut as we age might significantly influence the development of leukaemia and potentially other age-related diseases. The findings offer fresh insights into the complex interactions between our digestive system, immune function, and cancer risk, opening new avenues for early intervention and preventive care.
As people grow older, or when their gut health is compromised by illness, the intestinal lining can become more permeable, allowing bacteria and their metabolic byproducts to enter the bloodstream. One such molecule, a bacterial sugar known as ADP-heptose, has emerged as a critical signal that can drive the expansion of dormant, pre-leukaemic blood cells. This process is a crucial step in the progression from early, symptomless cell changes to full-blown blood cancer. By establishing this previously hidden link, the study marks a significant advance in understanding how age-related changes in the gut microbiome can trigger blood cell transformations.
Dr Daniel Starczynowski, PhD, director of the Advanced Leukaemia Therapies and Research Centre at Cincinnati Children’s and the study’s corresponding author, highlighted the importance of this discovery. “Our research shows that age-associated changes in the gut are a non-traditional but significant risk factor for blood cancers. This insight could transform our approach to preventing these diseases, potentially allowing us to intervene before pre-leukaemic cells evolve into aggressive malignancies,” he said. Co-author Dr Puneet Agarwal, PhD, an associate staff scientist in the Division of Experimental Hematology and Cancer Biology, added, “This study underscores the importance of maintaining gut health as we age, as it could significantly impact the risk of developing blood cancers.”
Leukaemia remains a significant health burden, particularly for older adults. According to the US National Cancer Institute, more than 470,000 Americans are currently living with leukaemia, and over 62,000 new cases are diagnosed each year, with nearly 24,000 deaths projected in 2024 alone. Despite improved survival rates, leukaemia remains a life-threatening condition, with individuals over the age of 65 facing a disproportionately high risk. While scientists have long recognised that the ageing immune system and genetic mutations play key roles in this elevated risk, the findings from Starczynowski’s team suggest that microbial shifts within the gut might also be a critical but underappreciated factor.
The team’s experiments revealed that as the gut lining becomes more permeable with age, common gut bacteria, including gram-negative strains, can release increasing amounts of ADP-heptose. This sugar, typically confined to the gut, can leak into the bloodstream and act as a potent activator of pre-leukaemic cells. Once in the blood, ADP-heptose triggers the formation of tiny cellular structures called TIFAsomes, which serve as internal signals promoting the growth of pre-cancerous cells. To track this process, the researchers developed a new diagnostic tool, the TIFAsome Assay, which detects ADP-heptose activity in blood samples, potentially offering an early warning system for individuals at increased leukaemia risk.
The study also sheds light on a little-known condition called clonal haematopoiesis of indeterminate potential (CHIP), which affects an estimated 10-20% of adults over 70. CHIP is characterised by the gradual accumulation of genetic mutations in blood cells, creating clones that can progress to cancer. Using genetically modified mice designed to mimic human CHIP, the researchers demonstrated that exposure to ADP-heptose significantly accelerates the expansion of these pre-leukaemic cells, providing a direct link between gut microbial activity and blood cancer risk. This finding suggests that older adults with CHIP may be particularly vulnerable to the effects of gut-derived bacterial byproducts.
Critically, the researchers identified a potential target for therapeutic intervention. They discovered that ADP-heptose’s ability to trigger pre-leukaemic cell growth depends on a receptor protein known as ALPK1, found on the surface of mutant blood cells. Although no drug exists to inhibit ALPK1, the team pinpointed a promising lead: an enzyme produced by the gene UBE2N. Blocking this enzyme significantly reduced pre-leukaemic cell expansion in their mouse models, even in ADP-heptose presence, suggesting a possible pathway for future drug development. The team hopes that further research will develop a targeted ALPK1 inhibitor suitable for human use.
The findings underscore the importance of maintaining gut health as a potential strategy to reduce cancer risk, especially in older adults. While a targeted drug remains a longer-term goal, practical steps like dietary adjustments, prebiotics, and probiotics might offer more immediate, albeit less specific, benefits for reducing the impact of gut-derived cancer triggers. “More than 10 million older adults might have CHIP without knowing it,” Starczynowski emphasised. “Our study highlights the critical role of gut health in potentially preventing blood disorders and other age-related diseases, providing a promising direction for future research.”
More information: Daniel Starczynowski et al, Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1, Nature. DOI: 10.1038/s41586-025-08938-8
Journal information: Nature Provided by Cincinnati Children’s Hospital Medical Center
