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Recent research conducted by scientists at Cincinnati Children’s Hospital, in collaboration with an international team, has unveiled a noteworthy link between gut health and the risk of blood cancer. This discovery poses transformative implications for our understanding of aging, inflammation, and early leukemia development.
As we age, or when gut health deteriorates due to various ailments, changes in the intestinal lining can lead to the leakage of bacterial byproducts into the bloodstream. One particular molecule, produced by certain bacteria, serves as a signal that accelerates the growth of dormant, pre-leukemic blood cells, a crucial step toward the onset of leukemia.
The findings of the study, published on April 23, 2025, in the journal Nature, are pioneering in detailing how this process unfolds. Furthermore, the research indicates that this mechanism might impact the risk of other diseases, especially among older adults with a condition known as clonal hematopoiesis of indeterminate potential (CHIP).
“This study significantly refines our understanding of the development and progression of blood cancers, particularly in older populations. The promising aspect is the potential for early intervention, which may prevent pre-leukemic cells from advancing to more severe forms of the disease,” notes Daniel Starczynowski, PhD, director of the Advanced Leukemia Therapies and Research Center at Cincinnati Children’s Hospital and the lead author of the study.
“Our findings indicate that changes in gut health related to aging represent an unconventional risk factor in blood cancer development. Therefore, maintaining gut health could be increasingly critical,” adds Puneet Agarwal, PhD, an associate staff scientist and the primary author of the study.
Leukemia, Aging, and the Gut
More than 470,000 individuals in the U.S. are living with leukemia, with over 62,000 new cases diagnosed annually. According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program, nearly 24,000 individuals are expected to succumb to this disease in 2024.
Although survival rates have improved, leukemia remains a serious threat, especially for those over 65. Researchers have long sought to uncover why aging is a significant risk factor, and Starczynowski’s team appears to have provided a compelling explanation.
A Cascade of Disease Risk Linked to a Bacteria-Derived Sugar
With advancing age, the integrity of the gut lining diminishes, enhancing the interactions between intestinal contents and the bloodstream. In older adults, specific “gram-negative” bacteria proliferate and produce increasing amounts of a bacterial sugar known as ADP-heptose, which can have detrimental effects once it enters the bloodstream.
“ADP-heptose is specifically found in the circulation of older adults and promotes the growth of pre-leukemic cells,” states Starczynowski. “It’s also present in younger individuals who have disrupted gut health.”
The research involved intricate experiments to unravel the mechanisms that enable ADP-heptose to fuel pre-leukemia. Notably, the team identified tiny signaling structures called TIFAsomes within cells, indicating that ADP-heptose activates the expansion of pre-leukemic blood cells.
Following the measurement of this process, the researchers recognized its potential widespread implications.
Understanding CHIP
Clonal hematopoiesis of indeterminate potential (CHIP) refers to a condition wherein blood cells accumulate mutations that pave the way for diseases. This leads to the clonal amplification of affected cells, some of which are linked to blood cancers, while others relate to various other health issues, such as cardiovascular diseases and inflammatory disorders.
Approximately 10-20% of adults over 70 may have CHIP, yet many are unaware, as it typically presents no symptoms and lacks routine screening protocols.
In this study, researchers utilized mice designed to replicate CHIP’s characteristics. They observed that pre-leukemic cells significantly intensified when exposed to ADP-heptose originating from gut bacteria.
“The convergence of age-related gut microbiota shifts, increased intestinal permeability, ADP-heptose exposure, and pre-leukemic cells creates an environment conducive to pre-leukemia expansion,” explains Starczynowski.
A Potential Method to Intervene
The team discovered that ADP-heptose’s capability to facilitate the growth of pre-leukemic cells hinges on a receptor protein known as ALPK1, found in mutated blood cells. Blocking this receptor could theoretically inhibit the progression of CHIP to leukemia and other associated chronic conditions. However, as of now, no pharmacological agents exist to inhibit ALPK1.
In their exploration of potential avenues to disrupt the ALPK1 pathway, the researchers identified an enzyme encoded by the gene UBE2N as a promising candidate. Treating pre-leukemic cells with the UBE2N inhibitor significantly restricted their expansion, even when ADP-heptose was present.
Future research is essential to translate these findings from animal models into preventive measures for human leukemia.
“We aim to develop an ALPK1 inhibitor for human application. Our findings open new avenues for exploration,” Starczynowski remarks.
Implications Beyond Leukemia
Emerging research suggests that CHIP may also play a role in various age-related conditions, including heart disease, arthritis, gout, and osteoporosis. These studies highlight the critical position of gut microbiota in regulating overall health.
“CHIP represents a burgeoning public health issue,” states Starczynowski. “Over 10 million older adults might have CHIP without awareness. Our investigation implies that maintaining gut health could be an effective strategy to prevent blood disorders and possibly other age-associated illnesses.”
How Can Individuals Mitigate Their Risk?
New treatments that leverage the gut health-leukemia connection may take years to develop. In the interim, seniors may seek ways to reduce their risk of developing CHIP.
Enhancements in gut health could potentially be achieved through dietary changes or the use of pre- and probiotics. Existing research indicates that gut microbiota composition and functionality can be modified.
However, precise dietary adjustments and effective probiotics specifically targeting CHIP have yet to be defined, according to Starczynowski.
About the Study
The research team at Cincinnati Children’s included co-authors Avery Sampson, Kathleen Hueneman, Kwangmin Choi, Emma Uible, Chiharu Ishikawa, Jennifer Yeung, and Lyndsey Bolanos, all affiliated with the Division of Experimental Hematology and Cancer Biology; Xueheng Zhao and Kenneth Setchell from the Division of Pathology and Laboratory Medicine; and David Haslam from the Division of Infectious Diseases. Experts from the University of Cincinnati, University of Oxford, and Texas A&M University also contributed to this research.
The study was funded by grants from the National Institutes of Health (U54DK126108, R35HL135787, R01CA275007), the National Institute of Environmental Health Sciences (T32ES007250), Cincinnati Children’s Hospital Research Foundation, Edwards P. Evans Foundation, and Cancer Free Kids.
This study benefited from several shared research facilities at Cincinnati Children’s, including the Comprehensive Rodent and Radiation Facility, the Viral Vector Facility, the Research Flow Cytometry Facility, the NMR-based Metabolomics Facility, and the DNA Genomics Sequencing Facility.
Starczynowski has acknowledged his role on the scientific advisory board at Kurome Therapeutics and holds equity in the company.
Source
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