Gut Bacteria Metabolite Found to Drive Pre-Leukemic Cell Growth

In a finding that could reshape our understanding of age-related blood disorders, researchers have identified a bacterial metabolite that flows into the bloodstream as we age and accelerates the growth of potentially dangerous pre-leukemic cells.

Scientists at multiple research institutions discovered that ADP-heptose, a substance produced exclusively by gram-negative bacteria in the gut, appears in the bloodstream of older adults and promotes the expansion of mutated blood stem cells – a condition known as clonal hematopoiesis of indeterminate potential (CHIP).

CHIP affects an estimated 10-20% of people over age 70 and substantially increases their risk of developing blood cancers and cardiovascular disease. While only a small fraction of individuals with CHIP progress to leukemia, the strongest predictor of this progression is the accumulation of these mutant blood cells.

The study, published in Nature, reveals that age-related changes in intestinal barriers allow this bacterial metabolite to leak into circulation, where it finds a ready target in pre-leukemic cells.

“Despite the known associations between CHIP and increased all-cause mortality, our understanding of environmental and regulatory factors that underlie this process during ageing remains rudimentary,” the researchers wrote in their paper.

What makes this discovery particularly intriguing is the mechanism involved. The team found that pre-leukemic cells bearing mutations in the DNMT3A gene express higher levels of ALPK1, the only known receptor for ADP-heptose in human cells. When ADP-heptose binds to this receptor, it triggers changes that give mutated cells a competitive advantage over healthy ones.

The research team confirmed this process through multiple laboratory experiments. When they transplanted DNMT3A-mutant blood stem cells into mice and then exposed them to ADP-heptose, the mutant cells multiplied significantly and outcompeted normal cells. When they genetically removed the ALPK1 receptor, this advantage disappeared completely.

The significance extends beyond blood disorders. The researchers found that ADP-heptose levels in CHIP patients were associated with higher rates of hypertension and venous thromboembolism, suggesting this bacterial product may contribute to the cardiovascular risks already linked to CHIP.

Dr. Daniel Starczynowski, one of the study’s authors, and colleagues suggest these findings might open new therapeutic possibilities. If scientists can develop methods to block the ADP-heptose-ALPK1 interaction, they might prevent CHIP from progressing to leukemia or reduce its associated inflammatory conditions.

The work connects several important biological domains – aging, gut health, inflammation, and cancer – adding evidence to the growing recognition that our microbiome influences health in ways far beyond the digestive system.

As populations age worldwide, understanding the specific mechanisms driving age-related diseases becomes increasingly crucial. This research suggests maintaining gut barrier integrity might be yet another important factor in healthy aging and cancer prevention strategies.