Gut Microbes Shape Cell Proliferation Through Competing Molecules

A study recently published in Nature Cell Biology by University of Chicago scientists reveals how two microbiome metabolites, queuine and its precursor pre‑queuosine 1 (preQ1), regulate cell proliferation in opposing ways.

Queuine and preQ1 are both part of the same bacterial biosynthetic pathway but exert contrasting effects once they enter mammalian cells. As senior author Tao Pan, explains, “It is remarkable to see how the two bacterial metabolites can reprogram fundamental processes like translation in opposing ways inside our own cells to dictate cell growth.” Queuine enhances cell proliferation, while preQ1 suppresses it, suggesting that microbial chemistry can act as a hidden regulator of cellular activity.

Inside each cell, transfer RNAs (tRNAs) play a central role in translating genetic information into proteins. These molecules undergo numerous chemical modifications—nearly forty types in mammals—that determine how precisely and efficiently they function. Among these, the queuosine (Q) modification is the most complex. Because human cells cannot synthesize queuine, they depend on gut bacteria or dietary sources to obtain it. Q‑modified tRNAs assist ribosomes, the protein‑producing machinery, in decoding genetic information smoothly, especially under stressful conditions.

Bacteria generate queuine via an eight‑step biosynthetic route beginning with guanosine triphosphate, releasing preQ1 as an intermediate product. Pan’s team investigated the effects of preQ1 in mice to see whether it influences mammalian cell behavior. They detected preQ1 in plasma and tissues and found it drastically reduced cell proliferation in culture. Treating the same cells with queuine reversed this effect, restoring normal growth. When preQ1 was administered to tumor‑bearing mice, it slowed tumor expansion, particularly affecting dendritic cells, key coordinators of immune responses.

“The strongest effect of preQ1 we observed was on dendritic cells … even small amounts completely stopped their proliferation,” Pan noted.

Timing appears crucial. After bacterial turnover in the gut, preQ1 becomes immediately available, while queuine takes longer to form. This sequence may allow a temporary growth‑limiting phase before queuine stimulates proliferation. Mechanistically, preQ1 competes with queuine for the same tRNA‑modifying enzyme complex, QTRT1/QTRT2. The resulting preQ1‑tRNAs are unstable and degraded by the quality control enzyme IRE1, altering the translation of genes linked to metabolism and growth. 

The findings show how gut bacterial molecules can reach deep inside mammalian cells to influence gene expression. As Pan summarized, “The two microbial metabolites, born from the same pathway, can push our cells in opposite directions.” The study underscores how subtle shifts in microbial metabolism could one day guide strategies to manage cancer or immune imbalances.