How microbes control mammalian cell growth

The microbiome—the trillions of bacteria, viruses, and fungi that live quietly in our body—plays a crucial role in shaping human health by providing a variety of micronutrients necessary for vital functions. But these tiny microorganisms can provide even more extraordinary benefits by reaching deep inside cells to accurately decode the genetic information that makes proteins, the building blocks of life. 

In a recent article published in Nature Cell Biology, University of Chicago researchers identified two small molecules made by gut bacteria, queuine and its chemical precursor pre- queuosine 1 (preQ1), that compete to control our cells’ protein building machinery. The discovery reveals that these two bacterial metabolites act in opposite directions, particularly queuine to promote cell growth, and preQ1 to halt cell growth. The study suggests the growth-suppressing nature of specific microbial metabolites may be useful in developing new cancer therapies. 

“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,” said senior author Tao Pan, PhD, Professor of Biochemistry and Molecular Biology and the Committee on Microbiology at the University of Chicago.

Vital function of microbial metabolites 

Inside every cell, a set of molecules called transfer RNAs (tRNAs) act as translators that read genetic code and build proteins, one amino acid at a time. These tRNAs often undergo chemical modifications to fine-tune how accurately and efficiently they function. When something goes wrong with these modifications, it can lead to pathological conditions like cancer and neurological disorders. 

In mammalian cells, there are nearly 40 tRNA modification chemical types; among these, the most complex one is the queuosine (Q) modification. Our cells can’t make it on their own and thus rely on gut bacteria or diet to provide queuine, a building block used to install this specific modification. The Q-modified tRNAs (Q-tRNAs) are critical for ribosomes, tiny factories inside the cells that make proteins, to decode genetic information more smoothly, improving speed and accuracy especially under stress. 

In bacteria, queuine is part of a longer, eight-step biosynthetic pathway that begins with guanosine triphosphate. One of the intermediate products in the biosynthesis of Q-tRNA is preQ1, which is constantly present in a bacterial cell and released into the gut when bacteria die.   

“Although the role of queuine in Q-tRNA production is well studied, we didn’t know the effects of preQ1 in tRNA modification in mammalian cells until our work,” Pan said. 

Surprising effects of preQ1 

Researchers in the Pan laboratory conducted experiments in mice to understand the role of preQ1 on mammalian cell physiology and found that preQ1 is present in the plasma and tissue of mice. Most importantly, they observed that preQ1 drastically reduced proliferation of cells grown in petri dishes. Interestingly, these effects were reversed by queuine treatment, restoring growth to normal levels.  

The researchers then went a step ahead and injected preQ1 into mice and found that the preQ1 wasn’t just floating in the bloodstream but also reached the tissue. Once preQ1 reached inside the cell, it made preQ1-tRNAs and decreased cell growth. When preQ1 was given to tumor-bearing mice, it reduced tumor growth, suggesting that preQ1 can be a potential new candidate for cancer treatments.  

“The strongest effect of preQ1 we observed was on dendritic cells, one of the key immune cells that initiate immune response, and even small amounts of preQ1 completely stopped their proliferation,” Pan said.  

Timing is everything 

Upon bacterial turnover in the gut, preQ1 would be immediately available whereas queuine might take longer, since it requires additional enzymatic reactions to release into the bloodstream. This means mammalian cells first encounter the growth-slowing preQ1, and later the growth-promoting queuine. This timing may prepare certain cells, such as immune cells, which could help fine-tune immune responses or maintain tissue balance. 

The team also uncovered the molecular machinery behind preQ1’s effect. Once inside the cell, preQ1 competes with queuine for the same enzyme called QTRT1/QTRT2, which modifies tRNAs. But preQ1-modified tRNAs are unstable and thus they are recognized as faulty and destroyed by the cell’s quality control enzyme, IRE1. This enzyme normally helps manage protein-folding during stress in the endoplasmic reticulum, a cellular highway system that helps package and transport proteins. This degradation could help translate genes critical for cell growth and metabolism. 

Significance of host-microbe interaction 

The current study reveals how bacterial metabolites can disrupt mammalian protein synthesis to slow cell division, and promote cell growth, suggesting bacterial chemistry not only influences digestion and immunity but also reaches into the very core of the cell’s biology to modulate how our genes are expressed. 

“These results show that the two microbial metabolites, born from the same pathway, can push our cells in opposite directions,” Pan said.  

The opposing effects of preQ1 and queuine provide an opportunity to explore ways to adjust the diet or microbiome composition to balance cell growth in cancer and prevent autoimmune diseases.  

The study, “Two microbiome metabolites compete for tRNA modification to impact mammalian cell proliferation and translation quality control,” was supported by grants from the National Institutes of Health, a pilot from the Univ. Chicago CIID Centre, the Chan-Zuckerberg Initiative, and the UCCCC Janet D. Rowley Discovery Fund. 

Additional authors include Wen Zhang, Sihao Huang, Olivia Zbihley, Dominika Rudzka, Luke Frietze, Mahdi Assari, Christopher Katanski, Marisha Singh, Christopher Watkins, Hankui Chen, Denis Cipurko, Amanda Sevilleja, Katherine Johnson, and Nicolas Chevrier from the University of Chicago; Kuldeep Lahry, Hélène Guillorit, Jennifer Falconi, Alexandre Djiane, Françoise Macari, Aurore Attina, Christophe Hirtz, and Alexandre David from the University of Montpellier, France; Delphine Gourlain and Didier Varlet from Hérouville Saint Clair, France.