How Gut Bacteria Control Asparagine in Colorectal Cancer

Asparagine is an amino acid present in asparagus, eggs, potatoes and numerous protein-rich foods.

For years, it attracted little attention on nutrition labels. That changed when a study followed precisely what occurs to it in the body following a cancer diagnosis.

Tumours and immune cells alike require asparagine to remain active. Diet is not the sole factor deciding which receives a greater supply: one gene in a widespread gut bacterium has been influencing the outcome.

A nutrient battlefield

Scientists at Weill Cornell Medicine tracked this unseen contest to the gut microbiome, the trillions of microbes that inhabit the human intestine.

Dr Chunjun Guo, of Weill Cornell Medicine, co-led the research. His group demonstrated that gut bacteria can determine how much of an essential nutrient gets to a tumour.

Asparagine is central to the process. It is a protein building block needed by both cancer cells and disease-fighting T cells for growth. The side that secures more gains an advantage within the tumour.

Asparagine on both sides

CD8 killer T cells directly seek out and destroy cancer, while tumour cells vie with them for the same nutrients. Both depend on asparagine.

The amino acid aids protein production and survival, making it a prized resource in the confined, nutrient-starved setting of a tumour.

Multiple studies have recorded cancer’s demand for this amino acid, including in colorectal disease. T cells also need it, particularly as they increase in number. The two sides draw from the same store.

It had not been known whether factors beyond the tumour determined how much asparagine reached it. Dietary intake alone could not account for the differences.

The bacterial enzyme

Guo’s team examined Bacteroides ovatus, a common gut bacterium, along with a gene it can carry, known as bo-ansB.

This gene produces an enzyme that breaks down asparagine before it is absorbed by the body.

When bo-ansB is active, B. ovatus breaks down a large proportion of asparagine in the gut. As a result, less enters the bloodstream and less arrives at the tumour.

If the gene is removed, the amino acid passes through to whichever cells require it most.

This arrangement gave the researchers a straightforward test: deleting that one bacterial gene leaves every other element unchanged.

Mice and microbes

The researchers worked with germ-free mice, raised without gut bacteria, and introduced human microbial communities into them.

Some mice received bacteria with an intact bo-ansB gene, while others received bacteria in which CRISPR had knocked out the gene. Every mouse was given colorectal tumours and a diet rich in asparagine.

They set out to establish whether the amino acid would nourish the tumour or immune cells, with bacterial activity as the sole variable.

To trace the entire pathway, the team followed labelled molecules, measured gene activity one cell at a time and sequentially switched off individual T-cell genes.

The mouse models allowed variables to remain controlled. Human microbial data connected the results to real-world relevance.

A variety of outcomes

For mice carrying bacteria with intact bo-ansB, an asparagine-rich diet enabled tumours to flourish. The bacteria used up the amino acid in the gut, less reached the tumour, and cancer cells gained the benefit.

Knocking out the gene reversed the effect of the identical diet. Greater amounts of asparagine travelled through the bloodstream to the tumour.

CD8 T cells took it up, multiplied and mounted a strong response against the cancer. That one gene changed the result.

Definitive cause-and-effect results are unusual in microbiome research, which more commonly identifies patterns across whole microbial communities rather than individual mechanisms.

A previous study associated gut bacteria with responses to immunotherapy in melanoma, but did not identify the activity involved.

A stem-like state

The most original finding emerged at cellular level. CD8 T cells given more asparagine did more than proliferate: they entered a state researchers describe as stem-like.

In this state, the cells could keep renewing themselves while generating successive waves of offspring able to kill tumours.

Immunotherapy relies on these cells. Mice given additional asparagine and lacking bo-ansB produced more of them than any other group.

Scientists had long thought microbes could affect T-cell fitness. This is the first instance in which a particular bacterial gene has been linked with the stem-like capacity of tumour-fighting T cells.

The SLC1A5 gate

SLC1A5 emerged as the crucial gatekeeper: a surface protein that lets asparagine enter T cells.

When more amino acids were available, CD8 cells increased their production of SLC1A5. This allowed more asparagine in and led to the stem-like response.

Directly blocking SLC1A5 removed the advantage. T cells could no longer take up the extra supply, and the anti-tumour effect disappeared.

That test completed the connection between the bacterial gene, the gut and the immune cell.

Human data showed that gut microbe genes which consume amino acids became more prevalent as colorectal cancer progressed.

Separate research has shown that later-stage colorectal tumours rely heavily on producing their own asparagine.

Toward personalised care

For the first time, researchers have identified a bacterial gene, an amino acid and a cellular transporter that collectively affect whether dietary protein supports or obstructs a tumour.

There will be practical implications. Clinicians may eventually test a patient’s microbiome for bo-ansB before beginning immunotherapy.

They may also apply that information when combining medicines with diets suited to an individual’s microbiome, or in developing probiotics that preserve more asparagine for immune cells.

“Our goal is personalized therapy,” said Dr. Nicholas Collins at Weill Cornell. Clinical application remains a long way off, but there is now a map to follow.