How a Freak Flood Revealed the Gut-Brain Axis

“There is a tide in the affairs of men, which taken at the flood, leads on to fortune.” —William Shakespeare

In May 2000, the Canadian town of Walkerton was flooded after a heavy rain. The town’s water supply became contaminated with E. coli and Campylobacter jejuni. It was caused by overflow from a cow and chicken farm known to have problems containing their pathogens. Over two thousand of the five thousand townsfolk became seriously ill. Seven died. The town basically shut down. And then it was noticed that hundreds of these people, after recovering from their original infections, came down with IBS. They also became depressed.

Although E. coli was present in the water, C. jejuni arguably played a bigger role in the disaster. C. jejuni is sensitive to stomach acids, which quickly killed many of the microbes. But people who regularly took antacids had lower levels of acidity, allowing more of the C. jejuni to pass through. Those using proton-pump inhibitors were twice as likely to get sick from C. jejuni.

Although diminished, many of these pathogens still made it to the intestines. These bacteria were recently inside a cow or a chicken, so they were pretty much at home in the human gut. In cows and chickens, C. jejuni is a commensal. Why it goes berserk in a human gut is unclear, but C. jejuni is potent: It is the number-one cause of diarrhea in the United States, ahead of Salmonella and E. coli. The odds are good that you’ve had it at least once in your life.

In response to C. jejuni, special cells lining the intestines secreted serotonin, which increased peristalsis in anticipation of purging.

C. jejuni caused anxiety even without a full-blown infection. Cells lining the gut called neuropods detected the invasion, causing the nervous system to go on alert before the immune system kicked in. This was an early shot across the bow; the brain now knew something was up down below.

Some heroic microbes emerged to face down the C. jejuni, including Bifidobacteria and Lactobacillus species. They worked to outcompete and crowd out the C. jejuni, preventing them from sticking to the cells lining the gut. Ironically, those who had taken antibiotics recently had lost this microbial defense and they were hit harder by the C. jejuni.

Sadly, the city officials of Walkerton insisted that the water was safe, and people kept drinking it. The C. jejuni soon overwhelmed their microbial defenses, eating through the mucus lining the gut and leaving tender gut cells exposed to infection.

Once attached to a cell, C. jejuni makes a toxin that stops gut cells from dividing. Without division, gut cells can't renew themselves and when they die, the gut lining begins to leak. A leaky gut leads to inflammation. Sure enough, the citizens of Walkerton came down with irritable bowel syndrome (IBS), along with its accompanying depression and anxiety.

Stephen Collins, a professor at McMaster University in Hamilton, Ontario, took the two-hour drive to Walkerton to see if there was a way to snatch some useful research from the town's misery.

For eight years Collins followed this group of unlucky Canadians and found that many of them had suffered intractable IBS ever since their initial infection. Collins recognized this as post-infectious IBS, which was first seen in soldiers who had picked up dysentery during World War II. About one in eight cases of IBS starts this way. Collins discovered a significant association between IBS and the mental conditions of depression and anxiety.

Intriguingly, Collins found that people with pre-existing depression had double the risk of contracting IBS. This observation underlines the dual nature of the gut-brain dialogue. It creates a positive-feedback loop, a vicious cycle that can be hard to break.

The initial infection caused the immune system to move swiftly to eradicate the offending bacteria. But in some people, the immune response failed to wind down after eliminating the pathogens, leading to treatment-resistant IBS.

Collins was joined in the research project by Premysl Bercik, also of McMaster University. Bercik took fecal matter from IBS patients and transplanted it into mice. The mice subsequently developed anxiety-like behavior, demonstrating that gut microbiota can affect mental states and that, intriguingly, those states can be transferred from one animal to another. The idea that mental states could be transmitted via fecal transplant took most scientists by surprise.

In the wake of the disaster, Walkerton erected a waterfall commemorating the victims. But the people who got IBS and became depressed started an important conversation about how the gut is related to the brain. Today, their suffering is also memorialized by the astonishing revelations of the gut-brain axis.

References