Two notable studies on the microbiome in colon cancer came out late last year. The first, published in Science, basically asked what happens when our native microbes are exposed to constant inflammation — how does it affect them, and how does this altered community affect us, their hosts?
The experiment occurred in mice that had a crucial immune signaling molecule knocked out called IL10. These mice respond to any microbes, friendly or unfriendly, with a flamethrower. The scientists dropped a carcinogen into this mix called azoxymethane. They did the same to regular mice without the genetic modification. Only the mutant mice developed cancer, not the wild type mice. What was the difference? Guess — the microbiome.
In the mutant mice, the community lost diversity. One type of bacterium then expanded to fill the vacant niche, a native E. coli. These mice harbored 100 times more E. coli than the wild type mice. Repeating the experiment with just E. coli also produced colon cancer. The bacteria seemed to thrive in the inflamed environment, even to profit from it. As the mucus barrier fell away, they sidled right up against the gut lining and fostered little terrible tumors.
We keep finding evidence that an intact mucus barrier is of utmost importance.
So, to recap: inflammation selects for an unfriendly community of microbes that expresses a set of genes associated with virulence. Treat your microbiota badly, in other words, and you select for a bad microbiota that treats you even worse.
This work suggests that you don’t need new arrivals to produce cancer. They’re already present. They then bloom in depleted, inflamed environments. This is troubling not least because the high-fat, calorie-dense western diet is increasingly recognized to select for a proinflammatory microbial community.
The incidence of colon cancer, of course, increases in direct proportion with Westernization around the world. It’s the No. 2 killer among cancers in the US. Here’s one possible reason: lousy food.
Another mouse study supports this idea. In mice lacking that anti-inflammatory IL10, a Western diet alone caused nasty bacteria to bloom, eventually producing colitis. You don’t even need a carcinogen to get colon cancer, just Happy Meals.
The second study is kookier, but revelatory. These mice had a gene called NOD2 incapacitated. The gene encodes for a receptor that — well, no one really knows what it does, but it’s apparently very important for our ability to communicate with our resident microbes. Carriers of certain NOD2 variants — presumably incapacitated versions — have a greater risk of Crohn’s disease.
So think of these mice as rodents with their line of communication to their microbes hobbled. Host and microbes just don’t understand each other.
In this experiment, mice with the incapacitated NOD2 gene ended up accruing a nasty, quite unfriendly community of microbes. They developed colitis, a chronic inflammation of the intestine. Then they developed colon cancer.
Here’s the kookiness. When the scientists transplanted that nasty microbiota from the mutant mouse to absolutely normal mice whose NOD2 receptors worked just fine, they, too, developed colitis. They developed cancer.
Likewise, transplanting the normal microbiota to the NOD-deficient mice fixed the inflammation, much like a fecal transplant can fix colitis caused by C. diff infections.
In one sense, this is just one of Koch’s postulates — proving that the microbes you think cause disease cause them. But in another, it’s like a post-modern version of Koch’s postulate. As you’ll recall, the original problem was genetic. Then the problem became microbial. And then it became inflammatory. And finally, carcinogenic.
What really caused what? Or maybe the lesson is: there are multiple paths to the same outcome — a dysbiosis of your microbial community. You could be seeded with an aberrant community of microbes; your lousy, junk-food diet might select for them; too many courses of antibiotics could produce a skewed microbiome; or maybe you just weren’t exposed to a sufficient richness and variety of microbes over your sheltered, sanitized life.
Or let’s say it didn’t even start with you; it began with your mother’s microbes while you were in the womb. They send signals via Mom’s immune system to the fetus. This group in the Netherlands has found that prenatal immune activation during pregnancy changes the immunological balance of the gut. In other words, your ability to control inflammation is partially set in the womb. You may be born like those mice lacking IL10. You’re preordained to accrue an unfriendly microbiome, because you can’t restrain yourself when the microbes show up.
You treat them badly. They treat you worse.
