By now we all know there are tons of bacteria living in our guts (we are made up of 10x more bacteria than human cells!) The bacteria help us digest food and make new molecules. If our microbiome gets disrupted it can lead to serious digestive problems. It has also been suggested that our bacteria help us fight infections by interacting with the immune system. Bacteria aren’t the only microorganisms living inside us, though. It turns out there is a diverse population of fungi living in our intestines, as reported by Iliev et al. in Science last week.
Fungus like mushrooms?
When we think of fungus, most people think about mushrooms. I can almost guarantee you no one is growing mushrooms in their colons. There are lots of other types of fungi, though, including single-celled creatures like Saccharomyces “yeast”. Fungi are one phylogenetic group, so they have characteristics in common with each other, including many of their DNA sequences.
In order to test for fungi in animal guts, the authors did PCR to test mice for the presence of a certain fungus-only DNA sequence. They found fungus throughout the entire mouse gastrointestinal tract, with the highest density towards the end of the colon (or large intestine). They also found fungi in rat, guinea pig, rabbit, pig, dog and human feces! I’m glad humans weren’t left out of this fungal bounty.
The authors isolated the DNA from mouse feces and sequenced all the fungal DNA they could find. They identified over 100 different known fungal species and more than 100 potentially new species of fungi! Most of these fungi were found in low concentrations, except for Candida tropicalis which accounted for 65% of all the fecal fungi. Candida tropicalis is an opportunistic pathogen, which only causes a problem when it grows out of control in people with suppressed immune systems.
Our immune systems are trained to seek out and destroy foreign invaders like bacteria, viruses and fungi. How does the immune system recognize fungi? They have a cell wall (human cells do not) that has the molecule B-1,3,-glucans (a sugar polymer). Macrophages in our immune system express a receptor called Dectin-1, which can recognize B-1,3-glucans and initiate an immune attack. Since we have potentially pathogenic fungi living in our guts, our immune systems are probably always keeping them in check, so they don’t grow out of control and make us sick. In fact, some of the diseases that cause inflammatory bowel disorders might be caused by fungi, and not bacteria, inducing an inflammatory response.
To test this idea, the authors chemically induced colitis (inflammation of the colon) in mice (I’ll spare you a photo). These mice were found to have circulating antibodies against fungal proteins, which implies that fungi have something to do with the pathology of colitis. The authors wondered what would happen to mice which do not have the Dectin-1 receptor. Since they can’t detect fungi, their immune systems would not be able to mount any attack. Sure enough, the mutant mice had much worse colitis symptoms. They had way more C. tropicalis (and other pathogenic fungi) in their guts than the wildtype mice which also had colitis. In other words, missing the fungal receptor didn’t necessarily cause colitis, but it made the symptoms much worse.
To further prove that colitis is aggravated by the native fungal population, the authors gave the mutant mice an antifungal drug during the induced colitis session. These mice were much healthier than their siblings who did not receive the drug. As long as something, an antifungal drug or the functioning immune system, can control fungal growth, then colitis is much milder.
Relevance to human disease
The inability to control fungi in the gut leads to more severe colitis in mice. What about in humans? Could a similar mutation be responsible for human colitis? The authors focused on patients who have ulcerative colitis. This comes in various forms; 30% of the patients have a severe form that does not respond to medical therapy. They sequenced the gene for the fungal receptor and found that patients with the severe form were more likely to have a particular gene sequence compared to patients with a more mild type of colitis. Though this doesn’t prove anything, it is in line with the idea that fungal growth can aggravate the inflamed colon. Perhaps this sequence difference in the severe patients prevents their fungal receptor from working at full efficiency.
To summarize all this, we have fungus living in our intestinal tract. Some of these fungi are totally harmless and I bet they help us with some physiological function (yet to be determined). Other native fungi, including C. tropicalis, are potentially pathogenic, but are controlled by the immune system normally. If the immune system cannot recognize fungal cells because the fungal receptor is defective, then the fungi will begin to grow out of control, which can upset the natural order in our guts. Inflammatory bowel diseases will become more severe when the fungi are able to grow unchecked by the immune system.
I have to say I don’t like the idea of a bunch of pathogenic fungi living in my intestines and just waiting for my immune system to let down its guard. Stay vigilant macrophages!
Check out this excellent article by Carl Zimmer in the NY Times about the human microbiome.