Wednesday, November 4, 2009

Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43

(Alternative title: Eating Poo is good for you!)

The information in this article relates only barely to my field of study. But it intrigued me, so I decided to review it. It’s also relatively short, which, given that I spent the first half of this week passed out in a sugar coma, made it very attractive.
It was the ITGeek who passed this article onto me. A media-fied version of the results had been published in a newspaper, he mentioned it, and I asked him to pass on the details. The media version of this was: Fibre will stop asthma, and, of course, referenced an Apple a Day (which must, by journalism law, appear every time the story relates to fruit or health. In fact, journalists have a quota of homilies they must include in their work. Otherwise your press pass is revoked and the other journalists don’t shout you at the bar).

The basics
Your intestines have a normal level of bacteria. They’re usually harmless, or, at worst, what we call opportunistic bacteria, ones that only do harm when a person’s already sick. They’re so normal that we use some of these bacteria to check that the sewerage hasn’t gotten mixed up with the drinking water. For a long time, these bacteria have been credited with keeping the bad bacteria at bay (by competing with them) and assisting with breaking down food.
This study suggests that they could also help regulate the immune system’s response, particularly allergies. The bacteria ferment fibre into Short-Chain Fatty Acids, which bind to G-protein coupled receptor 43, commonly found on eosinophils and neutrophils and decrease their production of inflammatory mediators.
If you’re thinking ‘WTF?’, I’ll break it down. Short-chain fatty acids are a type of compound, very common, that include acetate. They’re an end-product of bacteria breaking down fibre (or, as I prefer to think of it, what they vomit up after getting pissed on the fibre). The entire body runs on a system of proteins and receptors that connect like keys in a lock and set off chain reactions that control everything from making new proteins to cell proliferation. There’s a billion of the fucking things, and they’ve usually got a stupid name (one day, I’ll rant about naming conventions in science and why it hurts cramming undergrads). In this case, the short chain fatty acids connect to a receptor that’s part of the g protein coupled receptor family. Think of this like, oh, saying your car is a Ford sedan. For the sad obsessive types, there’s lots of varieties and types of engines and number of horsepower, but for most of us, it’s a car. Four wheels, four doors and a boot. All you need to know about GPR43 is that when something slots into it, a message is sent to inside the cell, and, like a Ford sedan, they’re just one of a million, and they’re everywhere. Eosinophils and neutrophils are two types of immune cells, and, particularly eosinophils, they’re common in allergic reactions. 'Inflammatory mediators' is just a fancy way of saying ‘proteins that fit into immune cell’s receptors’.

How the hell did they prove that?
I had to find out what colitis is here. Turns out, it’s an inflammatory bowel disorder and something I’m kinda glad I’ve not had much experience with. Scientists induced this in normal, bacteria-filled mice, and the same breed of mice that were entirely germ free (and man, that must have been fun to maintain). Then, by measuring a series of symptoms, including rectal bleeding(!), they showed that the germ-free mice were much, much sicker.
This doesn’t necessarily prove that it was the gut flora. In order to do that, they had to give these germ free mice the very same germs that their healthier counterparts had. Which means they were fed shit from the germy mice. For anybody dry-retching, they delivered the shit by taking a small tube and inserting it into the corner of their mouth. The mice swallow it, and that’s when you deliver the substance, bypassing their breathing tube and, most importantly in this case, their tastebuds. Regardless of the ick-factor, the germ free mice vastly improved.
The scientists already knew that bacteria could make certain short chain fatty acids. So they chose one, acetone, and gave it to a new batch of germ-free, colitis-y mice. And yay, they also improved!
At this point, the scientists felt pretty confident in saying that a) germs produced short chain fatty acids which b) improved the symptoms of colitis. But that’s not quite enough (well, not to get you in Nature, the Boffin’s Bible, anyway). They needed to know HOW.
Again, calling on the work of other scientists, they learnt that acetate was found to work on GPR43. When they looked a little closer at this receptor, they discovered that it liked to hang around with a lot of other innate immunity receptors. Well, the cool ones, at least. So they found themselves some mice that had no GPR43 and got busy.
First, they took a good look at the mouse’s immune system, and found it to be pretty normal. They worked out that GPR43 only really worked on short chain fatty acids. They did the colitis thing again, and, sure enough, the GPR43 deficient mice got much sicker than their normal counterparts. They did some stuff with bone marrow to prove it was all due to the immune cells.
Then they got bored with colitis (or their poor research assistant/student refused to look for any more bum bleeding) and moved onto the hardcore auto immune diseases – arthritis and asthma. And lo! The GPR43 deficient mice were royally screwed here, too.

So, following the logic path here – bacteria turn fibre into short chain fatty acids. Short chain fatty acids activate GPR43. GPR43 is mostly found on cells that cause allergic reactions. Specially bred mice that don’t have GPR43 get more sick from immune-related diseases. Mice that don’t have germs get more sick. Germ-free mice that get short chain fatty acids don’t get as sick. Hence, short chain fatty acids, bacteria and GPR43 work together to keep an out-of-control immune system on a leash.

Why is this important?

Trying to figure out anything involving the immune system is like trying to untangle your Christmas tree lights in the presence of fifteen hype-up kittens. Figuring out why modern western society has such a high rate of allergies and asthma has been a pretty big knot. As the scientists behind this study have suggested, this may be an explanation, especially when you consider our over-reliance on antibiotics and antiseptics, and the decrease in fibre that comes with all those processed foods. Basically, this study has loosened that knot, enough to see where a few of the cords are going. In order to have untied it completely, they’d have had to worked out how to use this information to reverse the existing conditions, which is a possibility now.

Despite my suggested alternative for a title, this doesn’t mean you should eat healthy people’s shit. No need to go that far. A bit of extra cereal will be fine.


  1. okay, there's a lot of words up there that even this 2nd cup of coffee can't help me with (although, this 2nd cup of coffee has a LOT to do with said words, it's all very circle-of-life).
    but my point is this: my roomie's HIV regimen causes him to have the scours sometimes, and i'm always like, eat more soluable fiber, dumbass, apples, oatmeal and nuts.
    why am i the only healthy colon around here?
    and why do i love you for giving me an early morning soapbox to share about it?
    and speaking of soapy boxes, 2 more sips of this joe and i'll need a damn shower.

    grossest blogging Ev-Er!

  2. Excellent! While the some of the scientific terminology left me doing a "huh?" you broke that down very well. I find the inter-connected relationships of the human body quite interesting and am hoping to avoid bleeding out of my ass at all costs. Hear that gp?

    Oh, I also learned I don't have to eat poo anymore.