The Guardians In Our Gut- Using Bacteria to Sense Disease

You’re sitting there, reading this post, and your skin should be crawling. Well it practically is, along with your nostrils, lungs, gut and any of your mucus-covered surfaces. You’re crawling with bacteria in all of these areas! But don’t panic, these bacteria are our ‘friendly’ bacteria or ‘microbiota’, and scientists have recently created something remarkable within the gastrointestinal microbiota. Prepare to meet the guardians in your gut.

But first, a little background.
The gastrointestinal tract (your stomach and intestines) is the most heavily colonised site of your microbiota and it is normally the first site of pathogenic attack. It’s also a common site of focus during auto-immune diseases which your microbiota can actually help combat (look up IBS or Crohn’s Disease if you fancy). It is dominated by two main genera; the Bacteroidetes and the Firmicutes. Whilst Escherichia coli (E. coli) belong to neither of these groups, they do manage to etch out a living in your guts alongside these two genera.

Contrary to popular belief, E. coli aren’t all that bad; admittedly some strains are dangerous – especially for children and the elderly – but many are what we call ‘commensal’ organisms. This means they live in your gut pretty harmlessly and can even keep the bad guys down (because the saying doesn’t say you can’t keep a bad guy down. Loopholes are the devils’ rollercoaster, people). Now, scientists have recently managed to genetically engineer an E. coli strain to monitor the state of a live mouse’s gut1,2, like a biological carbon monoxide detector. I hear you cry: “But scientists have been able to genetically tweak bacteria for years, so what’s new?”

This is the first time that a biological model has been able to monitor and diagnose health in vivo (within the living body), and most importantly, to survive and find its niche in the harsh conditions of the living gut. The intestines are a pretty nasty place with little to no oxygen, a lack of nutrition, constant jostling for space, as well as the fact that your host is constantly trying to flush you out, to say nothing of the smell. So the obvious solution to this hostility is to take a species already flourishing in the gut, one that is easily manipulated at the genetic level and tweak it to do its job before placing it back into the host. Step forward E. coli.

Arming Our Guardians

The key behind this breakthrough model was the insertion of a two-part system from the lambda phage (a type of virus that specifically attacks bacteria) into the E. coli bacterium. This consisted of the lambda Cro gene under the control of a tetracycline-inducible promoter and a “memory element derived from the cI/Cro region”2 of the lambda phage. So together this system means that, as the modified E. coli sits in the gut of the experimental mouse under normal ‘healthy’ conditions, the bacteria produce and secrete the cl protein which can be detected in the animal’s faeces. But when the mice are fed a diet supplemented with anhydrotetracycline (an antibiotic compound that will activate the tetracycline-inducible promoter) all of the modified E. coli switch to secreting the Cro protein, which again can be detected in the mouse’s faeces. (See the figure below for a diagrammatic representation).

In nature this genetic switch allows the lambda phage to alternate between dormancy and aggressive replication which bursts open its host bacterium, but here it allows the genetically engineered E. coli to fairly rapidly record the antibiotic’s presence in the mouse’s gut. While this situation may not seem very useful or even a bit pointless, think of the many diseases or health-states this system could be applied to diagnose. If the E. coli could be ‘programmed’ to sense the tell-tale molecular signals of colonic cancers, inflammation or attacking microbes, this example of a genetic circuit could remove the uncomfortable or painful diagnostic methods available to us at present. A simple orally administered bacterial dose wouldn’t require any form of surgery or the sticking of a camera in (or up!) any awkward places, which would come as a relief for many patients.

At the minute it’s more like “The Scouts In My Gut” but it’s possible that as we master this technique we could engineer bacteria to even produce antibiotics against invading pathogens, turning those scouts into guardians and removing the need for costly medical appointments. But don’t tell your GP.

The Guardians In My Gut Figure 1

Figure 1: Diagrammatic Representation of the experimental system in the living mouse model.

This is a fascinating step forward in the scientific understanding of our gut microbiota and of our knowledge in genetic manipulation in general, but while the fruits of it may seem a long way off, it’s a step in the right direction.

Ryan

 

References:

1) New Scientist Review Article-
http://www.newscientist.com/article/dn25244-hacked-bacteria-keep-tabs-on-the-health-of-the-gut.html#.U0Q4AvldVvA

2) Original Journal Article-
Kotula JW, Kerns SJ, Shaket LA, Siraj L, Collins JJ, Way JC, & Silver PA (2014). Programmable bacteria detect and record an environmental signal in the mammalian gut. Proceedings of the National Academy of Sciences of the United States of America, 111 (13), 4838-43 PMID: 24639514

Image adapted from-
 BBC News: Analysis: Antibiotic Apocalypse by James Gallagher (Health and Science Reporter, BBC News)
Fallout Wiki: Chinese Assault Rifle page

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