Secret Army: More Manoeuvres Revealed

 

I don’t know about you but I find it difficult to grasp the idea that there are more bugs in my body than there are ‘me’ cells. That is, microorganisms (mostly bacteria) outnumber the aggregate of liver, skin and what-have-you cells. They’re attracted, of course, to the warm, damp surfaces of the cavities in our bodies that are covered by a sticky, mucous membrane, e.g., the mouth, nose and especially the intestines (the gastrointestinal tract).

The story so far

Over the last few years it’s become clear that these co-residents — collectively called the microbiota — are not just free-loaders. They’re critical to our well-being in helping to fight infection by other microrganisms (as we noted in Our Inner Self), they influence our immune system and in the gut they extract the last scraps of nutrients from our diet. So maybe it makes them easier to live with if we keep in mind that we need them every bit as much as they depend on us.

We now know that there are about 2000 different species of bacteria in the human gut (yes, that really is 2,000 different types of bug) and, with all that diversity, it’s not surprising that the total number of genes they carry far exceeds our own complement (by several million to about 20,000). In it’s a small world we noted that obesity causes a switch in the proportions of two major sub-families of bacteria, resulting in a decrease in the number of bug genes. The flip side is that a more diverse bug population (microbiome) is associated with a healthy status. What’s more, shifts of this sort in the microbiota balance can influence cancer development. Even more remarkably, we saw in Hitchhiker Or Driver? That the microbiome may also play a role in the spread of tumours to secondary sites (metastasis).

Time for a deep breath

If all this is going on in the intestines you might well ask “What about the lungs?” — because, and if you didn’t know you might guess, their job of extracting oxygen from the air we inhale means that they are covered with the largest surface area of mucosal tissue in the body. They are literally an open invitation to passing microorganisms — as we all know from the ease with which we pick up infections.

In view of what we know about gut bugs a rather obvious question is “Could the bug community play a role in lung cancer?” It’s a particularly pressing question because not only is lung cancer the major global cause of cancer death but 70% lung cancer patients have bacterial infections and these markedly influence tumour development and patient survival. Tyler Jacks, Chengcheng Jin and colleagues at the Massachusetts Institute of Technology approached this using a mouse model for lung cancer (in which two mutated genes, Kras and P53 drive tumour formation).

In short they found that germ-free mice (or mice treated with antibiotics) were significantly protected from lung cancer in this model system.

How bacteria can drive lung cancer in mice. Left: scheme of a lung with low levels of bacteria and normal levels of immune system cells. Right: increased levels of bacteria accelerate tumour growth by stimulating the release of chemicals from blood cells that in turn activate cells of the immune system to release other effector molecules that promote tumour growth. The mice were genetically altered to promote lung tumour growth (by mutation of the Kras and P53 genes). In more detail the steps are that the bacteria cause macrophages to release interleukins (IL-1 & IL-23) that stick to a sub-set of T cells (γδ T cells): these in turn release factors that drive tumour cell proliferation, including IL-22. From Jin et al. 2019.

As lung tumours grow in this mouse model the total bacterial load increases. This abnormal regulation of the local bug community stimulates white blood cells (T cells present in the lung) to make and release small proteins (cytokines, in particular interleukin 17) that signal to neutrophils and tumour cells to promote growth.

This new finding reveals that cross-talk between the local microbiota and the immune system can drive lung tumour development. The extent of lung tumour growth correlated with the levels of bacteria in the airway but not with those in the intestinal tract — so this is an effect specific to the lung bugs.

Indeed, rather than the players prominent in the intestines (Bs & Fs) that we met in Hitchhiker Or Driver?, the most common members of the lung microbiome are Staphylococcus, Streptococcus and Lactobacillus.

In a final twist Jin & Co. took bacteria from late-stage tumours and inoculated them into the lungs of mice with early tumours that then grew faster.

These experiments have revealed a hitherto unknown role for bacteria in cancer and, of course, the molecular signals identified join the ever-expanding list of potential targets for drug intervention.

References

Jin, C. et al. (2019). Commensal Microbiota Promote Lung Cancer Development via γδ T Cells. Cell 176, 998-1013.e16.

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Fast Food Fix Focuses on Fibre

If you’re like me you’re probably more bored than absorbed by the seemingly continuous stream of ‘studies’ telling us what we should and shouldn’t eat. No one’s going to argue it’s unimportant but gee, I wish they’d make their minds up. Of course the study of diet and its effects is tricky – as we noted in Betrayed by Nature – not least because you generally need enormous numbers of people to tease out significant effects.

Fortunately authoritative sources like The American Heart Association offer generally sane and simple advice: “eat a balanced diet and do enough exercise to match the number of calories you take in.”

A balanced diet includes fibre, sometimes called roughage, the stuff we eat but can’t digest that assists in taking up water and generally keeping our insides working. There’s much evidence that eating plenty of fibre helps to prevent bowel cancer – usually accumulated from vast numbers (e.g., the European Prospective Investigation into Cancer and Nutrition study involved over half a million people from ten European countries). But even for fibre, when you might just be thinking the answer’s clear-cut, there are other studies showing no protective effect.

So hooray for Stephen O’Keefe and friends from the University of Pittsburgh and Imperial College London for coming up with a dead simple experiment – and some pretty astonishing results (though to prevent panic we should reveal at the outset that they confirm that a high fibre diet can substantially reduce the risk of colon cancer).

Doing the obvious

The experiment compared what happened to two groups of 20, one African Americans, the other from rural South Africa, when they swapped diets for two weeks. So, in principle ‘dead simple’ but to describe it thus does a great injustice to the huge amount of effort involved – for a start they had to find two lots of 20 volunteers willing to have a colonoscopy examination before and after the diet swap. The Western diet was, of course, high protein, high fat, low fibre, whereas the typical African diet was high in fibre and low in fat and protein. Just to be clear, the American diet included beef sausage and pancakes for breakfast, burger and chips for lunch, etc. The traditional African diet comprises corn based products, vegetables, fruit and pulses, e.g., corn fritters, spinach and red pepper for breakfast.

B'fast jpegCompare and contrast.

A rural South African diet (corn fritters for breakfast) and the American diet (Getty images)

Shock – and horror

Almost incredibly, within the two weeks of these experiments there were significant, reciprocal changes in both markers for cancer development and in the bug army – the microbiota – inhabiting the digestive tracts of the volunteers. That is, the dreaded colonoscopy revealed polyps (tumour precursors) in nine Americans (that were removed) but none in the Africans. Cells sampled from bowel linings had significantly higher proliferation rates (a biomarker of cancer risk) in African Americans than in Africans. After the diet switch the proliferation rates flipped, decreasing in African Americans whilst the Africans now had rates even higher than in the starting African American group. These changes were paralled by an influx of inflammation-associated cells (lymphocytes and macrophages) in the now high-fat diet Africans whilst these decreased in the Americans on their new, high-fibre diet.

Equally amazing, these reciprocal shifts were also associated with corresponding changes in specific microbes and their metabolites. You may recall meeting our microbiota (in The Best Laid Plans of Mice and Men and It’s a Small World) – the 1000 or so assorted species of bacteria that have made you their home, mostly in your digestive tract, of which there are two major sub-families, Bacteroidetes and Firmicutes (Bs & Fs). We saw that artificial sweeteners in the form of saccharin shifts our bug balance: Fs down, Bs up. Here feeding Americans high-fibre diet was associated with a shift from Bs To Fs. As we noted before, the composition of the bug army is important because of the chemicals (metabolites) they produce – in this case the diet switch resulted in more short chain fatty acids (e.g., butyrate) in the American group and a reciprocal drop therein for the Africans.

The bottom line

It really is quite remarkable that these indicators of cancer risk manifest themselves so rapidly following a change to a typical Western diet. Of course ‘markers’ are one thing, cancer is another. As one of the authors, Jeremy Nicholson of Imperial College London, said: “We can’t definitively tell from these measurements that the change in their diet would have led to more cancer in the African group or less in the American group, but there is good evidence from other studies that the changes we observed are signs of cancer risk.”

Put less scientifically, “a nod’s as good as a wink to a blind horse.”

Reference

O’Keefe, S.J.D. et al. (2015). Fat, fibre and cancer risk in African Americans and rural Africans. Nature Communications 6, Article number: 6342 doi:10.1038/ncomms7342

it’s a small world

Once upon a time I went to Disneyland. My excuse is that it was a long time ago. So long, in fact, that I don’t need to specify where — it was before theme park cloning got going. Goodness knows why I went — given that if I was inclined to sticking pins in things, Mickey Mouse would be a prime target — though, logically, a model of Walt would come first. But one memory of that visit recurs unbidden to this day: the song ‘it’s a small world (after all).’ I know. I shouldn’t blame Disney as it was the Sherman Brothers greatest hit — and what with also writing the scores for Mary Poppins and Chitty Chitty Bang Bang, they’ve got a lot to answer for. Nevertheless and irritating though the jingle may be, it contains a rather profound line:

There’s so much that we share that it’s time we’re aware, It’s a small world after all’.

And that will do very well as our theme for the day.

SmallWorldFront83_wbYour inner self

A sobering thought about being human is that we’re mostly bugs – that’s to say on a cell to cell basis the microbes in our bodies outnumber us by ten to one. Ten to one: time for lunch, to recycle the old Goon Show gag, but first perhaps you should survey your microbiota – the 1000 or so assorted species of bacteria that have made you their home. Most of them (99%) reside in your digestive tract and we don’t notice them, of course, because they’re so much smaller than the cells of our body (they make up less than 3% of our mass). Sometimes called gut flora, they’re important in squeezing the last ounce of energy from what we eat by helping to digest sugars and they also make some vitamins that we need. You could, then, think of this unseen army of tiny cells as an organ in their own right. Unnoticed they may be but you upset them at your peril, as everyone knows who’s taken a course of antibiotics (e.g., penicillin) to get rid of unwanted bugs.

Bugs tummy

This vast force of bacteria, toiling away on our behalf in the dungeon of our innards, includes two major sub-families, Bacteroidetes and Firmicutes. Don’t worry about pronunciation: think of them as B & F. What’s important is that obese animals (including humans) have about half the number of Bs and double that of Fs, compared to normal. That’s a startling shift – the sort of result that gets scientists thinking: something fishy going on here. But what really gets their antennae twitching is the follow-up result. Each bug has its own genetic material (DNA) carrying a set of genes — different for each species. From faecal samples (i.e. stools) the total number of microbial genes can be estimated and — astonishingly — it turns out that there are several hundred times the number of our own genes. We have about 20,000, the bugs muster several million. But the really provocative result is that this total of microbial genes in our gut drops if we become obese:

Fewer genes = more body fat

More genes (a more diverse microbiome) = healthy status.

Cause or effect?

A good question — that can be answered by man’s best friend. Yes, I’m afraid it’s Mickey again. Mice born under aseptic conditions by Caesarean section don’t have any gut microbes — they’re ‘germ-free’ mice — and they grow up with less body fat than normal mice. However, give them the gut army from a normal mouse and they more than double their body fat in a couple of weeks. The microbiota from an obese mouse makes them gain twice as much fat. What happens if you colonise germ-free mice with human gut microbes? If they’re from someone who’s obese the mice also become obese, if fed a high-fat rather than a normal diet.

Because obesity is all about the balance between energy extracted from food and that expended, all this suggests that obesity-associated microbiomes increase the efficiency of extraction.

But if that’s the case maybe there are some slackers in the bug world – types that are pretty hopeless at food processing. Might they offset obesity? Well, at least one (by the name of Akkermansia muciniphila) does just that — again in mice — and its numbers are much reduced in obese people but go up after gastric bypass surgery that reduces the absorption of nutrients from food. This offers the seductive notion that some types of bug might help to reduce obesity.

Debugging

You may have spotted a bit of a cause for concern: if the make up of our gut bugs can affect how our bodies work — and especially whether we put on weight — what happens when we zap ourselves with antibiotics? The problem is, of course, that these drugs target a range of bacteria — they’re not particularly choosy — which is why you get diarrhœa when you take penicillin for a throat infection. And it’s not just you. In the UK we consume 30 million antibiotic prescriptions a year: Americans get through over 250 million and their children get an average of 15 courses of antibiotics in their early years.

The problem here is not about antibiotics being wonderful and saving millions of lives but the possibility that they might have long-term effects. Evidence for this has come from Martin Blaser’s group at New York University who showed that some antibiotics make mice put on weight and build up fat. What’s more, a high-fat diet adds to this effect. Remarkably, changes in the mice microbiota occur before they become obese — and the effects are for life. It seems extraordinary that a short drug pulse, such as we might give a child to cure an ear infection, can have permanent effects. The explanation may be that some gut bacteria are better at surviving the drug treatment resulting in a shift of microbiota balance to give more efficient digestion — i.e. greater energy provision.

It may not be coincidence that the escalation in antibiotic use since the 1940s has paralleled the obesity explosion. In 1989 no USA state had an obesity level above 14%; by 2010 none was below 20% — and the national average is now 30%.

Bugs and cancer: drivers or mirrors?

Those who follow this blog will know that where obesity lurks cancer looms. Indeed transferring microbiota to germ-free mice has been shown to promote a wide range of tumours and, conversely, depleting intestinal bacteria reduces the development of liver and colon cancers. It’s also worth noting that bowel cancer occurs more frequently in the large intestine than in the small — which may reflect the much higher microbial density.

Is it a small world after all?

All these findings suggest that our bug contingent can influence the onset of obesity and various cancers and that even brief drug treatments can have permanent effects on its make up. We have only the vaguest idea how this happens and most of the evidence so far comes from Mickey’s rellos. Even so, maybe in time we will be able to manipulate our personal gut micro-worlds to augment our defences against these potent foes.

Reference

Martin J. Blaser: Missing microbes, Henry Holt & Company 2014

http://www.amazon.com/Missing-Microbes-Overuse-Antibiotics-Fueling/dp/0805098100/ref=sr_1_1_ha?s=books&ie=UTF8&qid=1400478180&sr=1-1&keywords=missing+microbes