Now wash your hands!

 

You must have spent the last 20 years on a distant planet if you’re unaware that we’re heading for Antibiotic Armaggedon — the rise of “Superbugs”, i.e., bacteria resistant to once-successful medication. Microbes resistant to multiple antimicrobials are called multidrug resistant. It’s a desperate matter because it means trivial infections may become fatal and currently safe surgical procedures may become dangerous.

Time-line of the discovery of different antibiotic classes in clinical use. The key point is that the last antibiotic class to become a successful treatment was discovered in 1987.

What’s the problem?
It’s 30 years since we came up a new class of antibiotics. The golden age launched by Fleming’s celebrated discovery of penicillin is long gone and while the discovery curve has drifted ever downwards since 1960 the bugs have been busy.

Just how busy a bug can be was shown by a large-scale experiment carried out by Roy Kishony and friends. They built a “Mega-Plate” — a Petri Dish 2 ft by 4 ft filled with a jelly for the bacteria to grow in. The bugs were seeded into channels at either end so they would grow towards the middle. The only thing stopping them was four channels dosed with antibiotic at increasing concentrations — 10 times more in each successive channel.

The bugs grow until they hit a wall of antibiotic. There they pause for a think — and, after a bit, an intrepid little group start to make their way into the higher dose of drug. Gradually the number of groups expand until a tidal wave sweeps over that barrier. This is repeated at each new ‘wall’ — four times until the whole tray is a bug fest.

When they pause at each new ‘wall’ they’re not ‘thinking’ of course. They’re just picking up random mutations in their DNA until they are able to advance into the high drug environment. So this experiment is a fantastic visual display of bugs becoming drug-resistant. And it’s terrifying because it takes about 11 days for them to overcome four levels of drug. It’s even more scary in the speeded-up movie as that lasts less than two minutes.

Sound familiar?
It should do as this is a cancer column and readers will know that cancers arise by picking up mutations. To highlight the similarities the picture below is the left-hand half of the bug tray with new colonies shown as linked dots. You could perfectly well think of these as early stage cancer cells acquiring mutations in ‘driver’ genes that push them towards tumour formation.

So that’s pretty scary too and the only good news is that animal cells reproduce much more slowly than bacteria. The fastest they can manage is about 48 hours to grow and divide into two new cells and for many it’s much slower than that. Bugs, on the other hand, can do it in 20 minutes if you feed them enough of the right stuff.

Which is why we don’t all get zonked by cancer at an early age.

The evolution of bacteria on a “Mega-Plate” Petri Dish. The vertical red lines mark the boundaries of increasing antibiotic concentrations. You could equally think of each dot that represents a new bacterial colony being early stage cancer cells acquiring mutations in ‘driver’ genes (white arrows) that push them towards tumour formation. From Roy Kishony’s Laboratory at Harvard Medical School.

Enough of that!
But for once I don’t want to talk about cancer but about a really fascinating piece of work that caught my eye in the journal Cell Reports. It’s by Gianni Panagiotou, Kang Kang and colleagues from The University of Hong Kong and The Hans Knöll Institute, Jena, Germany and it’s all about their travels on the Hong Kong MTR (Mass Transit Railway). This is the network of over 200 km of railway lines with 159 stations that serves the urbanised areas of Hong Kong IslandKowloon, and the New Territories and has a cross- border connection to the neighboring city of Shenzhen in mainland China.

An MTR train on the Tung Chung line that links Lantau Island with Hong Kong Island.

Being scientists of course they weren’t just having a day out. They wanted to know the contents of the microbiome that they and their fellow travellers picked up on the palms of their hands when riding the rails. ‘Microbiome’ means all of the collection of microorganisms — though in practice this is almost entirely bacteria. So they swabbed the palms of volunteers and then threw the full power of modern DNA sequencing and genetic analysis at what they’d scraped off. Or, as they put it: “We conducted a metagenomic study of the Hong Kong MTR system.”

And if you’re thinking it might be possible to take a trip on the Hong Kong Metro without grabbing a handrail or otherwise engaging in what on the London Underground used to be called ‘strap-hanging’ you clearly haven’t tried it!

Hong Kong MTR.

 

The MTR System and Sampling Procedure. Left: The eight urban lines studied: the Airport Express line and Disneyland Resort branch were excluded. The Central-Hong Kong station and the cross-border rail stations connecting with the MTR and the Shenzhen metro system are labeled. Right: The sampling procedure included handwashing, handrail touching for 30 min and swabbing. From Kang et al. 2018.

Hold very tight please! 

It’s going to become a seriously bumpy ride. The major findings were:

  1. Four groups (phyla) of bacteria dominated: Actinobacteria [51%], Proteobacteria [27%], Firmicutes [11%] and Bacteroidetes [2%]. Followers of this blog will be delighted to spot the last two (B & F) as we’ve met them several times before (in Hitchhiker Or Driver?, Fast Food Fix Focuses on Fibre, Our Inner Self, The Best Laid Plans In Mice and Men, and, of course, in it’s a small world) — that’s how important they are in the context of cancer.
  2. The dominant organism (29% of the community) was P. acnes (one of the Actinobacteria — it’s the bug linked to the skin condition of acne).
  3. Some non-human-associated species (e.g., soil organisms) also popped up that varied enormously in amount from day to day — perhaps because of weather conditions (e.g., humidity).
  4. Variation in the make-up of the microbial communities picked up depended, more than anything else, on the time of day. There was a marked decrease in diversity in afternoon samples compared with those taken in the morning.
  5. Specific species of bacteria associated with individual metro lines. That is, sets of bug types are relatively abundant on a given line compared with all other lines, giving a kind of line-specific signature — though the distinction declines from morning to afternoon. The most physically isolated line, MOS (Ma On Shan), had a greater number of signature species. The MOS runs entirely above ground alongside the Shing Mun Channel, a polluted brackish river, and its ‘signature’ includes bacteria found in sewage.
  6. All of which brings us to bugs with antibiotic resistance genes (ARGs). Across the network 136 ARG families were detected including 24 that are clinically important. Strikingly, lines closer to Shenzhen (ER (East Rail) and MOS) tend to have higher ARG input during the day. Critically, the ER line a.m. signatures become p.m.-enriched in all MTR lines far from Shenzhen — that is, these ARG families spread over the network during the day.

Simplified map of the Hong Kong MTR indicating how antibiotic resistance genes spread during the day from the ER and MOS lines to the entire network. Tetracycline resistance genes: tetA, tetO, tetRRPP and tetMWOS; vancomycin resistance genes: vanC, vanX. From Kang et al. 2018.

These results clearly suggest that the ER line, the only cross-border line linked to mainland China, may be a source of clinically important ARGs, especially against tetracycline, a commonly used antibiotic in China’s swine feedlots. Antibiotics, including tetracycline, can be detected in the soil in the Pearl River Delta area where the cities of Hong Kong and Shenzhen are located.

It should be said that this is by no means the first survey of bugs on rails. Notable ones have looked at the New York and Boston metro systems and they too revealed the potential health risks of the bug communities found on trains and in the stations, including the presence of pathogens and antibiotic resistance. The Boston survey highlighted that different types of materials have surfaces that are preferred by different microbes with high variation in functional capacity and pathogenic potential.

One obvious suggestion from these studies is that world-wide we could do a lot to improve sanitation, e.g., by having hand sanitizer dispensers in all sensible places (at the exits of metro, railway and bike-sharing stations and airports and of course in hospitals). The Hong Kong data are seriously frightening and most people seem blissfully unaware that the invisible world they reveal carries the potential for the destruction of us all.

But, as ever, there’s two sides to the matter. We’ve evolved over millions of years to live with bugs and they with us. However you wash your hands you won’t get rid of every bug and anyway, as what’s-his-name almost says, “They’ll be back!” We all carry around micro-organisms that can be fatal if they get to the wrong place. But, if you’re reasonably fit, there’s a lot to be said for simply following sensible, basic hygiene rules with a philosophy of ‘live and let live.’

Have a nice day commuters, wherever you are!

References

Kang K., et al. (2018). The Environmental Exposures and Inner- and Intercity Traffic Flows of the Metro System May Contribute to the Skin Microbiome and Resistome. Cell Reports 24, 1190–1202.

Wu, N., Qiao, M., Zhang, B., Cheng, W.D., and Zhu, Y.G. (2010). Abundance and diversity of tetracycline resistance genes in soils adjacent to representative swine feedlots in China. Environ. Sci. Technol. 44, 6933–6939.

Li, Y.W., Wu, X.L., Mo, C.H., Tai, Y.P., Huang, X.P., and Xiang, L. (2011). Investigation of sulfonamide, tetracycline, and quinolone antibiotics in vegetable farmland soil in the Pearl River Delta area, southern China. J. Agric. Food Chem. 59, 7268–7276.

Leung, M.H., Wilkins, D., Li, E.K., Kong, F.K., and Lee, P.K. (2014). Indoor-air microbiome in an urban subway network: diversity and dynamics. Appl. Environ. Microbiol. 80, 6760–6770.

Robertson, C.E., Baumgartner, L.K., Harris, J.K., Peterson, K.L., Stevens, M.J., Frank, D.N., and Pace, N.R. (2013). Culture-independent analysis of aerosol microbiology in a metropolitan subway system. Appl. Environ. Microbiol. 79, 3485–3493.

Afshinnekoo, E., Meydan, C., Chowdhury, S., Jaroudi, D., Boyer, C., Bernstein, N., Maritz, J.M., Reeves, D., Gandara, J., Chhangawala, S., et al. (2015). Geospatial Resolution of Human and Bacterial Diversity with City-Scale Metagenomics. Cell Syst 1, 72–87.

Hsu, T., Joice, R., Vallarino, J., Abu-Ali, G., Hartmann, E.M., Shafquat, A., Du- Long, C., Baranowski, C., Gevers, D., Green, J.L., et al. (2016). Urban Transit System Microbial Communities Differ by Surface Type and Interaction with Humans and the Environment. mSystems 1, e00018–e00016.

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Hitchhiker Or Driver?

 

It’s a little while since we talked about what you might call our hidden self — the vast army of bugs that colonises our nooks and crannies, especially our intestines, and that is essential to our survival.

In Our Inner Self we noted that these little guys outnumber the human cells that make up the body by about ten to one. Actually that estimate has recently been revised — downwards you might be relieved to hear — to about 1.3 bacterial cells per human cell but it doesn’t really matter. They are a major part of what’s called the microbiome — a vast army of microorganisms that call our bodies home but on which we also depend for our very survival.

In our personal army there’s something like 700 different species of bacteria, with thirty or forty making up the majority. We upset them at our peril. Artificial sweeteners, widely used as food additives, can change the proportions of types of gut bacteria. Some antibiotics that kill off bacteria can make mice obese — and they probably do the same to us. Obese humans do indeed have reduced numbers of bugs and obesity itself is associated with increased cancer risk.

In it’s a small world we met two major bacterial sub-families, Bacteroidetes and Firmicutes, and noted that their levels appear to affect the development of liver and bowel cancers. Well, the Bs & Fs are still around you’ll be glad to know but in a recent piece of work the limelight has been taken by another bunch of Fs — a sub-group (i.e. related to the Bs & Fs) called Fusobacterium.

It’s been known for a few years that human colon cancers carry enriched levels of these bugs compared to non-cancerous colon tissues — suggesting, though not proving, that Fusobacteria may be pro-tumorigenic. In the latest, pretty amazing, installment Susan Bullman and colleagues from Harvard, Yale and Barcelona have shown that not merely is Fusobacterium part of the microbiome that colonises human colon cancers but that when these growths spread to distant sites (i.e. metastasise) the little Fs tag along for the ride! 

Bacteria in a primary human bowel tumour.  The arrows show tumour cells infected with Fusobacteria (red dots).

Bacteria in a liver metastasis of the same bowel tumour.  Though more difficult to see, the  red dot (arrow) marks the presence of bacteria from the original tumour. From Bullman et al., 2017.

In other words, when metastasis kicks in it’s not just the tumour cells that escape from the primary site but a whole community of host cells and bugs that sets sail on the high seas of the circulatory system.

But doesn’t that suggest that these bugs might be doing something to help the growth and spread of these tumours? And if so might that suggest that … of course it does and Bullman & Co did the experiment. They tried an antibiotic that kills Fusobacteria (metronidazole) to see if it had any effect on F–carrying tumours. Sure enough it reduced the number of bugs and slowed the growth of human tumour cells in mice.

Growth of human tumour cells in mice. The antibiotic metronidazole slows the growth of these tumour by about 30%. From Bullman et al., 2017.

We’re still a long way from a human therapy but it is quite a startling thought that antibiotics might one day find a place in the cancer drug cabinet.

Reference

Bullman, S. et al. (2017). Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science  358, 1443-1448. DOI: 10.1126/science.aal5240

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

Our Inner Self

Richard Gettner is the anti-hero of Christopher Fry’s wonderful play The Dark is Light Enough, set in the Austro-Hungarian war of 1848. Viewing himself as a failed author, failed husband and all-round disaster, he’s just absented himself from the Austrian Army on the basis of not being too nifty at soldiering either. Their minions are hot on his heels, intent on meting out the retribution that the military traditionally reserve for deserters, and he’s taken refuge in the family home of his former wife. In a tête á tête with her she rebukes him for his knack of self-destruction and points out that his book was actually quite well received and wasn’t really a failure. All Gettner’s frustration then bursts forth in a tirade of brutal philosphising:

‘Is there another

Word in the language so unnecessary

As ‘fail’ or ‘failure’?

No one has ever failed to fail in the end;

And for the very evident reason

That we’re made in no fit proportion

To the universal occasion; which, as all

Children, poets and myth-makers know,

Was made to be inhabited

By giants, fiends, and angels of such size

The whole volume of human generations

Could be cupped in their hands;

And very ludicrous it is to see us,

With no more than enough spirit to pray with,

If as much, swarming under gigantic

Stars and spaces.’

Fry deserves to be remembered as one of the great poetic wordsmiths of the English language, if only for The Dark is Light Enough but, had he known that nine out of ten cells in our bodies are bugs, he might have added a final blast to his demolition of the human condition:

Our failings should not surprise as we are but a sinister symbiosis,

More bacterial than human,

Helpfully poised such that when our hour is done

The microbial hordes surge forth to reduce us to our component parts.

bacteria and virus cartoon

The range of the hordes

Our rising preoccupation with the bug army (see it’s a small world & The Best Laid Plans In Mice and Men …) has been promoted by several recent studies that have propelled our ‘inner organism’ from the bowels of biology into the limelight. The story is somewhat fragmented but it’s a good time to see if we can make sense of the current threads.

We’ve known for many years that a motley collection of microorganisms are happy residents in most of our nooks and crannies, ranging from tummy buttons and through the skin, to saliva and our guts. They include bacteria and fungi, they’ve become known as the human microbiome (or microbiota), are said to outnumber human cells 10 to 1 and, all-told, can be viewed as a co-evolved ‘super-organism’ that has many benefits, including making our metabolism more efficient and hence improving nutrition. However, as with everything else in biology, this close relationship is a balancing act, the disturbance of which carries risks for disease development.

It’s critical to note that this vast microbial army, toiling away on our behalf in the dungeon of our innards, mostly dwelling in our gut, is a really mixed lot. It’s estimated to include about 700 different species of bacteria, of which perhaps thirty or forty species make up the bulk. It’s a bit like a mini Great Barrier Reef, well known as the world’s largest coral reef system and extraordinary in that, although it’s made up of billions of tiny organisms, the thing can behave in an integrated way, most dramatically illustrated by mass spawning.

Within the gut there are two major sub-families of microorganisms (Bacteroidetes (Bs) and Firmicutes (Fs)). Although more close-knit genetically speaking, each of these still includes many different classes of microbe. So, they’re a bit of a rabble but, by and large, not only are they harmless, they actually play a vital part in keeping us healthy.

Bacterial army manoeuvres

The power of DNA sequencing means that we can now interrogate our inner armies as to their make up under different conditions, because each type of microbe has a distinctive genome. The first thing to emerge is a dramatic shift in the balance between the major sub-families in obese individuals, be they mice or humans. That is, obese animals have about half the number of Bs and double that of Fs, compared to normal. And the link here is that the bug switch alters the pool of genes available, the upshot being increased energy harvest from nutrients consumed. In other words the switch helps animals get fatter.

It’s possible to breed mice that do not have any gut bugs and ask what happens when you transfer a colony from another animal. Bacteria-free mice on receipt of a normal gut army promptly double body fat: microbiota transferred from obese mice makes ’em twice as fat and, remarkably, human gut microbes from someone who’s obese also makes mice obese, if fed a high-fat rather than a normal diet.

Chemical warfare

Because we use antibiotics on a massive scale to control infections, we might ask whether they cause the good guys to suffer what the military call collateral damage – the point being that antibiotics don’t target bacteria on the basis of whether they’re good for us or potentially fatal. Inevitably, it turns out that ‘good guys’ do get hit by some antibiotics, and when this happens mice gain weight and build up fat. Unsurprisingly, a high-fat diet makes things worse. The sequence is that the drug changes the balance in microbiota before mice become obese and – a real shock – one course of antibiotic treatment imprints these effects on the animal permanently: it acts for life.

To clever for our own good

In our panic to avoid obesity and still pander to our sweet tooth, mankind has taken to using artificial sweeteners on a massive scale in the mistaken belief that these low-calorie agents do no harm. Only recently has this come to light as yet another example of the old adage about there being no such thing as a free lunch. It’s remarkable: saccharin, the most commonly used artificial sweetener, causes big shifts in the proportions of different types of gut bacteria – some increasing whilst others go down – the overall effect again being much more efficient energy harvesting from food. This is a direct effect of saccharin on the bugs, blocked by commonly used antibiotics.

The story so far

The regiments from which our foot soldiers are drawn (i.e. the species that form the microbiota) affect our metabolism and in particular can influence obesity – and that’s inextricably linked with type 2 diabetes and heart disease. With that in mind, it seems obvious that upsetting them with drugs is a risky business. What’s more, seemingly harmless food supplements can also be fraught with danger.

Marching to a beat

Yet another amazing feature of our inner army is that it keeps time. That is, the abundance of different sub-types fluctuates in synchrony with the day/night cycle. Put another way, it marches to a circadian rhythm along with many other physical, mental and behavioral changes that respond mainly to light – and hence roughly follow a 24-hour cycle. These can be big changes in composition: a particular type of bug can double in amount in 6 hours and return to its initial level by 6 hours later. One of the most familiar examples of the importance of biological rhythms comes from upsetting them by flying long distances on an east–west axis. Sure enough, mice have the same problem and, just like us, their clock is disturbed by jet lag (rather than shuttling them business class across the Atlantic you can simulate the effect simply by shifting the light-dark cycle under which they live forwards or backwards by 8 hours every three days). This largely blocks microbiota rhythmicity, the overall effect being to reduce the total number of bacteria. This in turn raises blood sugar level and the mice become obese. These events are absolutely dependent on what has happened to the microbiota because they are replicated in germ-free mice after transfer of jet-lagged faeces.

That’s more astonishing than might appear at first glance because it places the daily variation in gut bug populations alongside the basic circadian rhythms of the sleep-wake cycle, body temperature and other important functions. Circadian rhythms are driven by a ‘master clock’ in the brain that coordinates all the body clocks so that they are in synch. Four proteins are at the heart of the clock (CLOCK and BMAL1, highly expressed during the light phase, and cryptochromes (CRYs) and period proteins (PERs) expressed in the dark phase). These regulate the expression of many genes, thereby controlling the overall response (see Twenty More Winks). The implication is, therefore, that far from being a kind of add-on that occasionally gets upset, our microbiota play central role in a healthy body.

A recent example of it doing just that comes from another mouse model showing our ‘inner organism’ acting to protect against bacteria from the outside world. In response to infection, cells that line the small intestine switch on the production of a particular sugar (fucose): that is then released from the cells and consumed by members of the microbiota – this novel energy source seemingly helping the host to survive the onslaught of infectious microorganisms.

And finally …

All this stuff about germs being our best friends is riveting but what about the important question? Well, there appears to be a complex interaction between diet, microbial metabolism and colorectal cancer, with bacteria able to make some agents that protect against cancer and some others that drive carcinogenesis. There’s evidence that a wide range of tumours can be promoted by transferring microbiota to germ-free mice and, on the other hand, that depleting intestinal bacteria reduces the development of liver and colon cancers.

Space invaders

Personal space is, apparently, a big thing for many of us these days. So big that ‘scientists’ have had a go at measuring it – they never miss an opportunity do they? Actually, boffins being boffins, they measured something called the defensive peripersonal space (DPPS) – a ‘vital safety margin surrounding the body’ – by sticking a pair of electrodes to the wrists of volunteers who held their hands different distances from their faces whilst receiving bursts of current through the electrodes. That made them blink (!) and the nearer the hand to the face the more they blinked, as the shock was perceived to be a greater threat to their face. There is, seemingly, a sharp boundary: up to somewhere between 20 cm and 40 cm is a high-risk area where we get very aerated: beyond that we don’t much care – with large personal variations depending on how twitchy you are. Debrett’s, which styles itself as the arbiter of society etiquette, has a simpler test, its distilled wisdom revealing that if you can feel the warmth of someone’s anxious breath upon your face, then you’re standing too close.

With all this neurosis it’s probably a good job no one mentioned our inner army: a ten-to-one cellular takeover (albeit that bugs are much smaller) is not so much a bit of heavy breathing as a blitzkrieg. Even so, it’s a delicately poised occupation upon which we depend for survival – and it’s one that we disturb at our peril.

References

Sambo, C.F. and Iannetti, G.D. (2013). Better Safe Than Sorry? The Safety Margin Surrounding the Body Is Increased by Anxiety. The Journal of Neuroscience 33, 14225-14230; doi: 10.1523/JNEUROSCI.0706-13.2013.

The Best Laid Plans In Mice and Men …

I never thought I’d find myself indebted to one R. Burns, said to be Scotland’s national poet, but as a title for today’s piece it’s hard to avoid a mild bit of adaptive plagiarism. And after all, if John Steinbeck could do it …

Artificial sweeteners are wonderful things …

The next thing to do is to pass up all pretence at suspense and give the upshot of a remarkable new bit of work first. The story is of artificial sweeteners (non-caloric artificial sweeteners: NAS for short – most commonly saccharin) – among the most widely used food additives worldwide. Introduced over a century ago, they’ve long been considered great as they pander to our sweet teeth yet are low on calories – what can possibly go wrong?

Saccharin  StructureSweet'N Low

Well, according to Jotham Suez and his pals in The Weizmann Institute, Israel, quite a lot, once you get round to looking in the right places. They found that artificial sweeteners, particularly saccharin, make normal folk glucose intolerant (i.e. cause metabolic conditions – including diabetes – in which blood glucose levels are raised, aka hyperglycemia). Moreover, they do so by changing the make up of the bacteria in our gut (our intestinal microbiota – we’ve already met these guys in it’s a small world). The effects of NAS are reversed by antibiotics which, as we described in it’s a small world, can have drastic, permanent effects on our insides.

It’s a real shocker because, put another way, it shows NAS can dirDiet Coke etcectly drive the very outcomes we’re trying to avoid – diabetes and obesity.

How do they do it?

Suez & Co first showed that saccharin increases blood glucose in mice (glucose intolerance). Treatment with commonly used antibiotics (e.g., ciprofloxacin) blocks this effect. Sequencing DNA extracted from faeces revealed big shifts in the proportions of different types bacteria (taxa) – with some increasing whilst others went down. The overall effect is that the intestinal bugs (microbiota) as a whole became much more efficient at energy harvesting from food (e.g., producing more short-chain fatty acids) – an effect known to be associated with obesity in both mice and humans.

Obese miceDirect or indirect?

To show whether saccharin does this by directly acting on gut bugs they grew samples of faeces in the lab with and without added saccharin and – you’ve guessed it – the bug balance changed: Firmicutes down, Bacteroidetes up (from 89 to 79% and 6 to 22%, respectively). Transferring the saccharin-treated microbiota to germ-free (normal) mice made them glucose intolerant.

Lolli the Saccharin by Trinity FateRe-think required

The upshot of all this is that NAS may be doing the very thing we’re trying to avoid. Suez et al. note that the cult of NAS use has coincided with the epidemics of diabetes and obesity – but their results suggest very strongly that, far from being coincidence, it is yet another example of optimism and our hunger for easy solutions diverting our attention from our ignorance of the underlying science.

Grim reaperSo the message is there isn’t a short-cut to dealing with our sugar craving – if we aren’t to go on making ourselves very ill on a big scale we just have to show more self-discipline.

Reference

Suez , J. et al. (2014). Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514, 181-186.

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