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Thursday, August 21, 2014

The Human Microbiome ~ Myth and mystery

In the 1990’s, antioxidants were the big fashion in food and health. These antioxidants were mainly vitamins (C and E), pre-vitamins (beta-carotene) and plant constituents of various kinds (e.g. coumarin, flavonoids, thymol). Studies showed that rates of cancers across many countries were directly correlated with plasma levels of antioxidants. Laboratory studies showed that the damaging effect of pro-oxidant metals such as copper could be reduced with the addition of antioxidants. Every disease imaginable was included in the antioxidant Klondike. And of course we had the race to the finish culminating in a trial of Chinese smokers (smoking is pro-oxidant) with antioxidant supplements which showed the opposite to what was hoped for - cancer rates were increased! Many other trials were conducted but to date, little evidence exists to support the theory that taking antioxidant supplements reduces any disease risk. Of course that doesn’t bother the health food industry and to some extent the food industry from hyping up the antioxidant myth.  This blogger learned one lesson from the antioxidant saga namely that any nutritional theory that is putatively related to many diseases, is a theory about to be shelved.

In today’s world of food and health, that role is played by the human gut microbiota. The front covers of The Economist, the New York Times magazine, Nature, Scientific American and others have highlighted articles with titles such as “Microbes maketh man” or “Our other genome”. There are wow statistics that journalists love: 100 trillion bacteria in our gut accounting for 1.5 kg of our bodyweight with 100 times more genes than we have (“We” are referred to as “Hosts”!). To journalists, it is an astonishing mystery that bacteria, previously thought to be bad for health were in fact our single most important protection against an array of diseases.  A search of the PubMed database shows the term “Gut microbiome” is associated with the following diseases (number of published papers in brackets): obesity (628), cancer (381), diabetes (350), allergy (260), depression (48) and autism (33). I stopped there but I’m sure I could go further. The point is that the gut microbiota is the new unifying theory of life and death.

A very welcome paper in this week’s Nature bears the title “Microbiome science needs a healthy dose of sceptism”[1]. The author’s first point of criticism is that the techniques used to characterise the microbiota genome often lack direct links to known functions. He points out that his team has shown that vaccination eliminated 30% of known pneumococcal strains in a human population but only because they knew which genes to focus on. In the case of the human microbiota genome, we might know that it differs between say normal weight and obese subjects. But that’s all we know. We cannot tell what part of the microbiota genome is directly linked in a causal manner to obesity.  His second criticism is linked to this in that cause and effect are misinterpreted when looking at gut microbiota. He cites a paper, which shows that changes in the human microbiota correlate with measures of frailty in older persons. So too did dietary patterns. The conclusion was that poor diet altered the gut microbiota and thus led to frailty. The opposite was not considered, namely, that frailty led to poor diets that in turn altered gut microbiome patterns. His third criticism is that most of the studies lack any mechanistic explanation based on experimental investigation. In that respect the field is similar to nutritional epidemiology where correlations dominate and shape policy in the absence of any experimental proof. So if we consider the microbiome-diet-frailty issue, a simple test would be to take a cohort of frail persons and through physiotherapy, counseling and nutritional support reduce their frailty. If a significant improvement in frailty had no effect on the microbiome, we can dismiss that theory. Alternatively, frail persons could receive faecal transplants to modify their microbiota and examine the effect of improved microbiota on frailty. His fourth criticism relates to the quality of the data on the microbiota and health vis-à-vis the real world. He highlights the fact that many of the studies that show the importance of the gut microbiota are conducted in germ-free mice. Such mice live in an aseptic bubble that makes them generally ill and with poor food intake. Finally he asks if there might be a confounding factor such that the real force driving the disease is one thing and the altered microbiota simply an observer, equally effected by the true driver.

In his paper, Professor Hanage who works in Harvard, cites a blog by Professor Jonathan Eisen of the University of California at Davis in which he makes an award for “Overselling the microbiome”[2]. He shows how research results are manipulated by university press offices and swallowed easily by journalists. Two collaborating Swedish university research groups published a paper in Nature Communications[3] and they wrote thus:

“Our finding of enriched levels of phytoene dehydrogenase in the metagenomes of healthy controls and its association with elevated levels of β-carotene in the serum may indicate that the possible production of this anti-oxidant by the gut microbiota may have a positive health benefit”.

In the press release[4] we read the following:
“Our results indicate that long-term exposure to carotenoids, through production by the bacteria in the digestive system, has important health benefits. These results should make it possible to develop new probiotics. We think that the bacterial species in the probiotics would establish themselves as a permanent culture in the gut and have a long-term effect”. “By examining the patient's bacterial microbiota, we should also be able to develop risk prognoses for cardiovascular disease", says Fredrik Bäckhed, Professor of Molecular Medicine at Gothenburg University. "It should be possible to provide completely new disease-prevention options".

The present fashion of the microbiota has a powerful scientific dimension but it is over-hyped and under-studied at the human experimental level. Whist many good human experiments are done to study the human microbiota, most are poorly constructed, observational and in rodents, normal or germ free.

[1] Hanage WP (2014) Nature 512, 247
[3] Karisson FK et al (2012) Nature Communications 3, Article 1245

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