Tuesday, April 22, 2014

Microbiomes and complexity

Obesity -- the more we know, the less we seem to know -- or, at least, the more complicated it gets.  But, have heart!  Because this is turning out to be true of much of biology.  The more we learn about cellular mechanisms, how genes work, gene networks, the effects of medications, the relationship between diet and disease, the effects of environmental exposures on risk, and so much else, the better we understand that reductionist science is not necessarily the best way to explain cause and effect.  Why are some people obese and some aren't, why can't a single genetic variant often explain much, why do some people benefit from a given medication and some not, can we predict who will get which disease, and so forth?  It's complicated. But absorbing that message can be the first step towards better understanding.

piece in the April 17 Science, "Microbiome: A Complicated Relationship Status" by Sarah Deweerdt. elucidates this well. "Nothing is simple about the links between the bacteria living in our guts and obesity," Deweerdt writes.  Studies comparing the gut microbiome of obese people with that of thin people have shown marked differences between them.  Indeed, researchers have shown that "...microbial genes sort the lean from the obese with 90% accuracy, whereas looking at human genes yields the right answer only 58% of the time."

Of course, this isn't predictive, it's the microbiota of individuals who are already obese.  Whether obesity is caused by obesity-related gut flora or gut flora are a by-product of obesity isn't yet known, though a number of experiments with mice, including this one ("The gut microbiota as an environmental factor that regulates fat storage", Bäckhed et al., PNAS, 2004), suggest that gut flora might in fact be causal.  A 2014 study of the effects of pre- and probiotics on lipid metabolism and weight suggests the same, as do a number of others in the intervening decade. Of course, even if that's the case, genomic and microbial and other environmental factors interact: none is 'the' cause by itself.

To test the causal relationship, Bäckhed et al. transferred the microbiota of obese mice to the guts of germ-free mice (born by Caesarian section into sterile environments).  Despite eating less than before the transfer, and expending more energy than the germ-free controls, the recipient mice showed a 60% weight gain by two weeks after receiving the microbiota from the obese donors.  However, they never actually became obese themselves.  And we wonder if this is specific to the strain of mice they used: how would results compare if tested comparably on many other laboratory strains?

Bäckhed et al. report direct evidence of metabolic responses to the presence of the new gut flora, including increased hepatic production of triglycerides and increased monosaccharide uptake from the gut, and "increased transactivation of lipogenic enzymes... The liver has at least two ways of responding to this augmented delivery of calories: increasing inefficient metabolism (futile cycles) and exporting these calories in the form of fat for deposition in peripheral tissues."

That is, Bäckhed et al. suggest, resident gut microbes help us efficiently store calories, but in the calorie-rich environment that western grocery stores and other food provisioners create, over-efficiency can lead to obesity.  

The "thrifty genotype" becomes the "thrifty microbiome"
It should not be ignored that this is the same argument that Jim Neel used in 1962 to explain the evolution of genetic predisposition to diabetes ("Diabetes Mellitus: A 'Thrifty' Genotype Rendered Detrimental by 'Progress'").  His idea was that genes and pathways for storing energy in pre-modern times to take people through times of famine become disease risks in our time of plenty.  But this paper has been cited, and 'thrifty' rhetoric used without much restraint, even after Neel basically acknowledged that the idea was oversimplified and didn't apply to the major adult-onset diabetes epidemic.  It's highly likely that the thrifty microbiome idea will prove to be overly simplified as well.  

The microbiome is a hot item these days.  Though, unlike 'the' human genome, no one has ever suggested that there is 'a' single microbiome, which means that the recognition of complexity has been there from the start, as it should have been in the genome project.  Nonetheless, we have to be careful not to bestow too much credit for depth of insight on  the microbiome bandwagon:  reductionist explanations for what the microbiome can explain are tempting, perhaps especially by the media.  So, it's nice to see Deweerdt giving attention to its complexity.  

Indeed, Deweerdt cites researchers who believe that microbiota can only be considered to be part of a causal chain with respect to obesity.  What we eat influences the bacteria in our gut, and that in turn may influence our weight.  Germ-free mice, for example, didn't gain weight on a sugar-laden diet, suggesting that if sugar is obeseogenic, it's the bacteria in the gut that make calories available from the carbohydrates that we can't.  And gut bacteria can digest other components of what we eat that we ourselves can't, again increasing the number of calories we metabolize from certain foods.  

As far as we know, no one is claiming that if the thrifty microbiome idea is valid, it will be the whole story behind obesity, even in a single individual.  To date, to be sure, the mouse results aren't being replicated in humans, and fecal transplants aren't causing weight loss.  But even if to some extent gut flora are involved in regulating weight gain or loss, some forms of obesity really will turn out to have a fairly simple genetic explanation, even if that will vary between people, and some really will be due to energy imbalance (more energy consumed than expended).  And, there will be other explanations as well, perhaps even including a role for inflammation which is turning out to be involved in many diseases and disorders, as well as a combination of all of the above, even in single individuals.  

And the possible involvement of microbes only pushes the question back a step.  E.g., where do these obesity microbes come from, and are some people more susceptible than others?   

The more we learn, the more complicated it gets.  

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