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Monday, August 5, 2019

Pooh poohing the obesity microbiome theory

Nutrition has fashions and the most attractive fashions are those that promise the most in terms of beneficial effects. An important determinant of durability of a nutrition fashion is the challenges it poses to experimental challenge. At present, the best example of a long living nutrition fashion is the human gut microbiome which represents all of the bacteria we house in our lower gut. Their main evolutionary basis was the extraction of energy from food carbohydrates that are not amenable to digestion by our digestive enzymes. However, in recent times these bacteria have been associated with many diseases. If you get the wrong bacteria in your gut you increase the risk of many diseases such as (non-exhaustive list: depression, anxiety, autism, cancer of the lung and colorectum, pancreatitis, liver disease and many gut disorders such as irritable bowel syndrome, Crohn’s disease and ulcerative colitis. Of particular importance is infection of the gut with Clostridium difficile which can be fatal in up to 30% of cases. Considerable success has been achieved using faecal transplants of such patients with encapsulated bacteria  from a healthy donor.

Another condition which receives considerable attention in relation to the gut microbiome is obesity The gut microflora of obese persons differ from those with a normal weight and when obese persons lose weight their gut microbe population moves in the direction of normal. But the big question is cause and effect. Does an adverse microbiome population cause obesity or does obesity cause an adverse microbiome population? In an attempt to answer that question, a recent study examined the impact of faecal transplantation of people with severe obesity (but who were metabolically healthy, with no sign of type 2 diabetes, fatty liver or the metabolic syndrome) with a capsule containing filtered faecal extract from a healthy normal weight female[1]. Twenty severely obese subjects (BMI 35+,Kg/M2) were randomly assigned to either the treatment arm (encapsulated faecal transplant) or a placebo arm (similar capsules with glycerol and colouring matter). The treatment arm began with a booster level of transplantation which was then followed by a reduced maintenance dose. They were told to eat normally and were closely monitored throughout the 12 week treatment period. Probiotics were not permitted for the study duration and for 4 weeks prior to treatment. Antibiotic treatment was not permitted for 8 weeks prior to the treatment and then throughout the treatment.

The obese patients did not lose weight. So, if the microbiome theory of obesity is correct, why not? The first question : “did the faecal transplant alter the gut microbiome composition’? And the answer is ‘yes, it did’. Faecal samples were taken at several instances during the intervention and the gut microbiome quickly resembled that of the healthy lean donor and that was sustained throughout the study. The gut-microbiome theory also states that the underlying effect is a change in the type of bile acids secreted with less taurocholic acid type bile in faeces. So did the faecal transplant cause a reduction of faecal taurocholic acid? Again, yes it did. And finally, central to the obesity-gut microbiome theory is that the obese type is that the obesity type microbiota alters the production of a gut hormone which plays a role in weight regulation, the hormone glucagon-like peptide (GLP). Did the change with treatment? No it didn’t.

Now, just as one swallow never made a summer, one experiment never copper fastened a scientific theory. But it opens the debate. It challenges the theory and that is what drives scientific enquiry. Flaws can be found in this study and the authors list a few. Maybe it wasn’t long enough for weight loss to occur. Maybe, but I doubt it since weight loss can rapidly respond to treatment. Maybe the faecal transplant dose wasn’t strong enough. Maybe, but I doubt this also, since the dose in use in the study changed the composition of the microbiota.

So I’m left with the view that more studies like this need to be completed to properly address this question. But let me leave you with my final thought. Obesity is a consequence of overeating and the caloric balance theory of obesity is to the microbiome theory what the Mona Lisa is to graffiti. To paraphrase Bill Clinton: It’s the calories, stupid.  

[1] Allegretti J et al (2019) Effects of Fecal Microbiota Transplantation With Oral Capsules in Obese Patients. Clinical Gastroenterology and Hepatology (In press, available online)

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