HEALTH


is a high level of fermentation in the gut, which causes gas and is uncomfortable,’ says Gavin Bewick from King’s College London’s Division of Diabetes and Nutritional Sciences in the UK.


The hope is that understanding inulin’s appetite-limiting mechanisms may pave the way to new drug treatments. ‘You basically want to hijack the mechanisms to design drugs that will have fewer side effects so that people are more likely to take them,’ he says. Recent studies suggest that diet,


gut bacteria and fat storage are all linked to a mechanism involving short chain fatty acids (SCFAs), which form when the gut ferments fibrous substances such as inulin. As well as being an energy


source, SCFAs are important signalling molecules between the gut microbiota and the body, locking onto free fatty acid receptors. The two main SCFAs are propionate and butyrate. In 2015, Gary Frost from Imperial


College London, UK, led a study showing that propionate appears to help regulate appetite through a mechanism involving two gut hormones known to reduce satiety peptide YY (PYY) and glucagon like peptide-1 (GLP-1). In vitro studies in the laboratory


revealed that propionate significantly increased the release of PYY and GLP- 1 from human colonic cells. So could increasing levels of propionate in the colon help to prevent weight gain in overweight people? An international team led by both Bewick and Frost recently suggested that fermentable carbohydrates can protect against diet-induced obesity by increasing SCFA production and signalling via a free fatty acid receptor in the colon called FFAR2.6 They have shown that wild type


mice fed a high-fat diet and an inulin supplement put on far less weight than those engineered to lack the FFAR2 receptor. They also used a kind of ‘gut-on-a-chip’ – a 3D cell system – to look for increases in the number of PYY-expressing cells. Their results show that SCFAs acting on FFAR2 increase the density of colonic cells producing PYY. By targeting the pathways with drugs or nutraceuticals, it may therefore be possible to prime the colon to produce a greater signal to reduce


appetite. The researchers suggest


that fermentable carbohydrates ‘remodel’ the gut, increasing the number of cells producing PYY and therefore boosting the chance of the brain receiving ‘full’ signals. Such remodelling works because the gut epithelium has a high rate of turnover, replacing itself every four to five days, in the same way as the skin’s outer layer does, explains Bewick.


‘Understanding the interactions


between dietary constituents and the microbiome, your gut epithelium and physiological outcomes is very important because we know very little about that,’ says Bewick. The team hopes to gain funding


to see if they obtain similar PYY- boosting results in humans. ‘If you can remodel the gut to increase the number of cells, for example, that produce PYY, which reduces food intake in mice, potentially we could do the same in man,’ Bewick suggests. ‘This is quite a new idea,’ Bewick


says. Gut hormones have tended to be used as targets for therapies. In many cases, researchers have tried to develop hormone mimics that bind to receptors. Other studies have focused on preventing endogenous hormones from breaking down. ‘We are trying to increase the number of cells that release the hormone and therefore respond to different nutrients. It’s a pretty new way of thinking about how we might treat diseases with gut hormones.’


Bypass boost The SCFA propionate may also hold the secret to the long-term success of gastric bypass surgery, originally thought to assist weight loss simply by reducing stomach size and


A study has found higher levels of AGEs in obese people showing some features of meta- bolic syndrome. Obese people without the symptoms had lower AGE levels, leading the researchers to suggest that high dietary AGE consumption could cause ‘at-risk’ as opposed to ‘healthy’ obesity.


Germ-free mice inoculated with gut bacteria from mice that had undergone gastric bypass surgery were found to lose weight even without surgery.


causing malabsorption of nutrients. ‘It turns out that neither a smaller stomach nor malabsorption explains why body weight is maintained at a lower level,’ says Schartz. What emerges is a more interesting story involving gut microbes. Bariatric surgery appears to


restructure the gut microbiota. In one oft-quoted 2013 study, a team led by Lee Kaplan from Massachusetts General Hospital in Boston, US, inoculated germ-free mice with gut bacteria from those that had undergone gastric bypass surgery.7 The results were astonishing: mice without gastric bypass lost weight, potentially because of SCFA production. ‘There is a mechanism that


is to do with reorganising the GI [gastrointestinal] tract. And the GI tract is talking to the brain through the so-called gut-brain axis,’ says Schwartz. ‘If you can figure out how that


References 1 M. Schwartz et al, Endocrine Reviews, 2017, 38 (4), 267.


2 C. E. Koch et al, J. Neuroendochrinol, 2014, 26 (2), 58.


3 M. Valdearcos et al, Cell Metabolism, doi: http:// dx.doi.org/10.1016/j. cmet.2017.05.015


4 Y. Gao et al, Molecular Metabolism; doi: http:// dx.doi.org/10.1016/j. molmet.2017.06.008


5 J. Ubarri et al, J. Clin. Endocrinol. Metab., 2015, 100, 1957.


6 L. Brooks et al, Molecular Metabolism, 2017, doi: 10.1016/j.molmet.2016.10.011


7 A. P. Liou et al, Sci Transl Med, doi: 10.1126/ scitranslmed.3005687


works, you might be able to come up with a strategy for weight loss that will do the same thing without requiring the surgery,’ he says. Meanwhile, Aberdeen’s Williams


isn’t necessarily looking for a treatment, but hopes to back up dietary advice with detailed biological mechanisms. ‘If you think about it, the experiment has been done in people. If you have a healthy diet you have a healthy outcome. If you eat junk food you will become obese.’


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