Obesity and plasticity: how your gut learns to deal with your diet

Abstract

Today you may be eating a sugar- and fat-rich diet, but tomorrow you may become a strict vegetarian who's also anti-sugar. These dramatic dietary changes are a challenge to your body. Your intestine needs to continue to harvest nutrients to maintain health, but is using outdated methods to do so. Much of the recent research has been on the important role of gut bacteria (Lupp et al. 2012), and how they respond to diet in a way that may benefit the host. However, new evidence published in The Journal of Physiology (Reichardt et al. 2013) suggests that our gastrointestinal tracts are not as helpless as we may think, but can adapt quickly and efficiently to dietary challenges. A defining feature of the gastrointestinal tract is the enteric nervous system (ENS), a rich and complex network of nerves in its wall that is often called the ‘little brain’ or ‘second brain’. At the turn of the last century, John Langley defined the ENS as the third division of the autonomic nervous system. Since then, many studies have found the ENS to be unlike other peripheral nerves and more closely related to the CNS. It has been difficult to link enteric neuronal behaviour with whole organ behaviour. The nerve circuits in the gut are complex, and the numbers and types of neurons make traditional research methods – like intracellular electrophysiological approaches – difficult, time-consuming and prone to sampling errors. New data from Reichardt et al. (2013) have overcome this problem by using a voltage-sensitive dye to record action potentials from many neurons at once. This has allowed them to quickly gather daa about the electrophysiological properties of a wide range of ENS neuronal phenotypes. That the small intestine responds rapidly to nutrients has been known for some time. When rodent models are fed a high-sugar diet, sugar transporters (SGLT1 and GLUT2) are rapidly up-regulated – an effect which is under the control of intestinal sweet taste receptors. In people with diabetes, faulty regulation can cause a sustained up-regulation of sweet taste receptors and of glucose absorption (Young et al. 2013). Now information is coming to light that the behaviour of enteric neurons is also very sensitive to feeding state. Recently, Baudry et al. (2011) showed that a Western diet, high in fat and simple sugars, had a neuroprotective effect on nitric oxide-producing neurons in mouse gastric antrum, which was coupled with increased gastric emptying. Similarly, Roosen et al. (2012) used calcium imaging to show that enteric neurons from fasted and then fed guinea pigs were more sensitive to serotonin but less sensitive to ghrelin versus a fasted-only group. Reichardt et al. (2013) took this line of research one step further showing that a high-fat diet enriched with simple sugars can change how the ENS processes information – in effect reprogramming the ENS. Using a voltage-sensitive dye technique, they have shown that the neurons of mice fed a Western diet are more sensitive to neurotransmitters that normally mediate enteric fast excitatory postsynaptic potentials than those of mice fed a standard chow. Acetylcholine and serotonin participate in fast synaptic transmission via nicotinic and 5-HT3 receptors, respectively. The authors found a strong correlation between body weight and the numbers of neurons responding to a nicotinic and 5-HT3 receptor agonist, or to the tissue availability of the endogenous neurotransmitters. Previously, changes in neurotransmission have been linked with gut inflammation, but the neuronal changes in this paper occurred without inflammation or increased mucosal permeability. This reprogramming translated directly into faster colonic transit in mice fed the Western diet for 12 weeks but not in those on the diet for 4 weeks, suggesting that the neuronal changes take time to develop. A key follow-up study will be to examine in detail which enteric neurons became sensitised and whether this can be prevented by dietary or lifestyle changes. The gut is equipped to extract all of the nutrients the body needs from a meal. In times of food scarcity this is a real benefit, but in times of plenty this system may extract too many nutrients. Stopping the gut from increasing its absorptive capacity may be a way to reduce excess nutrient absorption (similar to the action of lipase inhibitors). In fact, the ENS is likely to be smart enough to ignore very large nutrient loads altogether, but reprogramming may prove difficult with a lifetime of experience to work against.