Diet and gastric neurons

Diet induced obesity (DIO) is an ever increasing health problem. Most obesity in developed countries is due to over-consumption of fat and simple sugars, a diet common in adolescents. In a recent issue of The Journal of Physiology, Baudry et al. (2012) examined the effect of this ‘Western diet’ (WD) on the enteric nervous system (ENS) in the stomach and jejunum of young mice. It made them obese and produced a striking change in the normal maturation of the ENS in the gastric antrum. Consumption of a WD for 3 months in the period corresponding to human adolescence (first 25% of life) prevented the normal loss of antral enteric neurons; it was ‘neuroprotective’.

How the ENS matures and ages is not well understood, although much is known about migration, proliferation and differentiation of enteric neural and glial precursors during embryonic development (for review see Gershon, 2010). Baudry et al. (2012) have made a major contribution by showing that the number of myenteric neurons in the mouse gastric antrum normally declines markedly over the first 4 months of postnatal life, while the number of jejunal neurons remains constant. In contrast, colonic myenteric neurons increase by 40% over the same period (Liu et al. 2009). Thus, the mouse antral and colonic ENS exhibit opposite changes in neural numbers during adolescence. The WD prevented myenteric neuron loss, but did not alter jejunal neuron numbers. This contrasts with the global loss of enteric neurons seen in old age, which is prevented by a low energy diet (Philips & Powley, 2007). Thus, a high energy diet in adolescence is neuroprotective for antral enteric neurons, while energy restriction is neuroprotective in old age.

Baudry et al. (2012) also report data suggesting that the WD alters the neurochemical phenotypes of some enteric neurons. With a normal diet the proportion of antral neurons expressing neuronal nitric oxide synthase (nNOS) remains roughly constant (about 30%) over the 5–17 weeks of age study period. The WD, however, appears to increase the proportion of nNOS neurons in both antrum and jejunum. By contrast, the level of acetylcholine in the antrum was not significantly affected by the WD, despite the markedly larger number of antral neurons. Thus, either cholinergic neurons were not rescued by the WD or some changed phenotype.

Are the neuroprotective effects of the WD due to the diet or the obesity? Similar experiments using a DIO-resistant mouse strain (Little & Feinle-Bisset, 2010) may resolve this issue. Nevertheless, obesity is associated with altered appetite and abnormal responses to ingestion of a fatty meal (for review see Little & Feinle-Bisset, 2010). These changes result in part from reduced fatty acid sensing in the small intestine. Obesity also leads to accelerated gastric emptying, a notable functional effect of the adolescent WD. However, fatty acids in the intestinal lumen activate three physiological signalling pathways: release of hormones,(Little & Feinle-Bisset, 2010); activation of vagal afferents (Little & Feinle-Bisset, 2010); and activation of local enteric neurons (Gwynne & Bornstein, 2007). Furthermore, there are sweet taste receptors in the intestinal mucosa that excite the same physiological signalling pathways (for review see Young, 2011) and these too are regulated by diet and obesity. Thus, the functional effects of the WD will result from several interacting feedback mechanisms, as well as the sparing of antral myenteric neurons and upregulation of nNOS. Indeed, the altered neural activity in the antrum produced by increased activation of fatty acid and sweet receptor activated sensory pathways from the duodenum and jejunum may be partially responsible for the neuroprotective effects of the WD. This would make the effects of a WD on the gastric ENS analogous to the long established neurodevelopmental programming of the visual cortex by sensory patterning during a critical period. However, the components of the WD would also increase hormone release via the same fatty acid and sweet receptors and this may produce the increased gastric leptin levels identified by Baudry et al. (2012) as the probable molecular mechanism by which WD exerts its neuroprotective effects in the antrum.

Baudry et al. (2012) have begun the study of interactions of diet with maturation of the ENS and the functions it regulates. Their results indicate that dietary interventions early in life can have long lasting effects on enteric neural function by altering the number of enteric neurons and potentially by altering the phenotype of neurons within the stomach and elsewhere. In this case, the diet is detrimental to health, but prevents cell death within the antral ENS; is this beneficial or a part of the problem? Neuronal death appears to be part of the physiological maturation of the gastric ENS, unlike elsewhere in the gastrointestinal tract (Gershon, 2010). Prevention of this may actually be dysfunctional; for example, increased gastric emptying will alter feedback to the brain and contribute to the changes in behaviour associated with obesity (Little & Feinle-Bissett, 2010). A key issue is whether adolescence is a critical period after which the changes associated with a WD are irreversible or whether return to a lower energy diet brings neuronal numbers to normal levels? The health consequences of answering this question are potentially profound and the work of Baudry et al. (2012) shows how it can be done.