Brain-gut-microbiome interactions in obesity and food addiction

Abstract

Normal eating behaviour is coordinated by the tightly regulated balance between intestinal and extra-intestinal homeostatic and hedonic mechanisms. By contrast, food addiction is a complex, maladaptive eating behaviour that reflects alterations in brain-gut-microbiome (BGM) interactions and a shift of this balance towards hedonic mechanisms. Each component of the BGM axis has been implicated in the development of food addiction, with both brain to gut and gut to brain signalling playing a role. Early-life influences can prime the infant gut microbiome and brain for food addiction, which might be further reinforced by increased antibiotic usage and dietary patterns throughout adulthood. The ubiquitous availability and marketing of inexpensive, highly palatable and calorie-dense food can further shift this balance towards hedonic eating through both central (disruptions in dopaminergic signalling) and intestinal (vagal afferent function, metabolic endotoxaemia, systemic immune activation, changes to gut microbiome and metabolome) mechanisms. In this Review, we propose a systems biology model of BGM interactions, which incorporates published reports on food addiction, and provides novel insights into treatment targets aimed at each level of the BGM axis.

Figure 1.. Model of brain–gut–microbiome interactions in ingestive behavior.

In the periphery, gut-generated and vagally transmitted orexogenic and anorexogenic signals interact with specific nuclei in the hypothalamus in the homeostatic regulation of food intake. Food-related factors interact with gut microorganisms and gut microbial metabolites modulate the release of orexogenic and anorexogenic peptides from enteroendocrine cells in the distal small intestine, shifting the balance between anorexogenic and orexogenic signaling in the hypothalamus. In addition, gut microorganisms can signal to the brain via inflammatory mediators (such as lipopolysaccharides) and neuroactive metabolites (such as tryptophan metabolites). Centrally, interactions between several brain networks, including the prefrontal cortex, the dopaminergic reward system and the sensorimotor system underlie the hedonic regulation of food intake. Several environmental influences such as food advertisements, food cues engage the extended reward system which can override the homeostatic control mechanisms. Exposure to visual and sensory cues, as well as psychosocial stress play important role in this process. Blue boxes on the left represent different parts of the BGM axis. Light green boxes in the center show mechanisms involved in altered BGM interactions in food addiction. Upward arrows show upregulation, downward arrows show downregulation. Modified with permission from Volkow et al. Biological Psychiatry 2013 EM: DONE

Figure 2.. Model of altered brain network interactions in food addiction.

Several brain networks interact in the regulation of ingestive behavior. In food addiction, increased engagement of the salience network by food cues engages the executive control network leading to increased attention to food, and the emotional arousal network. Insufficient inhibitory control of the reward and of the emotional arousal networks by the executive control network plays a key part in shifting the balance from predominantly homeostatic to hedonic and regulation of food intake. The salience network (aMCC, anterior mid cingulate cortex; aINS, anterior insula) responds according to the subjective salience of any interoceptive or exteroceptive stimulus reaching the brain, or to the expectation of such stimuli, and coordinates appropriate attentional, behavioral, affective and visceral autonomic responses to such stimuli. The executive control network (dlPFC, dorsolateral prefrontal cortex; vlPFC, ventrolateral prefrontal cortex; mPFC, medial prefrontal cortex; OFG, orbitofrontal gyrus) is activated during tasks involving executive functions such as attention, working memory, planning and response selection. Under normal circumstances, it exerts an inhibitory influence on the emotional arousal and the reward networks. The reward network (Nacc, nucleus accumbens; VTA-SN, ventral tegmental area – substantia nigra; CaN, caudate nucleus; Pal, pallidum) is a group of neural structures responsible for motivation, ‘wanting’ desire or craving for a reward. It is under inhibitory control by the executive control network. Its main neurotransmitter is dopamine. The sensorimotor network (Thal, thalamus; Put, putamen; pINS, posterior insula; S1/S2, primary/secondary sensory cortex; M1/M2, primary/secondary motor cortex) receives sensory input from the body, is important for awareness of body sensations and the generation of appropriate motor responses and behaviors. The Emotional arousal network (ACC, anterior cingulate cortex; Hipp, hippocampus; Amyg, amygdala; sgACC, subgenual anterior cingulate cortex) is activated by perceived or real perturbation of the organism’s homeostasis. Bidirectional arrows between brains depict reported bidirectional network interactions. Up and down arrows next to brains illustrate reported up and down regulation of the individual networks

Figure 3.. Mechanisms in the homeostatic and hedonic systems leading to food addiction.

a ∣ Diet-induced disinhibition of vagal and hypothalamic satiety mechanisms. A high fat, low fibre diet reduces the release of satiety hormones (GLP1, PYY, CCK) from enteroendocrine cells (EECs) in the gut by dietary fibre-derived short-chain fatty acids (SCFAs), leads to downregulation of receptors for satiety hormones molecules on vagal afferents innervating the EECs, and to a downregulation of the vagally-mediated satiety signaling to the arcuate nucleus of the hypothalamus (ARC). Hypothalamic receptors mediating the effect of other anorexigenic signals (leptin) reaching the ARC via the systemic circulation are also downregulated, resulting in an unrestrained effect of orexogenic signals (ghrelin, insulin, cortisol). Thus, chronic exposure to a high fat, low fibre diet downregulates the inhibitory mechanisms of homeostatic regulation of ingestive behaviors. b ∣ Diet-induced changes in the extended reward system. According to the dopamine deficiency hypothesis, a reduction of dopaminergic stimulation of neurons in the NAc as a result of reduced dopamine relase from the VTA, and a downregulation of dopamine receptors on NAc neurons, reduces the rewarding effects of ingested foods, and leads to craving and overconsumption of unhealthy food in an attempt to compensate for the reduced dopamine signaling. Chronic stress-induced CRF release and glucocorticoid levels also have an inhibitory effect on dopamine signaling. Up and downward arrows inside boxes illustrate reported up and downregulation of respective mechanisms.

Figure 4.. Interactions between food, gut microbiota and intestinal permeability in the regulation of ingestive behavior.

Left panel: A healthy diet (high in fibre, low in fat and sugar) is associated with a high diversity of the gut microbiota, including an abundance of taxa involved in stimulating mucus production in humans and animal models.^, The combination of an intact mucus layer and tight intestinal epithelium results in an intact gut barrier. Right panel: An unhealthy diet (high in fat, sugar and low in fiber) is associated with a reduced microbial diversity, reduction of mucus stimulating microorganisms, reduction in mucus layer thickness and an increase in epithelial leakiness. This process results in reduced intestinal barrier function (leaky gut) and activation of the gut associated immune system by microbial products such as lipopolysaccharide (LPS). The combination of a leaky gut and an overabundance of inflammatory bacterial products is thought to result in elevated plasma levels of LPS and proinflammatory cytokines. This state of metabolic endotoxaemia has been shown to reduce central satiety mechanisms by influencing enteroendocrine secretion of the satiety hormones PYY, cholecystokinin and serotonin (5-HT), and by reducing the expression of anorexigenic peptide receptors and leptin receptors on vagal afferents and in the hypothalamus, respectively, leading to a disinhibition of satiety mechanisms. Up and downward arrows inside boxes represent reported up and downregulation of mechanisms and of microbiome measures. Modified with permission from Cani & Everard. Mol. Nutr Food Res 60:58-66; 2016 OK, but would replace the last one with reduction of net mucus production

Figure 5.. Circular model of brain gut microbiome interactions in obesity and targets for intervention.

The interaction of genetic and epigenetic factors influences the balance between hedonic and homeostatic control of ingestive behavior, and the risk for the development of hedonic dominance. When exposed to ubiquitous food of high caloric density (fat, sugar) and low in fiber, predisposed individual will overconsume such foods, resulting in changes in the gut and the microbiome as shown in Fig. 3. The resulting change in gut to brain signaling can further compromises homeostatic regulation of food intake and reinforces the disinhibition of the reward system. Targets for intervention and therapeutic modalities include altered ingestive behavior (cognitive behavioral therapy, CBT; time restricted eating; dietary counseling), alterations of gut and microbiome (bariatric endoscopic and surgical treatment; faecal microbota transplantation (FMT); prebiotics and probiotics); altered gut to brain feedback (postbiotics such as butyrate, tryptophan derived compounds, including indoles, and other amino acid metabolites.) and altered reward system (centrally acting medications).