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Microbial signals to the brain control weight

Nature volume 534, pages 185187 (09 June 2016) | Download Citation

The bacteria that inhabit the rodent gut promote insulin secretion and food intake by activating the parasympathetic nervous system — a hitherto unknown mode of action for this multifaceted microbiota. See Article p.213

We live in symbiosis with trillions of bacteria that populate our intestines, known collectively as the gut microbiota. These microbes influence many physiological processes in our bodies, from gut and immune maintenance to neurological regulation1. On page 213 of this issue, Perry et al.2 highlight a previously unknown role for the gut microbiota in stimulating insulin secretion by signalling to the brain. Moreover, the authors report that these microbes influence appetite, providing a hint as to how the microbiota might provoke obesity.

Mammals have evolved several responses to energy scarcity. As a result of these adaptations, obesity can arise in conditions of constant food abundance. This response is mediated by the hormone insulin, which is secreted from pancreatic β-cells in response to increased blood-glucose levels. Insulin tightly controls energy balance by enhancing cellular lipid synthesis and glucose uptake, causing calorie storage.

Investigating the effects of a high-fat diet, Perry and colleagues found that production and turnover of the short-chain fatty acid (SCFA) acetate was markedly increased in rats on a high-fat diet compared with animals fed a normal diet. Moreover, infusing the stomachs of rats on a normal diet with acetate for ten days increased glucose-stimulated insulin secretion (GSIS).

Although glucose is the main stimulus for insulin secretion, the process is also under the control of the parasympathetic nervous system3 — the part of the central nervous system that stimulates 'rest-and-digest' and 'feed-and-breed' processes. Parasympathetic activity is largely mediated by the vagus nerve, which sends motor inputs to many organs and is responsible for slowing heart rate, and for regulating gastrointestinal movement and the digestion of food, in addition to enhancing insulin secretion4. Perry et al. demonstrated that the ability of acetate infusion to increase GSIS could be blocked by administering the parasympathetic blocker molecules atropine or methylatropine, or by surgically severing one or more of the branches of the vagus nerve that connects to the gut. These results indicate that an acetate-induced increase in GSIS is controlled by the parasympathetic nervous system.

Further supporting the role of the parasympathetic nervous system in acetate-mediated GSIS, the authors demonstrated that acetate could not stimulate insulin secretion from isolated β-cell-containing pancreatic islets in vitro. This is consistent with some, but not all, previous investigations into a direct effect of acetate on β-cells (for a review, see ref. 5). Acetate administration into either the brain's ventricular system or a vertical column of grey matter embedded in the brainstem — both of which feed into the parasympathetic nervous system — increased GSIS, again highlighting the central-nervous effects of acetate.

Next, Perry et al. investigated the effects of increased acetate turnover on appetite. A chronic increase in acetate turnover promoted a constant drive to eat, known as hyperphagia, probably mediated by the 'hunger hormone' ghrelin — levels of which were elevated in the hyperphagic rats compared with controls. The hyperphagic rats developed obesity, probably owing to a combination of increased secretion of ghrelin and insulin.

Because SCFAs are products of bacterial fermentation, Perry and co-workers investigated the role of the gut microbiota in acetate turnover. The gut microbiota co-develops with the host and modulates whole-body metabolism by affecting energy balance6,7,8,9. The authors transplanted faecal matter from donor rats on a normal or high-fat diet into recipients on the opposing diet, and found that the acetate-turnover rate, faecal acetate levels and GSIS levels from the donor group were transferred to the recipients, implying that it is changes in the microbiota that regulate these factors. Furthermore, conditions of microbiota depletion (seen in germ-free mice, which lack a microbiota, or in rats treated with antibiotics) completely suppressed acetate turnover and decreased ghrelin levels compared to control mice — changes that were associated with two- and fivefold lower skeletal-muscle fat content, respectively.

These data suggest a mechanistic link between the onset of obesity and the gut microbiota. The microbiota-mediated increase in acetate turnover that occurs during exposure to a high-calorie diet might mediate a feedback loop between the gut microbiota and parasympathetic nervous system, promoting hyperphagia owing to increased ghrelin secretion, and increased energy storage as fat owing to increased GSIS (Fig. 1). However, this mechanism does not explain the observation10 that microbiota-depleted mice do not show suppressed food intake. It is also intriguing that supplementation of the diets of rats with two other SCFAs, butyrate and propionate, improves host physiology and glucose metabolism, which in the case of propionate seems to be mediated by vagus-nerve stimulation by the peripheral nervous system11. This might indicate that the site of stimulation — central or peripheral — is relevant for SCFA-mediated effects in the parasympathetic nervous system, and points to the need for further exploration of the general role of SCFAs in regulating obesity.

Figure 1: A mechanism for microbiota-mediated weight gain.
Figure 1

Perry et al.2 report that, in rodents, production of acetate molecules from dietary nutrients by the bacteria that colonize the gut (the microbiota) increases the brain's stimulation of the parasympathetic nervous system, which includes the vagus nerve. Signals from the vagus nerve trigger secretion of the 'hunger hormone' ghrelin from the stomach, leading to increased food intake. The vagus nerve also potentiates glucose-stimulated insulin secretion from β-cells in the pancreas, promoting calorie storage and fat gain. In this way, the gut microbiota influences obesity.

For instance, follow-up work could address whether the effects in the brain are mediated by the SCFA receptor proteins FFA2 and FFA3, and clarify the controversy5 regarding the direct effects of acetate on the β-cells. In addition, transplantation of the microbiota from rodents on a high-fat diet or from humans who are obese to germ-free rodents fed a normal diet could allow researchers to further test for a causal link between specific obesity-associated changes brought on by microbiotic acetate production and the development of metabolic syndrome (which involves obesity, insulin resistance, abnormal lipid levels in the blood and glucose intolerance). Analysis of how the genomes of the microbiota collectively change in rodents on a high-fat diet would allow researchers to identify acetate-producing microbes and to investigate their importance in the progression of diet-induced obesity.

Clinical trials3 have shown that vagus-nerve blockade by electrodes can help to reduce body weight and improve blood-glucose control in people with obesity. Moreover, specific antimicrobials and phage therapies12, as well as faecal or bacterial transfers, have attracted renewed interest in the past few years as potential tools to treat antibiotic-resistant enteritis (inflammation of the intestine) and ulcerative colitis13 (long-term inflammation of the colon and rectum). In the context of the increased global prevalence of obesity, Perry and colleagues' study might inform the development of such strategies for suppressing acetate or acetate-producing microbes as a means to treat obesity and diabetes.

Notes

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  1. Mirko Trajkovski and Claes B. Wollheim are in the Department of Cell Physiology and Metabolism, Centre Médical Universitaire, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.

    • Mirko Trajkovski
    •  & Claes B. Wollheim

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Correspondence to Mirko Trajkovski or Claes B. Wollheim.

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