Role of the gut microbiota in host appetite control: bacterial growth to animal feeding behaviour

Journal name:
Nature Reviews Endocrinology
Volume:
13,
Pages:
11–25
Year published:
DOI:
doi:10.1038/nrendo.2016.150
Published online
Corrected online

Abstract

The life of all animals is dominated by alternating feelings of hunger and satiety — the main involuntary motivations for feeding-related behaviour. Gut bacteria depend fully on their host for providing the nutrients necessary for their growth. The intrinsic ability of bacteria to regulate their growth and to maintain their population within the gut suggests that gut bacteria can interfere with molecular pathways controlling energy balance in the host. The current model of appetite control is based mainly on gut–brain signalling and the animal's own needs to maintain energy homeostasis; an alternative model might also involve bacteria–host communications. Several bacterial components and metabolites have been shown to stimulate intestinal satiety pathways; at the same time, their production depends on bacterial growth cycles. This short-term bacterial growth-linked modulation of intestinal satiety can be coupled with long-term regulation of appetite, controlled by the neuropeptidergic circuitry in the hypothalamus. Indeed, several bacterial products are detected in the systemic circulation, which might act directly on hypothalamic neurons. This Review analyses the data relevant to possible involvement of the gut bacteria in the regulation of host appetite and proposes an integrative homeostatic model of appetite control that includes energy needs of both the host and its gut bacteria.

At a glance

Figures

  1. Host factors influencing gut bacterial growth.
    Figure 1: Host factors influencing gut bacterial growth.

    a | Typical growth dynamics of a large versus small bacterial population illustrate the different durations of the exponential growth phase (Exp). b | Key host-related factors influencing the balance between stimulation and inhibition of the bacterial cell number in the gut. The role of the immune system is not shown, but it contributes by stabilizing the autochthonic community and neutralizing pathogenic invaders. c | Presence of chemical and digestive factors and the transit time along the gastrointestinal tract might underlie the increasing rostro–caudal gradient of bacterial content225. In the upper gut, the transit time is, apparently, shorter than the time necessary for the bacterial population to reach the stationary growth phase (Stat), as calculated using the formula: t (min) = G (generation time, 20 min, assumed based on in vitro experiments and in vivo infusions) × 3.3 log (minimal bacterial number in the Stat phase, that is, 109) / bacterial number before multiplication (for example, 103 in the duodenum). Figure 1a modified from Cell Metab. 23 (2), Breton, J. et al. Gut commensal E. coli proteins activate host satiety pathways following nutrient-induced bacterial growth. 324334 © (2016), with permission from Elsevier.

  2. Distribution of food-derived energy between the host and gut bacteria.
    Figure 2: Distribution of food-derived energy between the host and gut bacteria.

    Energy derived from ingested nutrients is directly and indirectly available to both gut bacteria and the host. Gut bacteria use this energy for bacterial multiplication, which results in population maintenance. In turn, bacteria generate energy as a part of bacterial catabolism and nutrient processing, which releases energy that is available to the host. The host, therefore, receives energy derived both directly from nutrient digestion and indirectly from gut bacteria to meet its metabolic needs. Part of the energy generated by both gut bacteria and the host is dissipated as heat and waste. Alternatively, during starvation, gut bacteria receive energy only from host energy stores.

  3. Satiety, bacterial growth and satiety hormone release.
    Figure 3: Satiety, bacterial growth and satiety hormone release.

    Meal-induced changes in satiety perception in humans (part a) temporally overlap with both nutrient-induced bacterial growth dynamics in vitro and in viscera in rats (part b), and with meal-induced plasmatic changes in intestinal satiety hormone release in humans (parts c and d). Release of glucagon-like peptide 1 (GLP1; part c) is associated with the exponential growth phase (Exp) and release of peptide tyrosine tyrosine (PYY; part d) with the stationary growth phase (Stat). Figure 3a modified with permission from The American Physiological Society © Labouré, H. et al. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R1501R1511 (2002). Figure 3b modified from Cell Metab. 23 (2), Breton, J. et al. Gut commensal E. coli proteins activate host satiety pathways following nutrient-induced bacterial growth. 324334 © (2016), with permission from Elsevier. Figure 3c and d modified with permission from The American Physiological Society © Gerspach, A. C. et al. Am. J. Physiol. Endocrinol. Metab. 301, E317E325 (2011).

  4. Bacterial growth dynamic-based model of appetite control.
    Figure 4: Bacterial growth dynamic-based model of appetite control.

    Hypothetical model linking bacterial growth phases with host-feeding cycles. During regular feeding schedules, the meal-induced exponential growth phase (Exp) of bacterial populations in the large intestine should be terminated after 20 min, a time usually associated with feeling full and with activation of satiety pathways. When the bacterial population size declines postprandially due to the natural lysis and elimination of bacteria, the feeling of satiety also declines resulting in a renewed feeling of hunger and the onset of the next meal. The inter-meal interval in regularly and spontaneously-fed healthy humans lasts ~5–6 h226. This time corresponds with the duration of the bacterial stationary phase (Stat) and the beginning of the decline phase accelerated by in viscera conditions. A new meal will reset the cycle of bacterial growth resulting in long-term maintenance of the gut bacterial population.

  5. Gut bacteria-derived chemical signals that might activate intestinal satiety pathways.
    Figure 5: Gut bacteria-derived chemical signals that might activate intestinal satiety pathways.

    During their life in the gut, bacteria metabolize non-digestible fibre and digestible nutrients and produce several energy substrates such as ATP, lactate and butyrate. Upon bacterial lysis, bioactive molecules such as lipopolysaccharide (LPS) and proteins are released that continue their enzymatic activities synthesizing bioactive metabolites, such as 5-hydroxytryptamine (5HT), or acting directly as mimetics of peptide hormones, such as caseinolytic peptidase B protein homologue (ClpB). All the bacteria-derived chemical signals, along with nutrients, have direct contact with the gut epithelium that carries chemical sensors. Direct or indirect (via the enterocytes) activation of enteroendocrine cells (EECs) by bacterial signals triggers local and systemic release of peptide tyrosine tyrosine (PYY) and glucagon-like peptide 1 (GLP1), thereby transmitting satiety. Paracrine actions of bacteria-derived molecules on EEC and entrochromaffin cells, producing 5HT, might activate the enteric nervous system regulating intestinal motility and gut barrier permeability, including the access of bacterial signals to the vagal afferents.

  6. Bacteria-host integrative homeostatic model of appetite control.
    Figure 6: Bacteria–host integrative homeostatic model of appetite control.

    Hypothetical model of appetite control that integrates gut bacteria-derived signals into host molecular pathways that control energy homeostasis. According to this model, activation of host intestinal satiety pathways by nutrients is integrated with nutrient-induced dynamics of gut bacterial growth (1). For example, glucagon-like peptide 1 (GLP1) is stimulated during the exponential growth phase (Exp) and functions as an incretin via stimulation of insulin; conversely, peptide tyrosine tyrosine (PYY) is stimulated during the stationary growth phase (Stat), which occurs 20 min after nutrient supply and leads to activation of the anorexigenic circuitry. The contribution of the gut microbiota to long-term control of appetite might involve systemic effects of bacterial components whose plasma levels depend on the composition of the microbiota. For example, caseinolytic peptidase B (protein homologue ClpB), an E. coli-derived antigen-mimetic protein of α-melanocyte stimulating hormone (αMSH), can activate POMC ARC neurons in a similar way to leptin, which suggests that the hypothalamic peptidergic network might integrate both host and gut microbiota energy states (2). Furthermore, while immunoglobulins modulate long-term stability and the functional activity of hunger and satiety hormones, such as ghrelin and αMSH, their plasma levels and affinity are influenced by molecular mimicry of gut bacterial antigens, such as between ClpB and αMSH (3). These natural antibodies might serve as molecular 'bridges' in communication between the gut microbiota and host appetite-controlling pathways as well as for other homeostatic functions. AgRP, agouti-related protein; ARC, arcuate nucleus; BDNF, brain-derived neurotrophic factor; CeA, central nucleus of amygdala; CGRP, calcitonin gene-related peptide; CRH, corticotropin-releasing factor; EEC, enteroendocrine cell; MC4R, melanocortin receptor type 4; NPY, neuropeptide tyrosine; NTS, nucleus of the solitary tract; OT, oxytocin; PBN, parabrachial nucleus; POMC, pro-opiomelanocortin; PVN, paraventricular nucleus; TH, tyrosine hydroxylase; VMN, ventromedial nucleus.

Change history

Corrected online 18 November 2016
In Figure 4 of the above article published online 12 September 2016, hunger signalling to the host was incorrectly labelled as decreased, when it should have been labelled as increased. This has been corrected in the online versions of the article. We apologize for this error.

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  1. Nutrition, Gut & Brain Laboratory, Inserm UMR 1073, University of Rouen Normandy, 22 Boulevard Gambetta, 76183 Rouen, France.

    • Sergueï O. Fetissov

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  • Sergueï O. Fetissov

    Sergueï O. Fetissov, MD, PhD, is currently a Professor of Physiology at Rouen University, France. He graduated from the Military Medical Academy in St Petersburg, Russia, and received his PhD from the Koltzov Institute of Developmental Biology at the Russian Academy of Science in Moscow. He then undertook research training at Pierre & Marie Curie University in Paris, France. He has worked for the past 20 years as a member of several research laboratories specialized in physiology, neuroscience and the regulation of appetite at academic institutions including College de France in Paris, Upstate Medical University in Syracuse, New York, USA, and the Karolinska Institutet in Stockholm, Sweden. Since 2004, he has been project leader at an Inserm “Nutrition, Gut & Brain” research unit in Rouen University, where he has developed an original line of research based on the link between gut bacteria and regulation of appetite by the brain in physiologic and pathologic conditions. This work involves bacterial mimetic proteins of peptide hormones and their crossreactive immunoglobulins.

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