Hypothesis: bacteria control host appetites - American Society for

23 Pages·2012·0.45 MB·English

JB Accepts, published online ahead of print on 9 November 2012
J. Bacteriol. doi:10.1128/JB.01384-12
Copyright © 2012, American Society for Microbiology. All Rights Reserved.
1 Hypothesis: bacteria control host appetites
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3 Vic Norris1#, Franck Molina2 and Andrew T. Gewirtz3
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5 1Theoretical Biology Unit, EA3829, Faculty of Science, University of Rouen, Mont Saint
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8 Sysdiag UMR 3145-CNRS/BIO-RAD, Cap Delta 1682 Rue de la Valsiere, 34184 Montpellier
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9 Cedex 4, France m

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11 3Center for Inflammation, Immunity & Infection, Department of Biology, Georgia State jb
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12 University, Atlanta, Georgia 30303, USA m
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15 corresponding author email: [email protected]; telephone: [phone] p
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16 Abstract ,
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18 To help investigate the relationship between inflammatory and other diseases and the
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19 composition of the gut microbiota, we propose that a positive feedback loop exists between s
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20 the preferences of the host for a particular dietary regime, the composition of the gut
21 microbiota that depends on this regime, and the preferences of the host as influenced by the
22 gut microbiota. We cite evidence in support of this hypothesis and make testable predictions.
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24 Introduction
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26 Few people underestimate the danger of bacteria. Shigellosis alone causes 1.1 million deaths a
27 year. Disease caused by certain species of the bacteria in the gut is the leading cause of death
28 in the world. What may be underestimated, however, is the full extent to which they can
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29 affect us. Bacteria both recognize and synthesize neuroendocrine hormones and this has led to
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30 the hypothesis that microbes within the gut comprise a community that forms a microbial n
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31 organ interfacing with the mammalian nervous system that innervates the gastrointestinal d
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32 tract, the enteric nervous system (1). f
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33
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34 The enteric nervous system is embedded in the lining of the gastrointestinal system and
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35 consists of around five hundred million neurons including afferent neurons (which carry nerve .
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36 impulses from receptors or sense organs towards the central nervous system), efferent neurons
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37 (which carry impulses the other way), and interneurons (which connect other neurons) (2). g
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38 The enteric nervous system contains support cells which resemble the astroglia in the brain as
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39 well as a diffusion barrier around the capillaries surrounding ganglia which resembles the r
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40 blood–brain barrier of cerebral blood vessels. The enteric nervous system can operate
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41 autonomously and has been likened to a second brain (3). This system regulates gastric acid 1
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42 secretion, peristalsis/motility, fluid flow across the lining epithelium, local blood flow, and
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43 nutrient handling; it also interacts with the endocrine and immune systems of the gut. u
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44 Normally, the communication of the enteric nervous system with the central nervous system
45 involves the parasympathetic nervous system (via, for example, the vagus nerve) and the
46 sympathetic nervous system (via, for example, the prevertebral ganglia). The enteric nervous
47 system uses over 30 neurotransmitters, most of which are the same as those used by the
48 central nervous system, including acetylcholine, dopamine, and serotonin. A wide range of
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49 such neurohormones, neurotransmitters and their receptors – including corticotropin,
50 somatostatin, and γ-aminobutyric acid (GABA) – are homologous to those found in
51 microorganisms (for references see (1)).
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53 The brain can influence gut microbiota via changes in gastrointestinal motility, secretion, and
54 permeability and via signaling molecules released into the gut lumen from cells in the lamina D
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55 propria such as neurons, immune cells and enterochromaffin cells (which regulate n
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56 communication between the gut lumen and the nervous system (4)); indeed, d
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57 enterochromaffin-cell signaling to neuronal circuits via vagal, afferent innervation is believed
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58 to have an important role in pain and immune-response modulation, control of background

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59 emotions and other homeostatic functions (4). Reciprocally, there is evidence that certain tp
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60 bacteria in the gastrointestinal tract may influence brain function and behavior (5). jb
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61 m
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62 Over three billion years of evolution have honed the capacities of bacteria to exploit their r
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63 environments. Millions of years of co-evolution of bacteria and their hosts have presumably n

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64 selected those bacteria that best manipulate their hosts. It has been proposed that the species p
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65 composition of the microbial organ influences the disease susceptibility of the host whilst,
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66 reciprocally, the host's nervous system influences the species composition of the microbial 0
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67 organ (1). It has also been proposed that "changes in microbial diversity and hence the b
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68 microbial organ, influence the function of components of the CNS (i.e. brain) as reflected
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69 in altered cognition" (1). One evident area in which feedback can occur is between cognition t
70 and nutrition. The question has been raised as to whether "daily variables, such as food
71 preferences, that determine homeostasis (could) be, in part, determined by a bacterial species
72 that informs the brain, via the vagus nerve carrying information gathered by the neuronal
73 elements innervating the GI tract, what it wants from a nutritional standpoint to survive?" (1).
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74 In other words, the capacity of bacteria to adapt is such that if it is to their advantage to
75 influence their host preferences for food, they will. Here we explore the hypothesis that there
76 is a positive feedback relationship between the composition of the gut microbiota and food
77 preferences.
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79 D
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80 Hypothesis lo
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81 d

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82 The hypothesis is based on two sets of findings. First, as is well attested, human behavior o
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83 helps control which species of bacteria are present in the gut and, second – and more t
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84 speculatively – bacteria influence human behavior. In the hypothesis, there is a mutual //
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85 reinforcement between the behavior of the human host and the bacterial population within s
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86 that host. o
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87 o
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88 1/ Dependence of bacterial composition on human behavior r
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89 The composition of the population of bacteria in the gut is selected to a large extent by the 4
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90 nutrients consumed by the host and by the stresses to which the host is subjected. 1
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91 2/ Bacteria influence host appetite
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92 The bacteria in the gut possess several mechanisms for influencing the physiology of their s
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93 hosts and, in particular, can influence the preferences of their hosts for certain nutrients.
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94 3/ Positive feedback between gut microbiota and appetite
95 A system of selection exists based on the positive feedback relationship between the
96 particular nutrients consumed by the host and the bacterial composition in the gut such that
97 this system leads to stable attractors of bacterial composition and host behavior.
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99 D
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100 Evidence lo
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101 d

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102 There are three lines of evidence for the hypothesis. First, the composition of bacteria in the m

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103 gut depends on the behavior of the host and, in particular, on what food is eaten and on t
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104 whether the host is under stress. Second, bacteria in the gut have many established /jb
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105 mechanisms for influencing their hosts as in the case of susceptibility to a variety of diseases; s
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106 such influence can extend to emotional disturbances and eating disorders. Third, eating entails o
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107 both pleasure and the sensation of satiety. Both experiences involve processes that may be o
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108 modulated by bacteria p
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109 1
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110 1/ Dependence of bacterial composition on human behavior 1
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111 y

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112 The quantity, frequency and nature of the food ingested by the hosts and the hormones they e
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113 release during stresses have major effects on the bacterial composition in the gut.
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115 Nutrients determine the gut microbiota
116 The composition of the population of bacteria in the gut is selected to a large extent by the
117 nutrients consumed by the host. If food intake determines the gut microbiota, feasting and
118 fasting, the two most extreme dietary life-styles, should be expected to produce major
119 changes in the microbiota. Using the Burmese python as a model system, it was indeed found
120 that fasting was associated with increased abundances in the large intestine of the genera D
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121 Bacteroides, Rikenella, Synergistes and Akkermansia, and with reduced overall diversity n
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122 whilst after feeding, Firmicutes, including the taxa Clostridium, Lactobacillus and d
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123 Peptostreptococcaceae, gradually outnumbered the fasting-dominant Bacteroidetes, and
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124 increased overall 'species'-level diversity (6). In humans, Bacteroides proliferate in response

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125 to fructans, a class of fructose-based dietary polysaccharides. This was attributed to a tp
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126 fructose-binding, hybrid two-component signaling sensor that controls the fructan utilization jb
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127 locus; this locus is different in different Bacteroides species and results in different fructans m
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128 being useable by the bacteria (7). Comparison of the fecal microbiota of African children with rg
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129 a high fiber, low fat diet, and European children with a modern diet and revealed that the n

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130 former had more Bacteriodetes and less Firmicutes and a particular abundance of bacteria r
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131 from the genus Prevotella and Xylanibacter (8); this led to the conclusion that that gut 4
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132 microbiota coevolved with the polysaccharide-rich diet of the children from Burkina Faso to 0
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133 allow them to maximize energy intake from fibers and to protect them from inflammation and b
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134 colonic disease. It should, however, be noted that giving a low fat, high carbohydrate diet for u
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135 ten days to a group of subjects who started with the Bacteroides enterotype did not result in t
136 switching to the Prevotella enterotype (9)
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138 Stress
139 Psychological stress increases the circulating levels of the catecholamine hormones
140 norepinephrine and epinephrine, which play a central role in the 'flight or fight' response in
141 higher animals. These hormones affect bacterial growth by scavenging iron or by inducing the
142 production of autoinducers and, in a study of 43 oral bacteria, catecholamines elicited the
143 greatest response from the periodontal pathogens most closely associated with gum disease D
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144 (10). Overgrowth by species such as Escherichia coli is responsible for gut-derived sepsis n
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145 following surgery (11). Significantly, norepinephrine, epinephrine and dopamine, increased d
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146 the growth of commensal E. coli in vitro by over four orders of magnitude (12). Mice exposed
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147 to a social stressor have increased levels of circulating cytokines and an innate immune

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148 system that is primed for enhanced reactivity. Stressor exposure significantly changed the tp
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149 community structure of the microbiota in the cecum by decreasing the proportion of jb
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150 Bacteroides and increasing the proportion of bacteria in the genus Clostridium. The stressor m
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151 also increased circulating levels of IL-6 and MCP-1, which were correlated with changes to rg
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152 the proportions of Coprococcus, Pseudobutyrivibrio, and Dorea (13). n

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153 r
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154 2/ Influence of the bacteria in the gut on their hosts ,
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155 9

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156 The molecules that bacteria use to exert control over host behavior may have originated in
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157 several different ways; for example, such host-control compounds may have originated (and s
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158 may still function) as signals between bacteria in biofilms, or as the fermentation products of
159 indigestible foods, or as co-metabolites, or as the products of bacterial lysis. Indeed, it has
160 been suggested that quorum sensing might also be a "language" by which bacteria and host
161 cells communicate (14). The evolution of host-control compounds was probably guided by
162 molecular complementarity which selects from the diversity of biological molecules those
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163 that are able to stabilize and interact functionally with each other (15); hence, candidate host-
164 control compounds produced by bacteria include the macromolecules or fragments of
165 macromolecules (16) that bind to metabolites or that bind to the receptors of those metabolites
166 or even the receptors themselves (such as the bacterial adrenergic receptors (17)). One
167 possible example of molecular complementarity is the major cell wall breakdown product,
168 muramyl dipeptide or "adjuvant peptide" which not only stimulates an inflammatory response D
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169 via the NOD proteins (18) but also mimics serotonin to cause drowsiness (19, 20).
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170 Drowsiness may also be caused by the administration of another bacterial product, flagellin, a
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171 which acts via a Toll-like Receptor, TLR5 (A. Gewirtz, unpublished). The abundance of a d
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172 wide variety of other molecules in the gut have also been attributed to the action of the m

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173 microbiota. These molecules, some of which may help bacterial control the behavior of their tp
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174 hosts, include short-chain fatty acids, branched chain fatty acids, γ-aminobutyric acid jb
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175 (GABA), biotin, vitamin K, p-hydroxyphenylacetic acid, m-hydrophenylacetic acid, m
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176 hydroxycinnamic acid, phenylvaleric acid, p-aminobenzoic acid, indoxyl sulfate, indoleacetic r
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177 acid, indolecarboxylic acid, indoleacetaldehyde, 6-hydroxymelatonin sulfate, putrescine, n

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178 spermidine, spermine, taurine, cadaverine, tryptophan, tyrosine and peptides (21-25). p
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179 4
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180 There are several examples in which the ensemble of the gut microbiota, rather than an 1
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181 individual species, has major effects on the health of their hosts. Sometimes, transplanting y

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182 “diseased” – but “pathogen”-free – microbiota to a healthy but susceptible host also transfers e
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183 the disease. Moreover, some of the molecular mechanisms responsible for this control by
184 bacteria of their hosts are known. They include signaling pathways such as those involving c-
185 Fos, Toll-like Receptors (TLR), NF-kB, MAPK, JNK and CyclinD whilst signals include
186 flagellin, lipopolysaccharide, and trimethylamine N-oxide (TMAO). These different
187 mechanisms reveal the capacity of bacteria in the gut to influence human health – or the
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188 behavior associated with health. The effects of these mechanisms range from Metabolic
189 Syndrome and even to thyroid disease, cardiovascular disease, cancer and anxious behavior.
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191 Mood disorders and illnesses
192 The Hypothalamus-Pituitary-Adrenal response is involved in the neurobiology of mood
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193 disorders and illnesses that include anxiety disorder, bipolar disorder, insomnia, post- o
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194 traumatic stress disorder, borderline personality disorder, ADHD, major depressive disorder, lo
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195 burnout, chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, and alcoholism . e
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196 The normalization of this response, as well as increased angiogenesis, are correlated with ro
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197 increased numbers of Bacillus infantis (26). As mentioned above, a role for the microbiota in h
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198 stressor-induced increases in circulating cytokines in normal mice was shown in antibiotic- :/
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199 treated mice in which the stressor did not increase IL-6 and MCP-1 (13). In a remarkable a
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200 experiment, challenging mice with live Campylobacter jejuni led to a reduction in their .
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201 exploratory behavior – consistent with anxiety – and an activation of brain regions implicated /
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202 in anxious behavior, including the lateral septum, paraventricular and dorsomedial A
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203 hypothalamic nuclei, basolateral and central nuclei of the amygdala, bed nucleus of the stria il
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204 terminalis and periaquiductal grey (5); this activation was correlated with c-Fos expression in ,
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205 the bed nucleus of the stria terminalis. The higher motor activity and reduced anxiety of germ- 9

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206 free mice, compared with pathogen-free mice with a normal gut microbiota, are associated y

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207 with altered expression of genes involved in second messenger pathways and synaptic long- e
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208 term potentiation in brain regions implicated in motor control and anxious behaviour (27).
209 Moreover, germ-free mice exposed to gut microbiota early in life resemble mice with a
210 normal microbiota and have reduced expression of PSD-95 and synaptophysin in the striatum
211 (28). To explain how the treatment of Helicobacter pylori helps those suffering from
212 Parkinson's disease, it has been proposed, with some experimental support, that this is because
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213 the L-DOPA supplements given to these patients are actually used by H. pylori (29). This
214 would be consistent with yet another connection between neurotransmitters and bacteria.
215 Finally, Desulfovibrio species are more common in autistic subjects than in controls (30). The
216 controversial idea is that these anaerobic bacilli may actually be selected during the treatment
217 of common childhood infections because of their resistance to antimicrobial agents such as
218 cephalosporins. D
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220 Inflammatory Bowel Disease (IBD) e
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221 Murine models of IBD require “normal” microbiota for disease development suggesting ro
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222 human IBD is mediated by aberrant immune response to gut microbiota. The mechanism h
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223 involves TLRs on the surface of the host cells which bind to bacterial constituents such as :/
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224 flagellin, lipoprotein, lipopolysaccharide and DNA and then activate proinflammatory gene a
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225 expression via NF-kB and IRF. Macrophages respond to lipopolysaccharide whilst epithelial .
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226 cells respond to flagellin. Both bacterial constituents lead to increases in the level of serum /
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227 cytokines, in the former case, TNFα and in the latter, IL-8. In the absence of TLR5 in A
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228 particular, a variety of inflammatory gut conditions can result, including colitis and metabolic il
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229 diseases. Improvements in immunocompetence and tolerance are correlated with increased ,
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230 numbers of (1) Lactobacillus spp. via the tolerization of dendritic cells and (2) Bacteroides 9

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231 fragilis via cellular immunity, lymphoid organogenesis and mucosal immunity (26). y

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232 Immunocompetence tolerance, angiogenesis and lipid metabolism are also affected by of e
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233 Bacteroides thetaiotaomicron (26). A major gut commensal, B. fragilis, uses polysaccharide
234 A to signal via TLR2 on Foxp3(+) regulatory T cells to allow niche-specific, colonization
235 (31); this has led to the proposal that the immune system can discriminate between pathogens
236 and the microbiota through recognition of bacterial molecules to allow symbiosis (31).
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