Accepted Manuscript

Diet, gut microbiota composition and feeding behavior

Jiyoung S. Kim, Claire B. de La Serre

PII: S0031-9384(18)30149-5
DOI: doi:10.1016/j.physbeh.2018.03.026
Reference: PHB 12140
To appear in: Physiology & Behavior
Received date: 1 December 2017
Revised date: 23 March 2018
Accepted date: 23 March 2018

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 ACCEPTED MANUSCRIPT

Diet, gut microbiota composition and feeding behavior

Jiyoung S Kim, Claire B de La Serre*

Department of Foods and Nutrition, College of Family and Consumer Sciences, University of

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Georgia, Athens, GA 30602, USA

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Corresponding author:

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*
Claire Barbier de La Serre, Ph.D.
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Department of Foods and Nutrition, College of Family and Consumer Sciences, University of
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Georgia, 280 Dawson Hall, 305 Sanford Dr., Athens, GA 30602, United States, Phone: 706-542-

4873, e-mail: [email protected]

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ABSTRACT

Advances in sequencing technologies have allowed for a more complete analysis of the

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microbiota composition and identification of differences among individuals and/or physiologies.

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Changes in microbiota composition and associated inflammation have been linked to both

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metabolic and behavioral disorders, and abnormality in microbiota composition, or dysbiosis,

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may play a causal role in the etiology and maintenance of these pathologies. There is

accumulating evidence showing that the gut microbiota can communicate to the central nervous
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system to alter host behavior. Supplementation with L. Rhamnosus in mice notably causes a

decrease in anxiety. Interestingly, these effects are abolished by vagotomy, identifying the vagus
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nerve as a potential communication route for microbiota-originating signals. Chronic high fat
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feeding notably leads to remodeling of the vagal afferent pathway and is associated with an

increase in energy intake; these effects appear to be mediated by microbiota-induced

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inflammation. Therefore, preventing bacterial-driven inflammation, via dietary manipulation for

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example, may have potential therapeutic effects for both metabolic and behavioral disorders.
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Keywords: Microbiota, microglia, vagal afferents, food intake

Abbreviations: BDNF: brain-derived neurotrophic factor, CCK: cholecystokinin, CNS: central

nervous system, GDNF: glia-derived neurotrophic factor, GF: germ-free, GI: gastrointestinal,
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HF: high fat, IRS1: Insulin receptor substrate 1, IB4: isolectin B4, LPS: lipopolysaccharide,

MyD88: myeloid differentiation primary response 88, NG: nodose ganglion, NTS: nucleus of

solitary tract, PRRs: pattern recognition receptors, SOCS3: suppressor of cytokine signaling 3,

STAT3: signal transducer and activator of transcription 3, TLR: Toll-like receptor, VAN: vagal

afferent neurons

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INTRODUCTION

In the early 1910’s, Elie Metchnikoff’s studies of microbes and immunity led to the

discovery of phagocytosis [1]. Later in his career, Metchnikoff also hypothesized that

gastrointestinal (GI) “good bacteria” such as Lactobacillus spp could override “toxic bacteria” to

improve the aging process and recommended the consumption of sour milk [2]. Recent

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technological advances, especially next-generation sequencing, have deepened our understanding

of the gut microbiota dynamics and its influence on the host’s health. The GI tract is home to

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over 100 trillion microbial cells (bacteria, archaea, fungi and viruses) that encode for 100-fold

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more genes than the human genome. Microbiota composition is highly dynamic and region-

dependent [3]. Changes in composition can affect host physiology and health, and there is
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accumulating evidence linking the microbiota to the etiology and persistence of both metabolic
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and behavioral disorders [4, 5].

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Obesity has been characterized by an abnormal microbiota composition or dysbiosis [5]. In

rodents, chronic consumption of energy-dense food promotes dysbiosis before any changes in
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body weight are observed [6]. High fat (HF) feeding notably leads to an increase in abundance of
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Proteobacteria species and an increase in the ratio of Firmicutes to Bacteriodetes, the two main

phyla present in the gut [6]. Interestingly, colonization of germ-free (GF) animals with a
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dysbiotic “obese-type” microbiota leads to abnormal weight gain [7]. In Ridaura et al. study, GF

mice were conventionalized with human microbiomes from twins discordant for obesity. Mice

that received the “obese” microbiota displayed significantly increased abundances of several

genera of Clostridia (Firmicutes), including Clostridium, Ruminococcus and Blautia when

compared to the “lean” recipient mice. Colonization-induced obesity could be rescued via co-
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housing with non-dysbiotic mice, and microbiota transfer between animals pointing towards a

causal role for microbiota dysbiosis in obesity [7].

Consumption of energy-dense, HF food results in an increase in meal size and hyperphagia [8].

Gut-originating satiety peptides, such as cholecystokinin (CCK) signal via the vagus nerve to

prompt meal termination. HF feeding hinders vagally-mediated satiation [9, 10] and leads to an

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increase in gut permeability and translocation of bacterial products to the circulation, including

pro-inflammatory lipopolysaccharide (LPS) [11]. Vagal afferent neurons are ideally located for

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sensing microbe-originating signals, and there is evidence that 1) bacterial by-products can alter

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vagal-driven satiety, potentially via a pro-inflammatory pathway [12], 2) dysbiosis is

accompanied by recruitment of immune cells neighboring vagal afferent neurons (VAN) and
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remodeling of vagal outputs to the CNS [13], and 3) normalization of the microbiota
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composition in HF fed rodents prevents vagal remodeling and diet-driven hyperphagia [6].

Taken together, these data highlight a new pathway by which the gut microbiota may influence
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vagal function and regulation of food intake.

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1. Microbiota composition, GI permeability and inflammation

Birth delivery method, sanitation, antibiotic usage, exercise, age and disease state have

been reported to affect the microbiota composition; however, dietary intake is the main

modulator of microbiota composition [14]. Microbiota composition changes rapidly in response

to diet [15, 16], and the western world favors the chronic intake of energy-dense food. In both

humans [5] and rats [6, 11], diet-induced obesity leads to microbiota dysbiosis. Interestingly,
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gastric-bypass, the most efficient strategy against obesity, has a profound effect on microbiota

composition, and these changes have been found to be sufficient to induce weight loss [17].

Conversely, colonization of bacteria-depleted animals with a “HF-type” microbiota leads to

excessive weight gain [5, 7], but also behavioral impairment, including an increase in anxiety-

like behavior [4]. HF diet-associated microbiota is generally characterized by a decrease in

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bacterial diversity and an increase in the ratio of Firmicutes to Bacteriodetes [5, 13]. Diet-driven

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dysbiosis has been linked to increased food efficiency and nutrient absorption [5, 18]. Specific

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Firmicutes species have notably been found to promote expression of glucose and fatty acids

transporters [18].

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Diet-associated dysbiosis can also result in an increase in the inflammatory potential of the
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microbiota, characterized by elevated levels of pro-inflammatory bacterial factors such as LPS or
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flagellin in the distal gut [13, 19]. A “pro-inflammatory” microbiota composition has been found

to be necessary and sufficient to induce metabolic syndrome, supporting a causal relationship

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between bacterial-originating inflammation and metabolic disorders [19]. Bacteria-driven GI

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inflammation can impair intestinal epithelial function. Activation of pattern recognition receptors

(PRRs), including Toll-like receptors (TLRs), triggers the release of cytokines such as TNF-α
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and IL-1β [20]. These cytokines can alter the integrity of tight junction proteins and promote gut
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permeability [21]. HF diet consumption induces TLRs activation on intestinal epithelial cells

[11] and leads to rapid impairment in intestinal permeability, especially in the distal gut where

bacterial abundance is the highest [3]. Maintaining gut integrity, potentially via microbiota

manipulation, may be critical in preventing metabolic disorders. Supplementation with prebiotics

lowers gut permeability and hinders weight gain in obese animals [22]. Moreover, intestinal
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deletion of myeloid differentiation primary response 88 (Myd88) protein, a key molecule in

TLRs signaling, prevents diet-induced obesity [23].

A leaky gut allows for translocation of pro-inflammatory bacterial products into the circulation

[11, 24], and microbiota-driven inflammation may be a crucial triggering factor in the

development of obesity-associated pathologies, including insulin resistance. In rodent models,

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chronic administration of pro-inflammatory bacterial LPS, a by-product of gram-negative

bacteria, is sufficient to induce weight gain and insulin resistance [12, 24] while knocking-down

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of the LPS receptor in mice confers resistance to diet-induced metabolic syndrome [25].

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Similarly, in Zucker obese rats, which lack a functional leptin receptor, blocking of TNF-α

increases insulin-driven glucose uptake in peripheral tissues, improving insulin sensitivity [26].
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Cytokines, particularly TNF-α [27, 28] and Il-1β [29], can impair insulin signaling by
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phosphorylating insulin receptor substrate 1 (IRS1) at a serine (Ser307 ) site which prevents

phosphorylation at the active tyrosine site. Interestingly, in HF fed rats supplementation with
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anthocyanin-rich blueberries leads to changes in microbiota composition associated with

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reduction in hepatic pSer307 IRS1 phosphorylation [30]. Abnormal immune signaling appears to

be key in microbiota-driven metabolic syndrome; lack of TLR5 signaling in mice is sufficient to

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induce dysbiosis-driven weight gain and insulin resistance [31].

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Microbiota-driven inflammation is not limited to peripheral tissues; dysbiosis has also been

linked to neuro-inflammation and behavioral disorders. LPS is a known inducer of pro-

inflammatory cytokines in brain tissues [32], and dysbiotic microbiota transfer is sufficient to

induce an increase in inflammatory gene expression in the medial prefrontal cortex associated

with anxiety and memory impairment [4]. Conversely, silencing of the LPS receptor reduces

frontal cortex inflammation in a mouse model of Gulf War Illness [33]. Microbiota dysbiosis
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may trigger the chronic activation of microglia, the resident parenchymal myeloid cells within

the central nervous system (CNS). Microglia are recruited in response to inflammation and injury

[34], and chronic microglia activation is observed in numerous brain pathologies [35-37]. LPS

administration leads to microglia activation in the amygdala [32], and dysbiotic microbiota

transfer results in an increase in microglia recruitment to the prefrontal cortex [4]. There is

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evidence that HF diet-induced dysbiosis is associated with microglia activation in the brainstem,

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identifying inflammation of the vagal afferent pathway as a potential mechanism for bacteria-

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driven hyperphagia [38].

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2. The vagus nerve, potential relay between microbiota and brain
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The vagus nerve is a bidirectional communication line between visceral organs and the
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CNS that relays motor information from the brain to peripheral organs and sensory information
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from the periphery to the CNS [39]. VAN, located in the nodose ganglion (NG), notably transmit

signals on quantity and quality of nutrients ingested to the nucleus of solitary tract (NTS) in the
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brainstem to regulate feeding behavior [9, 10]. In animal models, HF diet consumption alters
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vagal afferent signaling, resulting in overeating [9, 10]. HF feeding notably leads to alteration in

meal patterns in rodents, specifically to an increase in meal size in the light phase, when animals

are usually not actively consuming food. This may be related to a loss in circadian rhythm of

vagal afferents [40]. Interestingly, microbiota composition has also been found to fluctuate based

on circadian rhythm, and these oscillations are lost in rodents fed a HF diet [41].
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The vagus nerve may play a key role in transmitting microbiota-originating signals to the brain

to affect host behavior, including feeding behavior. LPS has been found to modulate vagal

afferent neurons’ mechanosensitivity [50], and intraduodenal administration of LPS leads to cFos

activation in the NTS [51]. Similarly, oral gavage with Salmonella typhimurium induces cFos in

the NTS, and this response is abolished by capsaicin-induced vagal denervation [42]. In mice,

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infection with Campylobacter jejuni increases anxiety-like behavior [43, 44], whereas

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Lactobacillus rhamnosus supplementation has the opposite modulatory effect [45]. Interestingly,

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C. jejuni induces vagal activation [43] while L. rhamonus’ positive effects on anxiety are

abolished by vagotomy [45]. Vagal afferent terminals are located in the lamina propria and are

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ideally positioned to sense microbiota-originating signals. Commensal bacteria have been shown
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to produce neurotransmitters such as serotonin [46], GABA [47], dopamine, and noradrenaline

[48] which may activate vagal terminals. Additionally, there is evidence that bacterial product
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LPS can directly influence cell depolarization; LPS notably inhibits the pacemaker activity of the
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interstitial cells of Cajal [49].

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Recent studies also point towards indirect interactions between the gut microbiota and the vagal

afferent pathway, notably via an inflammatory pathway. The LPS receptor, TLR-4, is expressed
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in the NG, either by VAN or immune cells [12]. In rats, chronic LPS administration
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(intraperitoneally) results in TLR-4 over-activation in the NG [12]. TLR-4 activation leads to

pro-inflammatory cytokine secretion but also engages negative feedback signals aimed at

regulating cytokine signal transduction, including suppressor of cytokine signaling 3 (SOCS3)

[52]. SOCS3 is a known inhibitor of leptin signaling and prevents leptin-induced

phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) [52].

Interestingly, in rats, chronic LPS treatment results in a decrease in exogenous leptin induced-
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STAT3 phosphorylation in the NG [12]. Leptin signaling in NG potentiates CCK-induced

satiety, and vagal leptin resistance in HF fed rodents leads to a decrease in vagally-mediated

meal termination [9]. Similarly to HF feeding, LPS administration in rats results in blunted

leptin-induced STAT3 phosphorylation and reduced CCK-induced satiation associated with

overeating [12]. These data provide a potential pathway by which bacteria-driven inflammation

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could alter feeding behavior.

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In addition to vagal signaling, microbiota-driven inflammation may result in alterations to the

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vagus nerve itself. Dysbiotic animals exhibit a decrease in isolectin B4 (IB4) staining at the level

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of the NTS [13]. IB4 is expressed by unmyelinated c fibers, which at the level of the area

postrema in the NTS, are predominantly of vagal origin [53]. Changes in vagal outputs to the
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NTS have previously been reported following vagotomy or capsaicin treatment [54, 55]. These
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procedures result in nerve injury and microglia recruitment [56] and are accompanied by a

decrease in neurotransmitter release in the NTS [54]. In rats, diet-driven dysbiosis is associated
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with microglia activation in the NG and the NTS [6, 13]. Interestingly, chronic treatment with
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minocycline, a broad-spectrum antibiotic, prevents both dysbiosis and microglia activation in HF

fed rats while normalizing food intake [6]. Therefore, microbiota-driven vagal inflammation may
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play a critical role in altering the vagal pathway and promoting food intake in HF fed animals.
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3. Dietary manipulations of the microbiota

As microbiota dysbiosis has been linked to several pathologies, there has been a growing

interest in potential therapeutic effects of microbiota manipulation. Traditionally, HF feeding has

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been used to induce microbiota dysbiosis in rodent models. Studies with diets that vary from 20

to 72% of Kcal coming from fat have found rapid (within days) significant effect on the

microbiota composition (reviewed in [57]). In rodents, HF feeding generally results in an

increase in Erysipelotrichaceae abundance, a family of Firmicutes, and Clostridia abundance,

the major class of Firmicutes. However, the Firmicutes order Clostridiales and the Lactobacillus

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genus are more abundant in low fat (LF) fed animals. Bifidobacterium (Actinobacteria) and

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Prevotella (Bacteriodetes) genera are also more abundant in LF fed rodents [57]. Refined HF

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diets used in research to induce obesity are also commonly rich in sugars and low in fibers. High

sugar content in the diet may also detrimentally affect the microbiota composition; in mice,

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consumption of a high sugar diet (70% sucrose) leads to dysbiosis associated with cognitive
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impairment [58]. Lower sugar consumption (11% sugars in liquid form) appears to have similar

effects in young rats and significantly alters their microbiota composition with a notable decrease
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in Prevotella abundance [59]. In adult rats, consumption of a diet low in fat but rich in sugar
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(17% fructose) leads to marked changes in the microbiota composition, comparable to the ones

induced by HF feeding [13]. In these studies, diets were low in fibers; reduced fiber
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consumption, rather than macronutrient content, may be a key driver of both diet-induced
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dysbiosis and obesity. In mice, addition of soluble fiber to a HF diet prevents diet-induced

hyperphagia and weight gain. These effects are microbiota-dependent and can be partially
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recapitulated by short chain fatty acids (SCFAs) supplementation [60].

SCFAs are produced during bacterial fermentation of indigestible carbohydrates, such as fibers

or resistant starch. Acetate, propionate and butyrate are the most abundant SCFAs in the intestine

[61]. Alteration in SCFAs production ratio may be involved in the development of insulin-

resistance because diet-induced dysbiosis has been associated with an increase in acetate
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production, which has been found to promote hyperinsulinemia [62]. SCFAs, especially butyrate,

have a trophic role in the gut, promoting the proliferation and differentiation of enterocytes,

ultimately strengthening the gut epithelial barrier [63]. Additionally, SCFAs are able to stimulate

G-protein coupled receptors such as GPR43 [64], promoting enteroendocrine cells differentiation

[65] and production of GI satiety peptides, for example, glucagon-like peptide-1 (GLP-1) [64].

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SCFAs binding to G-protein coupled receptors expressed on immune cells can also modulate

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differentiation of Foxp3+ T cells (Tregs). Tregs are notably critical for regulating intestinal

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inflammation. SCFAs-driven GPR43 activation in neutrophils, eosinophils and Tregs induces

Tregs differentiation and lessens inflammatory signals [66, 67]. Similarly, butyrate’s action on

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GPR109A results in production of anti-inflammatory Il-10 and promotes Treg differentiation
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[68]. Butyrate and propionate have also been reported to inhibit pro-inflammatory cytokine TNF-

α production in macrophages [69]. In the brain, SCFAs have neuroprotective effects; sodium
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butyrate notably increases the expression of brain-derived neurotrophic factor (BDNF) and glia-
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derived neurotrophic factor (GDNF) and improves memory-dependent tasks [70, 71].
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Supplementation with probiotics that increase bacterial fermentation have been found to have

positive effects on host health outcomes. Oligofructose, for example, can be fermented into short
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SCFAs by Bifidobacteria [72], and supplementing a HF diet with oligofructose leads to an

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increase in satiety peptide GLP-1 expression in mice, improving metabolic outcomes [73].

Similarly, pectin supplementation (5% wt/wt) in HF rats restores microbiota composition and

ameliorates weight gain and systemic inflammation [74]. Polyphenol supplementation has also

been found to protect against HF diet-induced metabolic syndrome [75]. Polyphenols’ positive

effects on metabolic outcomes may be related to increased abundance of mucin-degrading

bacteria, especially Akkermansia muciniphila [76]. A. muciniphila abundance has previously

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been linked to positive health outcomes [77]. Proteins from A. muciniphila outer membrane can

notably interact with TLR2 to enhance gut barrier function [78]. Interestingly, consumption of

polyphenol-rich beverages leads to an increase in A. muciniphila abundance [79] and improves

insulin sensitivity in humans [80]. Microbiota manipulation via antibiotics has also been shown

to have a positive effect on body weight and insulin resistance in rodent models of diet-induced

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obesity [6, 81].

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Positive effects of prebiotics on neurological pathologies

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have also been reported;

oligosaccharides have protective effects against neurodegeneration in animal models of

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amyotrophic lateral sclerosis (ALS) and are associated with a decrease in markers of microglia

activation in spinal cord sections [82]. Additionally, non-digestible galacto-oligosaccharide

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supplementation in a LPS-treated mouse model improves anxiety behavior in the light-dark box
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test [83]. Similarly, in humans, oligosaccharide supplementation is associated with lower levels

of cortisol [84], while probiotic-induced microbiota manipulation reduces psychological distress

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[85]. Therefore, microbiota manipulation may improve host metabolism and behavior,
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potentially via a reduction in systemic and neuro-inflammation, including vagal inflammation.

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4. Limitations and future directions

Recent research has provided significant insights into gut microbiota’s influence on host

physiology and behavior. However, bacteria-host interaction studies often fail to rigorously

establish causal relationship. Dietary changes are commonly used to experimentally manipulate

microbiota composition, making it difficult to tease apart microbiota-driven effects from diet-
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driven effects. One way to bypass the confounding influence of diet is the use of GF animals. GF

mice are most commonly used and can be colonized with a specific microbiota while consuming

a set diet; any observed changes in physiology or behavior is then attributed to the changes in

microbiota composition. It should, however, be noted that GF animals are not conventional

animals with no microbiome. They have altered neurophysiology [87], neuroanatomy [88],

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energy metabolism [89], and immune function [90], which may affect the way they will respond

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to conventionalization. Another limitation to microbiome research is the technical variability in

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sequencing methods. Next generation sequencing technology has enabled researchers to identify

aerobic and anaerobic members. However, there is evidence suggesting that results can vary

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across platforms, choice of 16S target region, databases and bioinformatics pipelines [91-93]
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which can limit comparisons between different studies.
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Despite these hurdles, there is growing evidence that the microbiota is important for the

development and maintenance of glia in the enteric nervous system [95]. Microbiota-depleted
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animals lack mucosal enteric glial cells, and differentiation can be restored by bacterial
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colonization [95]. Glia have been found to play a critical role in the formation of neuronal

synapses and function [94]; therefore, future research should also focus on the role of various
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glial cell types and their relationship with VAN in the transmission of microbiota-originating
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signals, including the identification of specific signals, receptors and pathways. A new tool to

enable these studies could be targeted vagal deafferentation [97]. Historically, vagotomy or

capsaicin application has been used to ablate vagal input. These techniques, on their own, induce

microglia activation. They also alter vagal efferent innervation, triggering changes in gastric

emptying and gut motility, which are sufficient to alter microbiota composition [96]. Afferent-
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specific denervation may help identify the mechanisms of dysbiosis-induced behavioral

alterations in future microbiota-brain research.

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CONCLUSION

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Microbiota composition is highly dynamic and influenced by environmental pressures.

Chronic consumption of foods rich in energy and low in fibers triggers microbiota dysbiosis and

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impairs intestinal barrier function. Bacteria-originating inflammation is sufficient to induce

hyperphagia, weight gain and insulin resistance. Dysbiosis leads to deleterious effects on feeding
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behavior, which may involve vagal microglia recruitment and alteration of both vagal
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morphology and signaling. Further investigation into the mechanisms underlying gut microbiota-

brain signaling may support the development of new therapies for the treatment of physiological
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and behavioral disorders, including metabolic syndrome.

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REFERENCES

[1] Gordon, S. Elie Metchnikoff: father of natural immunity. Eur J Immunol. 2008,38:3257-64.
[2] Mackowiak, P. A. Recycling Metchnikoff: probiotics, the intestinal microbiome and the quest
for long life. Frontiers in public health. 2013,1.
[3] Hamilton, M. K., Boudry, G., Lemay, D. G., Raybould, H. E. Changes in intestinal barrier
function and gut microbiota in high-fat diet-fed rats are dynamic and region dependent.
American Journal of Physiology - Gastrointestinal and Liver Physiology. 2015,308:G840-G51.

T
IP
[4] Bruce-Keller, A. J., Salbaum, J. M., Luo, M., Blanchard, E., Taylor, C. M., Welsh, D. A., et
al. Obese-type Gut Microbiota Induce Neurobehavioral Changes in the Absence of Obesity.

CR
Biological psychiatry. 2015,77:607-15.
[5] Turnbaugh, P., Ley, R., Mahowald, M., Magrini, V., Mardis, E., Gordon, J. An obesity-
associated gut microbiome with increased capacity for energy harvest. Nature. 2006,444:1027 -

US
31.
[6] Vaughn, A. C., Cooper, E. M., DiLorenzo, P. M., O’Loughlin, L. J., Konkel, M. E., Peters, J.
H., et al. Energy-dense diet triggers changes in gut microbiota, reorganization of gut-brain vagal
AN
communication and increases body fat accumulation. Acta neurobiologiae experimentalis.
2017,77:18-30.
M

[7] Ridaura, V. K., Faith, J. J., Rey, F. E., Cheng, J., Duncan, A. E., Kau, A. L., et al. Gut
microbiota from twins discordant for obesity modulate metabolism in mice. Science.
2013,341:1241214.
ED

[8] Treesukosol, Y., Moran, T. H. Analyses of meal patterns across dietary shifts. Appetite.
2014,75:21-9.
PT

[9] de Lartigue, G., Barbier de la Serre, C., Espero, E., Lee, J., Raybould, H. E. Leptin
Resistance in Vagal Afferent Neurons Inhibits Cholecystokinin Signaling and Satiation in Diet
CE

Induced Obese Rats. PLoS ONE. 2012,7:e32967.

[10] Savastano, D. M., Covasa, M. Adaptation to a high-fat diet leads to hyperphagia and
diminished sensitivity to cholecystokinin in rats. J Nutr. 2005,135:1953-9.
AC

[11] de La Serre, C. B., Ellis, C. L., Lee, J., Hartman, A. L., Rutledge, J. C., Raybould, H. E.
Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut
microbiota and gut inflammation. Am J Physiol Gastrointest Liver Physiol. 2010,299:G440-8.
[12] de La Serre, C. B., de Lartigue, G., Raybould, H. E. Chronic exposure to Low dose bacterial
lipopolysaccharide inhibits leptin signaling in vagal afferent neurons. Physiology & Behavior.
2015,139:188-94.
[13] Sen, T., Cawthon, C. R., Ihde, B. T., Hajnal, A., DiLorenzo, P. M., de La Serre, C. B., et al.
Diet-driven microbiota dysbiosis is associated with vagal remodeling and obesity. Physiology &
Behavior. 2017,173:305-17.
 ACCEPTED MANUSCRIPT

[14] David, L. A., Maurice, C. F., Carmody, R. N., Gootenberg, D. B., Button, J. E., Wolfe, B.
E., et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014,505:559-
63.
[15] David, L. A., Maurice, C. F., Carmody, R. N., Gootenberg, D. B., Button, J. E., Wolfe, B.
E., et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014,505:559-
63.
[16] Turnbaugh, P. J., Ridaura, V. K., Faith, J. J., Rey, F. E., Knight, R., Gordon, J. I. The Effect
of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic

T
Mice. Science Translational Medicine. 2009,1:6ra14.

IP
[17] Liou, A. P., Paziuk, M., Luevano, J.-M., Machineni, S., Turnbaugh, P. J., Kaplan, L. M.
Conserved Shifts in the Gut Microbiota Due to Gastric Bypass Reduce Host Weight and

CR
Adiposity. Science translational medicine. 2013,5:178ra41-ra41.
[18] Woting, A., Pfeiffer, N., Loh, G., Klaus, S., Blaut, M. Clostridium ramosum Promotes
High-Fat Diet-Induced Obesity in Gnotobiotic Mouse Models. mBio. 2014,5.

US
[19] Chassaing, B., Koren, O., Goodrich, J. K., Poole, A. C., Srinivasan, S., Ley, R. E., et al.
Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome.
AN
Nature. 2015,519:92-6.

[20] Cario, E., Podolsky, D. K. Intestinal epithelial TOLLerance versus inTOLLerance of

commensals. Mol Immunol. 2005,42:887-93.
M

[21] Turner, J. R. Molecular basis of epithelial barrier regulation: from basic mechanisms to
clinical application. Am J Pathol. 2006,169:1901-9.
ED

[22] Cani, P. D., Possemiers, S., Van de Wiele, T., Guiot, Y., Everard, A., Rottier, O., et al.
Changes in gut microbiota control inflammation in obese mice through a mechanism involving
PT

GLP-2-driven improvement of gut permeability. Gut. 2009,58 1044-55.

[23] Everard, A., Geurts, L., Caesar, R., Van Hul, M., Matamoros, S., Duparc, T., et al. Intestinal
CE

epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional
status. Nature communications. 2014,5:5648-.
[24] Cani, P. D., Amar, J., Iglesias, M. A., Poggi, M., Knauf, C., Bastelica, D., et al. Metabolic
AC

endotoxemia initiates obesity and insulin resistance. Diabetes. 2007,56:1761-72.

[25] Pierre, N., Deldicque, L., Barbe, C., Naslain, D., Cani, P. D., Francaux, M. Toll-like
receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-
fat diet. PLoS One. 2013,8:e65061.
[26] Hotamisligil, G. S., Shargill, N. S., Spiegelman, B. M. Adipose expression of tumor
necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993,259:87.
[27] Hotamisligil, G. S., Murray, D. L., Choy, L. N., Spiegelman, B. M. Tumor necrosis factor
alpha inhibits signaling from the insulin receptor. Proceedings of the National Academy of
Sciences of the United States of America. 1994,91:4854-8.
 ACCEPTED MANUSCRIPT

[28] Aguirre, V., Werner, E. D., Giraud, J., Lee, Y. H., Shoelson, S. E., White, M. F.
Phosphorylation of Ser307 in Insulin Receptor Substrate-1 Blocks Interactions with the Insulin
Receptor and Inhibits Insulin Action. Journal of Biological Chemistry. 2002,277:1531-7.
[29] Jager, J., Gremeaux, T., Cormont, M., Le Marchand-Brustel, Y., Tanti, J. F. Interleukin-
1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor
substrate-1 expression. Endocrinology. 2007,148:241-51.
[30] Lee, S., Keirsey, K. I., Kirkland, R., Grunewald, Z. I., Fischer, J. G., de La Serre, C. B.
Blueberry Supplementation Influences the Gut Microbiota, Inflammation, and Insulin Resistance

T
in High-Fat-Diet–Fed Rats. The Journal of nutrition. 2018,148:209-19.

IP
[31] Vijay-Kumar, M., Aitken, J. D., Carvalho, F. A., Cullender, T. C., Mwangi, S., Srinivasan,
S., et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5.

CR
Science. 2010,328:228-31.
[32] O’Loughlin, E., Pakan, J. M. P., Yilmazer-Hanke, D., McDermott, K. W. Acute in utero
exposure to lipopolysaccharide induces inflammation in the pre- and postnatal brain and alters

US
the glial cytoarchitecture in the developing amygdala. Journal of Neuroinflammation.
2017,14:212.
AN
[33] Alhasson, F., Das, S., Seth, R., Dattaroy, D., Chandrashekaran, V., Ryan, C. N., et al.
Altered gut microbiome in a mouse model of Gulf War Illness causes neuroinflammation and
intestinal injury via leaky gut and TLR4 activation. PLoS ONE. 2017,12:e0172914.
M

[34] Aguzzi, A., Barres, B. A., Bennett, M. L. Microglia: scapegoat, saboteur, or something else?
Science. 2013,339:156-61.
ED

[35] Perry, V. H., Nicoll, J. A., Holmes, C. Microglia in neurodegenerative disease. Nat Rev
Neurol. 2010,6:193-201.
PT

[36] Kettenmann, H., Hanisch, U. K., Noda, M., Verkhratsky, A. Physiology of microglia.
Physiological reviews. 2011,91:461-553.
CE

[37] Kingwell, K. Neurodegenerative disease: Microglia in early disease stages. Nat Rev Neurol.
2012,8:475.
[38] Vaughn, A. C., Cooper, E. M., DiLorenzo, P. M., O'Loughlin, L. J., Konkel, M. E., Peters,
AC

J. H., et al. Energy-dense diet triggers changes in gut microbiota, reorganization of gut-brain
vagal communication and increases body fat accumulation. Acta Neurobiologiae Experimentalis
(Wars). 2017,77:18-30.
[39] Foley, J., DuBois, F. Quantitative studies of the vagus nerve in the cat. I. The ratio of
sensory to motor fibers. J. Comp. Neurol. 1937,67:49-67.
[40] Kentish, S. J., Vincent, A. D., Kennaway, D. J., Wittert, G. A., Page, A. J. High-Fat Diet-
Induced Obesity Ablates Gastric Vagal Afferent Circadian Rhythms. The Journal of
Neuroscience. 2016,36:3199.
 ACCEPTED MANUSCRIPT

[41] Zarrinpar, A., Chaix, A., Yooseph, S., Panda, S. Diet and Feeding Pattern Affect the Diurnal
Dynamics of the Gut Microbiome. Cell metabolism. 2014,20:1006-17.

[42] Riley, T. P., Neal-McKinney, J. M., Buelow, D. R., Konkel, M. E., Simasko, S. M.
Capsaicin-sensitive vagal afferent neurons contribute to the detection of pathogenic bacterial
colonization in the gut. Journal of Neuroimmunology. 2013,257:36-45.

[43] Goehler, L. E., Gaykema, R. P., Opitz, N., Reddaway, R., Badr, N., Lyte, M. Activation in
vagal afferents and central autonomic pathways: early responses to intestinal infection with
Campylobacter jejuni. Brain. Behav. Immun. 2005,19:334-44.

T
[44] Goehler, L. E., Park, S. M., Opitz, N., Lyte, M., Gaykema, R. P. Campylobacter jejuni

IP
infection increases anxiety-like behavior in the holeboard: possible anatomical substrates for
viscersensory modulation of exploratory behavior. Brain. Behav. Immun. 2008,22:354-66.

CR
[45] Bravo, J. A., Forsythe, P., Chew, M. V., Escaravage, E., Savignac, H. M., Dinan, T. G., et
al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor
expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011,108:16050-5.

US
[46] Hsu, S.-C., Johansson, K. R., Donahue, M. J. The Bacterial Flora of the Intestine of Ascaris
suum and 5-Hydroxytryptamine Prodcution. The Journal of Parasitology. 1986,72:545-9.
AN
[47] Barrett, E., Ross, R. P., O'Toole, P. W., Fitzgerald, G. F., Stanton, C. gamma-Aminobutyric
acid production by culturable bacteria from the human intestine. J. Appl. Microbiol.
2012,113:411-7.
M

[48] Oleskin, A. V., El’-Registan, G. I., Shenderov, B. A. Role of neuromediators in the

functioning of the human microbiota: “Business talks” among microorganisms and the
ED

microbiota- host dialogue. Microbiology. 2016,85:1-22.

[49] Zuo, D. C., Choi, S., Shahi, P. K., Kim, M. Y., Park, C. G., Kim, Y. D., et al. Inhibition of
PT

pacemaker activity in interstitial cells of Cajal by LPS via NF-κB and MAP kinase. World
Journal of Gastroenterology : WJG. 2013,19:1210-8.
CE

[50] Liu, C. Y., Mueller, M. H., Grundy, D., Kreis, M. E. Vagal modulation of intestinal afferent
sensitivity to systemic LPS in the rat. American Journal of Physiology-Gastrointestinal and Liver
Physiology. 2007,292:G1213-G20.
AC

[51] Gakis, G., Mueller, M. H., Hahn, J., Glatzle, J., Grundy, D., Kreis, M. E. Neuronal
activation in the nucleus of the solitary tract following jejunal lipopolysaccharide in the rat.
Autonomic Neuroscience. 2009,148:63-8.
[52] de Lartigue, G., Barbier de la Serre, C., Espero, E., Lee, J., Raybould, H. E. Diet-induced
obesity leads to the development of leptin resistance in vagal afferent neurons. Am J Physiol
Endocrinol Metab. 2011,301:E187-95.
[53] Hermes, S. M., Colbert, J. F., Aicher, S. A. Differential content of vesicular glutamate
transporters in subsets of vagal afferents projecting to the nucleus tractus solitarii in the rat. J.
Comp. Neurol. 2014,522:642-53.
 ACCEPTED MANUSCRIPT

[54] Peters, J. H., Gallaher, Z. R., Ryu, V., Czaja, K. Withdrawal and Restoration of Central
Vagal Afferents Within the Dorsal Vagal Complex Following Subdiaphragmatic Vagotomy. The
Journal of comparative neurology. 2013,521:3584-99.
[55] Czaja, K., Burns, G. A., Ritter, R. C. Capsaicin-induced neuronal death and proliferation of
the primary sensory neurons located in the nodose ganglia of adult rats. Neuroscience.
2008,154:621-30.
[56] Gallaher, Z. R., Ryu, V., Herzog, T., Ritter, R. C., Czaja, K. Changes in microglial
activation within the hindbrain, nodose ganglia, and the spinal cord following subdiaphragmatic

T
vagotomy. Neuroscience Letters. 2012,513:31-6.

IP
[57] Araújo, J. R., Tomas, J., Brenner, C., Sansonetti, P. J. Impact of high-fat diet on the
intestinal microbiota and small intestinal physiology before and after the onset of obesity.

CR
Biochimie. 2017,141:97-106.
[58] Magnusson, K. R., Hauck, L., Jeffrey, B. M., Elias, V., Humphrey, A., Nath, R., et al.
Relationships between diet-related changes in the gut microbiome and cognitive flexibility.

US
Neuroscience. 2015,300:128-40.
[59] Noble, E. E., Hsu, T. M., Jones, R. B., Fodor, A. A., Goran, M. I., Kanoski, S. E. Early-Life
AN
Sugar Consumption Affects the Rat Microbiome Independently of Obesity. J Nutr. 2017,147:20-
8.
[60] Chassaing, B., Miles-Brown, J., Pellizzon, M., Ulman, E., Ricci, M., Zhang, L., et al. Lack
M

of soluble fiber drives diet-induced adiposity in mice. American Journal of Physiology -

Gastrointestinal and Liver Physiology. 2015,309:G528-G41.
ED

[61] Topping, D. L., & Clifton, P. M. Short-chain fatty acids and human colonic function: roles
of resistant starch and nonstarch polysaccharides. Physiological reviews. 2001,81(3):1031-64.
PT

[62] Perry, R. J., Peng, L., Barry, N. A., Cline, G. W., Zhang, D., Cardone, R. L., et al. Acetate
mediates a microbiome-brain-β cell axis promoting metabolic syndrome. Nature. 2016,534:213-
7.
CE

[63] Ohira, H., Tsutsui, W., Fujioka, Y. Are Short Chain Fatty Acids in Gut Microbiota
Defensive Players for Inflammation and Atherosclerosis? J Atheroscler Thromb. 2017,24:660-
AC

72.

[64] Tolhurst, G., Heffron, H., Lam, Y. S., Parker, H. E., Habib, A. M., Diakogiannaki, E., et al.
Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled
receptor FFAR2. Diabetes. 2012,61:364-71.

[65] Brooks, L., Viardot, A., Tsakmaki, A., Stolarczyk, E., Howard, J. K., Cani, P. D., et al.
Fermentable carbohydrate stimulates FFAR2-dependent colonic PYY cell expansion to increase
satiety. Molecular Metabolism. 2017,6:48-60.

[66] Zeng, H., Chi, H. Metabolic control of regulatory T cell development and function. Trends
in immunology. 2015,36:3-12.
 ACCEPTED MANUSCRIPT

[67] Smith, P. M., Howitt, M. R., Panikov, N., Michaud, M., Gallini, C. A., Bohlooly-Y, M., et
al. The microbial metabolites, short chain fatty acids, regulate colonic Treg cell homeostasis.
Science (New York, N.Y.). 2013,341:10.1126/science.1241165.
[68] Singh, N., Gurav, A., Sivaprakasam, S., Brady, E., Padia, R., Shi, H., et al. Activation of the
receptor (Gpr109a) for niacin and the commensal metabolite butyrate suppresses colonic
inflammation and carcinogenesis. Immunity. 2014,40:128-39.
[69] Vinolo, M. A., Rodrigues, H. G., Hatanaka, E., Sato, F. T., Sampaio, S. C., Curi, R.
Suppressive effect of short-chain fatty acids on production of proinflammatory mediators by

T
neutrophils. J Nutr Biochem. 2011,22:849-55.

IP
[70] Wu, X., Chen, P. S., Dallas, S., Wilson, B., Block, M. L., Wang, C.-C., et al. Histone
deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect

CR
dopaminergic neurons. The international journal of neuropsychopharmacology / official
scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP).
2008,11:1123-34.

US
[71] Stefanko, D. P., Barrett, R. M., Ly, A. R., Reolon, G. K., Wood, M. A. Modulation of long-
term memory for object recognition via HDAC inhibition. Proceedings of the National Academy
of Sciences of the United States of America. 2009,106:9447-52.
AN
[72] Meyer, D., Stasse-Wolthuis, M. The bifidogenic effect of inulin and oligofructose and its
consequences for gut health. Eur. J. Clin. Nutr. 2009,63:1277-89.
M

[73] Cani, P. D., Neyrinck, A. M., Maton, N., Delzenne, N. M. Oligofructose Promotes Satiety in
Rats Fed a High-Fat Diet: Involvement of Glucagon-Like Peptide-1. Obes. Res. 2005,13:1000-7.
ED

[74] Jiang, T., Gao, X., Wu, C., Tian, F., Lei, Q., Bi, J., et al. Apple-Derived Pectin Modulates
Gut Microbiota, Improves Gut Barrier Function, and Attenuates Metabolic Endotoxemia in Rats
with Diet-Induced Obesity. Nutrients. 2016,8:126.
PT

[75] Roopchand, D. E., Carmody, R. N., Kuhn, P., Moskal, K., Rojas-Silva, P., Turnbaugh, P. J.,
et al. Dietary Polyphenols Promote Growth of the Gut Bacterium <em>Akkermansia
CE

muciniphila</em> and Attenuate High-Fat Diet–Induced Metabolic Syndrome. Diabetes.

2015,64:2847-58.
AC

[76] Anhê, F. F., Roy, D., Pilon, G., Dudonné, S., Matamoros, S., Varin, T. V., et al. A
polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and
intestinal inflammation in association with increased &lt;em&gt;Akkermansia&lt;/em&gt; spp.
population in the gut microbiota of mice. Gut. 2015,64:872.
[77] Schneeberger, M., Everard, A., Gómez-Valadés, A. G., Matamoros, S., Ramírez, S.,
Delzenne, N. M., et al. Akkermansia muciniphila inversely correlates with the onset of
inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice.
Scientific Reports. 2015,5:16643.
[78] Plovier, H., Everard, A., Druart, C., Depommier, C., Van Hul, M., Geurts, L., et al. A
purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium
improves metabolism in obese and diabetic mice. Nat Med. 2017,23:107-13.
 ACCEPTED MANUSCRIPT

[79] Li, Z., Henning, S. M., Lee, R.-P., Lu, Q.-Y., Summanen, P. H., Thames, G., et al.
Pomegranate extract induces ellagitannin metabolite formation and changes stool microbiota in
healthy volunteers. Food & Function. 2015,6:2487-95.
[80] Paquette, M., Medina Larqué, A. S., Weisnagel, S. J., Desjardins, Y., Marois, J., Pilon, G.,
et al. Strawberry and cranberry polyphenols improve insulin sensitivity in insulin-resistant, non-
diabetic adults: a parallel, double-blind, controlled and randomised clinical trial. The British
Journal of Nutrition. 2017,117:519-31.
[81] Membrez, M., Blancher, F., Jaquet, M., Bibiloni, R., Cani, P. D., Burcelin, R. G., et al. Gut

T
microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice.
Faseb J. 2008,22:2416-26.

IP
[82] Song, L., Gao, Y., Zhang, X., Le, W. Galactooligosaccharide improves the animal survival

CR
and alleviates motor neuron death in SOD1G93A mouse model of amyotrophic lateral sclerosis.
Neuroscience. 2013,246:281-90.
[83] Savignac, H. M., Couch, Y., Stratford, M., Bannerman, D. M., Tzortzis, G., Anthony, D. C.,

US
et al. Prebiotic administration normalizes lipopolysaccharide (LPS)-induced anxiety and cortical
5-HT2A receptor and IL1-beta levels in male mice. Brain Behav Immun. 2016,52:120-31.
AN
[84] Schmidt, K., Cowen, P. J., Harmer, C. J., Tzortzis, G., Errington, S., Burnet, P. W. J.
Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy
volunteers. Psychopharmacology. 2015,232:1793-801.
M

[85] Messaoudi, M., Lalonde, R., Violle, N., Javelot, H., Desor, D., Nejdi, A., et al. Assessment
of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and
ED

Bifidobacterium longum R0175) in rats and human subjects. British Journal of Nutrition.
2010,105:755-64.
[86] Le Blay, G., Michel, C., Blottiere, H., Cherbut, C. Raw potato starch and short-chain fructo
PT

oligosaccharides affect the composition and metabolic activity of rat intestinal microbiota
differently depending on the caecocolonic segment involved. J. Appl. Microbiol. 2003,94:312-
20.
CE

[87] McVey Neufeld, K. A., Mao, Y. K., Bienenstock, J., Foster, J. A., Kunze, W. A. The
microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the
AC

mouse. Neurogastroenterol. Motil. 2013,25:183-e88.

[88] Castillo-Ruiz, A., Mosley, M., George, A. J., Mussaji, L. F., Fullerton, E. F., Ruszkowski,
E. M., et al. The microbiota influences cell death and microglial colonization in the perinatal
mouse brain. Brain. Behav. Immun. 2017.
[89] Wostman, B., Larkin, C., Moriarity, A., Bruckner-Kardoss, E. Dietary intake, energy
metabolism, and excretory losses of adult make germfree Wistar rats. Lab. Anim. Sci.
1983,33:46-50.
[90] Yamamoto, M., Yamaguchi, R., Munakata, K., Takashima, K., Nishiyama, M., Hioki, K., et
al. A microarray analysis of gnotobiotic mice indicating that microbial exposure during the
 ACCEPTED MANUSCRIPT

neonatal period plays an essential role in immune system development. BMC Genomics.
2012,13:335.

[91] Myer, P. R., Kim, M., Freetly, H. C., Smith, T. P. Evaluation of 16S rRNA amplicon
sequencing using two next-generation sequencing technologies for phylogenetic analysis of the
rumen bacterial community in steers. J. Microbiol. Methods. 2016,127:132-40.

[92] Hahn, A., Sanyal, A., Perez, G. F., Colberg-Poley, A. M., Campos, J., Rose, M. C., et al.
Different next generation sequencing platforms produce different microbial profiles and diversity
in cystic fibrosis sputum. J. Microbiol. Methods. 2016,130:95-9.

T
[93] Rintala, A., Pietila, S., Munukka, E., Eerola, E., Pursiheimo, J. P., Laiho, A., et al. Gut

IP
Microbiota Analysis Results Are Highly Dependent on the 16S rRNA Gene Target Region,
Whereas the Impact of DNA Extraction Is Minor. J Biomol Tech. 2017,28:19-30.

CR
[94] Allen, N. J., Barres, B. A. Neuroscience: Glia -- more than just brain glue. Nature.
2009,457:675-7.

US
[95] Kabouridis, P. S., Lasrado, R., McCallum, S., Chng, S. H., Snippert, H. J., Clevers, H., et al.
Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron.
2015,85:289-95.
AN
[96] Vantrappen, G., Janssens, J., Hellemans, J., Ghoos, Y. The Interdigestive Motor Complex of
Normal Subjects and Patients with Bacterial Overgrowth of the Small Intestine. Journal of
Clinical Investigation. 1977,59:1158-66.
M

[97] Diepenbroek, C., Quinn, D., Stephens, R., Zollinger, B., Anderson, S., Pan, A., et al.
Validation and characterization of a novel method for selective vagal deafferentation of the gut.
ED

Am J Physiol Gastrointest Liver Physiol. 2017:ajpgi 00095 2017.

PT
CE
AC