ArticlePDF AvailableLiterature Review

Abstract and Figures

The human gut is a composite anaerobic environment with a large, diverse and dynamic enteric microbiota, represented by more than 100 trillion microorganisms, including at least 1000 distinct species. The discovery that a different microbial composition can influence behavior and cognition, and in turn the nervous system can indirectly influence enteric microbiota composition, has significantly contributed to establish the well-accepted concept of gut-brain axis. This hypothesis is supported by several evidence showing mutual mechanisms, which involve the vague nerve, the immune system, the hypothalamic-pituitary-adrenal (HPA) axis modulation and the bacteria-derived metabolites. Many studies have focused on delineating a role for this axis in health and disease, ranging from stress-related disorders such as depression, anxiety and irritable bowel syndrome (IBS) to neurodevelopmental disorders, such as autism, and to neurodegenerative diseases, such as Parkinson Disease, Alzheimer Disease etc. Based on this background, and considering the relevance of alteration of the symbiotic state between host and microbiota, this review focuses on the role and the involvement of bioactive lipids, such as the N-acylethanolamine (NAE) family whose main members are N-arachidonoylethanolamine (AEA), palmitoylethanolamide (PEA) and oleoilethanolamide (OEA), and short chain fatty acids (SCFAs), such as butyrate, belonging to a large group of bioactive lipids able to modulate peripheral and central pathologic processes. It is well established their effective role in inflammation, acute and chronic pain, obesity and central nervous system diseases. It has been shown a possible correlation between these lipids and gut microbiota through different mechanisms. Indeed, systemic administration of specific bacteria can reduce abdominal pain through the involvement of cannabinoid receptor 1 in rat; on the other hand, PEA reduces inflammation markers in a murine model of inflammatory bowel disease (IBD), and butyrate, producted by gut microbiota, is effective in reducing inflammation and pain in irritable bowel syndrome and IBD animal models. In this review, we underline the relationship among inflammation, pain, microbiota and the different lipids, focusing on a possible involvement of NAEs and SCFAs in the gut-brain axis and their role in central nervous system diseases. .
Content may be subject to copyright.
Send Orders for Reprints to reprints@benthamscience.ae
Current Medicinal Chemistry, 2017, 24, 1-22 1
REVIEW ARTICLE
0929-8673/17 $58.00+.00 © 2017 Bentham Science Publishers
Gut-brain Axis: Role of Lipids in the Regulation of Inflammation,
Pain and CNS Diseases
Roberto Russo†,a,*, Claudia Cristiano†,a, Carmen Avaglianoa, Carmen De Caroa,
Giovanna La Ranaa, Giuseppina Mattace Rasoa, Roberto Berni Cananib, Rosaria Melia and
Antonio Calignanoa
aDepartment of Pharmacy, “Federico II” University of Naples, via Domenico Montesano 49, 80131 Naples,
Italy; bDepartment of Translational Medicine-Pediatric Section, University of Naples “Federico II”, Naples,
Italy
A R T I C L E H I S T O R Y
Received: October 31, 2016
Revised: January 02, 2017
Accepted: January 09, 2017
DOI: 10.2174/09298673246661702161
13756
Abstract: The human gut is a composite anaerobic environment with a large, diverse and dy-
namic enteric microbiota, represented by more than 100 trillion microorganisms, including at
least 1000 distinct species. The discovery that a different microbial composition can influence
behavior and cognition, and in turn the nervous system can indirectly influence enteric mi-
crobiota composition, has significantly contributed to establish the well-accepted concept of
gut-brain axis. This hypothesis is supported by several evidence showing mutual mechanisms,
which involve the vague nerve, the immune system, the hypothalamic-pituitary-adrenal
(HPA) axis modulation and the bacteria-derived metabolites. Many studies have focused on
delineating a role for this axis in health and disease, ranging from stress-related disorders
such as depression, anxiety and irritable bowel syndrome (IBS) to neurodevelopmental disor-
ders, such as autism, and to neurodegenerative diseases, such as Parkinson Disease, Alz-
heimer’s Disease etc. Based on this background, and considering the relevance of alteration
of the symbiotic state between host and microbiota, this review focuses on the role and the
involvement of bioactive lipids, such as the N-acylethanolamine (NAE) family whose main
members are N-arachidonoylethanolamine (AEA), palmitoylethanolamide (PEA) and oleoile-
thanolamide (OEA), and short chain fatty acids (SCFAs), such as butyrate, belonging to a
large group of bioactive lipids able to modulate peripheral and central pathologic processes.
Their effective role has been studied in inflammation, acute and chronic pain, obesity and
central nervous system diseases. A possible correlation has been shown between these lipids
and gut microbiota through different mechanisms. Indeed, systemic administration of specific
bacteria can reduce abdominal pain through the involvement of cannabinoid receptor 1 in the
rat; on the other hand, PEA reduces inflammation markers in a murine model of inflammatory
bowel disease (IBD), and butyrate, producted by gut microbiota, is effective in reducing in-
flammation and pain in irritable bowel syndrome and IBD animal models. In this review, we
underline the relationship among inflammation, pain, microbiota and the different lipids, fo-
cusing on a possible involvement of NAEs and SCFAs in the gut-brain axis and their role in
the central nervous system diseases.
Keywords: Gut, brain, inflammation, IBS, pain, AEA, PEA, butyrate, mood, neurodegenerative disease.
1. INTRODUCTION
The human body, primarily the gastrointestinal (GI)
tract, is widely colonized by several species of bacteria
*Address correspondence to this author at the Via D. Montesano,
49; 80131 Naples, Italy; Tel: +39 081678465; Fax: +39 081678403;
E-mail: roberto.russo@unina.it
These authors contributed equally to this work
(about 1014 bacterialcells and 500-1,000 species), col-
lectively termed as the “human microbiota”. Their
whole genome is called “human microbiome” [1, 2].
Before birth, the human fetal gut is sterile, but few
hours after delivery, all the external stimuli, such as
environment, diet, maternal transfer or even the early
introduction of antibiotics, start to influence the coloni-
2 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Russo et al.
zation process leading, in each different infant, to an
adult-like gut microbiota profile, that will reach a cer-
tain stability in composition and number at 1 year of
age [3]. Given the high variability of bacterial commu-
nities among individuals, lately subjects have been
classified into three distinct clusters -enterotypes-
based on the prevalence of key bacterial genera in their
gut microbiota composition (i.e. Bacteroides,
Prevotella or Ruminococcus genes). However, different
sampling analysis and methods influence the detection
of enterotypes, with divergent interpretation of results
[4].
It is worth noting that the relationship established by
commensal bacteria with the host seems to be more
mutually symbiotic rather than a parasitism with hu-
man host [5]. In fact, the gut microbiota contributes to
the development of immune system, behavior and cog-
nition [6] and, remarkably, concur to maintain normal
homeostasis through three major functions: (i) it helps
and protects the host against pathogen colonization by
nutrient competition and production of active anti-
microbial agents, such as hydrogen peroxide, acido-
phylin, acidolin, lactallin, etc. (ii) It stimulates the in-
nate immunity and limits production of toxins and
penetration of pathogenic microorganism into gut tis-
sues adjusting the sensitization and/or the tolerance (iii)
It facilitates nutrient absorption by metabolizing indi-
gestible dietary fibers, or tri/tetrasaccharides, to mono-
saccharides producing B-group vitamins.
Microbiota and central nervous system (CNS)
comunication, known as microbiota-gut-brain axis, is
able to influence neurotransmission and behavior and
occurs through different pathways [7, 8]. In particular,
visceral afferent activity is known to modulate behav-
ioral and cognitive process through brainstem nuclei
and cholinergic and noradrenergic projections, to cor-
tex/cognitive process [9]. This relationship is strongly
strenghtened by the high comorbidity between GI al-
terations and psychiatric disorders. Interestingly, im-
balance of the gut microbiota (dysbiosis) can contrib-
ute, among others, to the pathogenesis of inflammatory
bowel disorders (IBD) [10] and irritable bowel syn-
drome (IBS) [11], commonly described as gut-brain
axis disorders. These pathologies are characterized by
abdominal pain and/or discomfort associated with al-
tered bowel habits. In more than one case, chronic in-
flammation or immune activation, in IBD and IBS, can
contribute to predispose individuals to neurological and
neurodegenerative diseases through the cytokines re-
lease into the bloodstream [12,13]. Specific changes in
the inflammatory process, in pain threshold and in the
intestinal innate immune system have been supposedly
linked to be under lipid regulation and host metabo-
lism. A large body of evidence underlines the correla-
tion between lipids and microbiota [14] identyfing en-
docannabionids, N-acylethanolamines (NAEs) and bu-
tyrate among the main compounds having a key role in
several pathologies associated to gut inflammation,
pain and central disorders. As reported by Rousseaux et
coworkers [15], systemic administration of Lactobacil-
lus acidophilus strain reduces abdominal pain through
the involvement of cannabinoid receptor (CB); moreo-
ver, it has been reported that an indirect cannabi-
nomimetic acylethanolamide, palmitoylethanolomide
(PEA), reduces inflammation in a mouse model of IBD
[16]. On the other side, butyrate, a short chain fatty
acid (SCFA) produced in the colon and nowadays
considered an active postbiotic, has proved to be highly
effective in reducing pain discomfort in IBS and IBD,
controlling inflammation and peripheral nerves sensiti-
zation [17].
The multiplicity of different lipids involved in
pathological status, as well as in spontaneous recovery
or therapeutic approach, underlines the role of these
molecules in cellular trafficking and signalling, in
structure and in energy storage, thus indicating their
possible role as risk markers in distinct cellular
physiopathological functions. Here we analyze how the
gut microbiota and lipidic transmitters are able to
modulate the inflammatory diseases of the intestinal
tract which represent the “primo movens” to CNS dis-
eases (Fig. 1).
2. GUT-BRAIN AXIS
Many evidences have shown that gut microbiota in-
fluences human brain development and its function.
The exchange of regulatory signals through an integra-
tive and bidirectional communication between the gas-
trointestinal tract and the CNS represents the gut-brain
axis. The complexity of these interactions suggested,
for the first time in the 1880s, the term gut-brain axis
by William James andCarl Lange, refined later by Wal-
ter Cannon [18]. Specifically, this network includes the
CNS, both brain and spinal cords, the autonomic nerv-
ous system, the enteric nervous system (ENS) and the
HPA. This crosstalk has revealed a complex communi-
cation system that not only ensures the proper mainte-
nance of GI homeostasis, but also is likely to have mul-
tiple effects influencing brain development, mood and
cognitive functions. Indeed, emerging data supports the
role of microbiota in anxiety and depressive-like be-
haviors [19, 20] and, more recently, in autism too [21].
Role of Lipids in the Gut-brain Axis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 3
Furthermore, the direct or indirect release of signaling
molecules, such as serotonin, norepinephrine and
dynorphins, cytokines and antimicrobial peptides into
the gut lumen, underlines that the CNS has an immedi-
ate influence on gut microbiota [22]. Indeed, disregula-
tion of serotonin in the human gut has been implicated
in anassorted group of GI disorders, such as IBD and
IBS. Moreover, norepinephrine and dynorphins are re-
leased into the gut lumen during perturbation of GI
homeostasis [23]. Recently, it has been suggested that
there is a direct interaction between gut microbiota and
ENS. Kunze et al. [24] observed that Lactobacillus
reuteri enhanced the excitability of colonic neurons in
naive rats and, more recently, it has been found that
both Lactobacillus rhamnosus and Bacteroides fragilis
are able to activate intestinal afferent neurons [25].
In the recent years, most studies using germ-free
(GF) and probiotic- or antibiotic-treated animals indi-
cate that enteric microbiota strongly impacts gut-brain
axis. Accordingly, in the absence of gut bacteria, as
happens in GF rodents, the HPA axis abnormally de-
velops, leading to altered stress response, reducing hip-
pocampus levels of brain derived neurotrophic factor
(BDNF)-mRNA and protein [26]. In addition, GF mice
also show immune defects at both structural and cellu-
lar levels [27, 28]. During early stages of life, the colo-
nization of the body by different microorganisms offers
abundance of antigens, which are critical for a healthy
maturation of the immune system [29,30].
As above mentioned, vagal activation is necessary
for a series of physiological effects and, with its
approximately 80% afferent fibers, it relays signals
from peripheral organs -including GI tract- to the CNS,
modulating with a still unclear mechanism cognition
and behavior. Although vagotomy abolished some of
these effects, as reported in the studies on mice fed
with probiotics or pathogens [31-33], others revealed
that behavior modification are independent from vagus
Fig. (1).
4 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Russo et al.
pathway [34]. Therefore, vagous nerve seems not to
be the only mediator of microbiota-gut-brain interac-
tion. An example of vagal-independent communication
is given by the immune signaling, which plays a role in
both normal brain function and neurodegenerative dis-
eases [35]. The immune activation in the gut elicited by
local microbes can cause an alteration of barrier func-
tion, activation of ENS and changes in sensory-motor
function [36]. Several evidences demonstrated that
probiotics can improve intestinal barrier function and
decrease the immune cell activation both locally and
systemically [37, 38]. Moreover, they can induce im-
mune modulatory effects in gut-brain axis disorders
characterized by “leaky gut.” This hypothesis, is sup-
ported by the evidence that chronic stress is able to dis-
rupt the continuity of intestinal barrier, making it
“leaky” and increasing the permeability to ions and
bacterial peptides [39], triggering the immune re-
sponse. Other studies have shown that stress can influ-
ence microbial colonization, affecting pain pathways.
In addition, treatment with antibiotics in early life is
associated with visceral hypersensitivity [40]. Actually,
mice exposed to a social disruption stressor showed an
altered gut microbiota, as well as increased circulating
levels of cytokines [41]. In particular, stress-induced
reduction of Lactobacillus reuteri, a specific immuno-
modulatory species of bacteria, leads to an increased
proinflammatory gene expression and monocyte differ-
entiation [42, 43]. This results in an altered gut micro-
biota, which in turn can enhance the ability of enteric
pathogens to colonize the intestine [44]. It has also
been shown that stress is able to modulate the levels of
intestinal secretory IgA, influencing intestinal homeo-
stasis, inflammatory response and dysbiosis [45]. Fur-
thermore, gut bacteria can stimulate circulating cytoki-
nes, which in turn can influence the brain function [46,
47]. This condition occurs for example, in the clas-
sic sickness behavior where pro-inflammatory cyto-
kines, acting on the CNS, cause low motivation to eat,
exaggerated pain response and slowed psychomotor
functions [48].
3. ENDOCANNABINOIDS, ACYLETHANOLA-
MIDES AND SHORT CHAIN FATTY ACIDS
(SCFAS)
N-arachidonoylethanolamine (anandamide or AEA),
a member of a large group of bioactive lipids named N-
acylethanolamine family, was the first endogenous
agonist discovered for CB [49]. Another class of lipids
active on CB are the fatty acid glycerol esters to which
belongs the second ligand of CB, 2-arachidonoyl-
glycerol (2-AG), identified for the first time in the in-
testine [50]. During the last decade, it has been pointed
out that the physiological and pharmacological activi-
ties of endocannabinoids are the result of the modula-
tion of several cellular systems. This is not only re-
stricted on CB receptors, called cannabinoid receptor
CB1 and CB2. They are also able to interact with perox-
isome proliferator-activated receptors (PPAR)-types α
and γ, G-protein-coupled receptor (GPR)55 [51], vanil-
loid receptor 1 [52], and through the modulation of cal-
cium and potassium channels. CB receptors are the
members of G-protein-coupled membrane receptors
family: in particular, CB1 is mostly abundant in differ-
ent brain areas, as well as in peripheral nerve terminals,
while CB2 is mainly expressed in lymphoid tissues,
myeloid cells and spinal cord, modulating immune re-
sponse and pain [53]. The endocannabinoid system also
contributes by multiple mechanisms to the regulation
of both gut and adipose tissue functions. In particular,
it modulates gastric emptying and motility [54], food
intake, satiety and postprandial glycaemia [55, 56].
Moreover, it also has a major role in facilitating adipo-
genesis and adipose tissue expansion and in regulating
inflammation [57, 58]. The modulation of visceral pain
perception by bacteria through the endocannabinoid
system was shown in patients with irritable bowel syn-
drome, who commonly have abdominal pain. Indeed,
oral administration of specific Lactobacillus acidophi-
lus strain modulates the expression of CB receptors, as
well as µ-opioid receptor in intestinal epithelial cells,
enhancing the analgesic pathways underlying these re-
ceptors [15]. Obesity is usually associated with changes
in the composition of the gut microbiota, which in turn
induce gut barrier dysfunction and increase gut perme-
ability [59]. This leads to the increased levels of
lipopolysaccharide serum (LPS). Several studies have
shown that treatment with LPS influences the produc-
tion of endocannabinoids by immune cells, suggesting
a strong link between bacterial components and the
endocannabinoid system [60, 61]. In addition, in obese
mice, the gut microbiota modulates the endocannabi-
noid tone and adipose tissue, regulating key enzymes
related to NAEs metabolism and activity as N-acyl
phosphatidylethanolamine-specific phospholipase D
(NAPE-PLD), CB1 and fatty acid amide hydrolase
(FAAH) expression, and AEA concentration [62]. The
endocannabinoid system controls gut permeability and
endotoxaemia in obesity and diabetes, through a CB1-
dependent mechanism. Specific CB antagonism de-
creases gut permeability, acting as ‘gate keepers’ [63].
Furthermore, it has been proven that specific deletion
of NAPE-PLD in adipose tissue induces an obese phe-
notype in normal-diet-fed mice, characterized by glu-
Role of Lipids in the Gut-brain Axis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 5
cose intolerance, adipose tissue inflammation, altered
lipid metabolism and affects gut microbiota composi-
tion. It has been demonstrated that chronic administra-
tion of a potent CB1 agonist, HU-210, leads to severe
metabolic disorders, such as glucose intolerance, mus-
cle macrophage infiltration and lipid content [64].
However, the effect of the endocannabinoid system
on gut-barrier function might be due to other mecha-
nisms during intestinal inflammation [65]. Everard and
co-workers [66] showed that administration of Akker-
mansia muciniphila in high-fat diet fed mice increased
the intestinal levels of 2-AG, improved gut-barrier
function and decreased endotoxaemia. Although the
mechanisms involved are unknown, the increased level
of 2-AG by a selective inhibitor of monoacylglycerol
lipase can protect mice from colitis and reduce endo-
toxaemia and systemic inflammation [67]. Moreover,
the deletion of the intestinal epithelial Myeloid differ-
entiation primary response gene (MYD)88, which is
involved in the signaling of most Toll-like receptors,
partially protects against obesity, diabetes, inflamma-
tion and disruption of the gut barrier, increasing the
anti-inflammatory endocannabinoids (2-AG and AEA)
[68].
In addition to these “sheer” endocannabionoids,
other related NAEs, such as N-palmitoylethanolamine
and N-oleoylethanolamine (OEA), have also shown to
modulate gut microbiota. Specifically, PEA has a
prominent role in acute and chronic inflammation, as
well as in pain [69]. Moreover, it has been suggested
that these compounds have a role in the regulation of
energy homeostasis, through PPAR-α mediated
mechanism. Reduction of PEA levels was found in ge-
netic obese mice, possibly linked to increased N-
acylethanolamine acid amidase (NAAA) activity, the
enzyme responsible for the metabolism of PEA that
regulates its levels in the colon. In two murine models
of IBD, NAAA inhibition increases PEA levels and
reduces inflammation in colon [70, 71]. Apart from the
well known role of PEA on behavior, inflammation and
pain [72], it has been demonstrated that peripheral ad-
ministration of PEA in ovariectomized obese rats in-
creases the expression of leptin receptor in the hypo-
thalamus and this effect is related to the reversal of
leptin resistance and the suppression of food intake and
fat accumulation [73]. OEA is considered a fat sensor,
as it mediates the response of the gut to the consump-
tion of high-fat meals [74], and regulates thermogenic
processes through PPAR-α [75]. PPARs have been
shown to be regulated by a number of bacterial patho-
gens, including Helicobacter pylori and Mycobacte-
rium tuberculosis [76, 77], greatly impacting disease
severity.The role of PPARs in gut inflammation has
been recognized. Indeed, PPARγ agonists are used to
treat type-2 diabetes and are known to reduce colitis in
mice [78]. Moreover, PPARγ heterozygous mice ex-
hibit an increased susceptibility to experimentally in-
duced colitis [79], indicating that PPARγ are involved
in maintaining gut homeostasis. PPARs activation has
been shown to improve the severity of inflammatory
bowel disease in rodent DSS, trinitrobenzene sulphonic
acid, and ischemic colitis model [80]. Finally, PPARγ
is reduced in colonic epithelial cells from ulcerative
colitis (UC) patients, suggesting PPARγ role in the gut
[81].
Butyrate, a SCFA, can reduce, as PEA or OEA, in-
flammation and glucose tolerance too in a model of
steatosis induced by high fat diet in rats [82]. SCFAs,
the final products of fermentation of dietary fiber in the
colon, are compounds with an aliphatic tail of less than
six carbon atoms. Among different SCFAs, butyrate is
known to modulate numerous processes, from the main
energy source for colonocytes [83], to signal metabolite
affecting epithelial cell proliferation, to apoptosis and
differentiation [84]. All these intestinal effects are as-
cribed to butyrate [85], indicating its possible therapeu-
tic indications in many GI disorders and in IBD, where
butyrate reveals anti-inflammatory properties [86].
Based on all its characteristics, butyrate can be consid-
ered a post-biotic given that is a nonviable bacterial
metabolic product obtained from microorganisms that
have biologic activity in the host. The importance of
butyrate supplementation in UC has been proven by the
impaired butyrate metabolism in intestinal inflamed
mucosa [87]. This deficiency results from the reduction
of butyrate uptake by the inflamed mucosa due to down
regulation of the monocarboxylate transporter (MCT)-1
expressed on the apical membrane of intestinal epithe-
lium [88]. Luhers and coworkes [89] showed that the
administration of butyrate to patients with UC sup-
pressed mucosal inflammation and decreased NF-κB
activation in lamina propria macrophages. Moreover, in
IBS, supplemental therapy with butyrate can reduce the
frequency of selected clinical symptoms, without a sig-
nificant effect on the reduction symptoms severity [90].
The effects exerted by butyrate are multiple and in-
volve several distinct mechanisms of action. It is an
anti-inflammatory agent, primarily inhibiting NF-κB
activation [91], moreover it has a well-known epige-
netic mechanism through inhibition of histone deacety-
lase (HDAC) [92], and also acts as signal molecules on
Free Fatty Acid Receptor 2 (FFAR2, GPR43) and
FFAR3 (GPR41) [93]. Recently, it has been demon-
6 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Russo et al.
strated that the effect of butyrate is related to PPARs
involved in the control of inflammatory enzymes ex-
pression and pain [94]. In fact repeated oral butyrate-
based compound administrations increase pain thresh-
old in mice both in acute and chronic pain models, and
these effects are PPARs mediated. In agreement with
these data, many studies have shown that the anti-
inflammatory activity of butyrate could be related to
the up-regulation of PPARγ [95].
4. DYSBIOSIS (IBD AND IBS) AND LIPIDS
The GI tract is the most complex organ of the hu-
man body. The intestinal mucosa, which is continu-
ously exposed to a variety of commensal microbiota
and food antigens, maintains intestinal homeostasis and
integrates both acquired and innate immune systems.
An alteration of this homeostasis can lead to abnormal
immune response to the enteric microbiota, causing
chronic inflammation. IBD are characterized by pro-
longed inflammation of all or part of the GI tract,
which in turn led to a malfunction of GI organs along
with abdominal pain, persistent diarrhea, cramping,
weight loss, rectal bleeding, fatigue with consequent
compromised quality of life [96, 97]. The two types of
IBD are Crohn’s Disease (CD) and UC. In details, CD
affects the GI tract from mouth to anus and is charac-
terized by abdominal pain, fever, weight loss and clini-
cal signs of bowel obstruction or diarrhea [98]. Instead,
UC damages solely colon, extending proximally
through the entire colon and rectum [99]. In 2011, Di
Sabatino and coworkers [100] showed that the content
of the major endocannabinoid AEA is reduced in IBD
inflamed mucosa as a consequence of both defective
synthesis and increased degradation. In this study, the
authors detected AEA, 2-AG, and PEA levels in gut
mucosa of IBD patients, and they found that AEA lev-
els, but not 2-AG and PEA ones, are significantly re-
duced in inflamed compared to uninflamed areas.
Moreover, they found a higher expression of CB1 but
not CB2. However, even today no clear causes have
been found about IBD; pathology development and
course may be affected by the complex interactions
between genetic factors [101], breast feeding, diet,
smoking, drugs etc. [102], and microbial factors [103],
sustaining inflammation, changes of mucosal barrier,
and defects in the immune system [104]. Intestinal in-
flammation in animal models related to the expression
of genes to IBD susceptibility suggests that IBD may
be caused by a dysregulated GI immune response to-
wards microbiota.
It has been reported that some immune processes
are modulated by the endocannabinoid system. Indeed,
cannabinoids reduce the MHC class II expression on
the surface of dendritic cells and inhibit peripheral T-
cell activation in response to LPS and anti-CD3 anti-
bodies [105]. Many in vivo studies on various animal
models of IBD demonstrated that the administration of
CB1 and/or CB
2 agonists improved colitis [106].
Moreover, several evidences indicate that FAAH plays
an important protective and restorative role in the early
stages of inflammation [107]. As shown by Storr and
coworkers [108] FAAH mRNA expression was altered
following TNBS injection in mice. Thus, the inhibition
of FAAH alleviates colitis symptoms by raising the
levels of endogenous cannabinoids [109]. Furthermore,
there are evidence supporting the role of PEA as an
anti-inflammatory compound, capable of alleviate in-
flammation in murine models of IBD. In a matter of
fact, PEA reduces the macroscopic parameters of mur-
ine colitis, namely the colon weight/length ratio and the
weight of the cecal content [110]. Furthermore, PEA
significantly reduces proinflammatory cytokine pro-
duction and immune cell infiltration. Recently, it has
been shown that NAAA inhibitors were able to prolong
PEA half life, as a potential therapeutic strategy in the
IBD [16].
Recent studies have suggested that diet has an im-
portant role in the etiology of IBD. In particular, popu-
lation who eat several starch kinds (the main precursors
of SCFA) has low incidence to develop GI ailments,
such as IBD and IBS. Therapeutic use of butyrate has
been suggested in the treatment of chronic IBD. In-
deed, butyrate is an effective remedy to histological
healing of experimental colitis induced in rats by trini-
trobenzenesulphonic acid [111]. Moreover, UC exhib-
its an altered metabolism of SCFA in epithelial cells of
the colon [112] leading to low intra-luminal concentra-
tions of these fatty acids, contributing to mucosal dam-
age [113]. In some studies, butyrate administered lo-
cally in patients with UC, has shown positive effects,
accelerating the clinical, endoscopic and histological
healing process, when administered along with anti-
inflammatory drugs, such as mesalazine [114,115]. Fi-
nally, quantitative and qualitative changes in the com-
position of the enteric microbiota have been observed
in the IBD, through a decrease in the diversity and an
increase in the concentration of bacterial species [116,
117]. It was observed that in CD, the dysbiosis is char-
acterized by the loss of intestinal bacteria from the
Firmicutes phylum, including Faecalibacterium praus-
nitzii, which are the most important butyrate producing
Role of Lipids in the Gut-brain Axis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 7
bacterium in cluster IV of the Clostridium leptum
phylogenetic group in the gut [118].
IBS is characterized by the presence of abdominal
pain with one or a combination of the following symp-
toms: comorbid changes in stool appearance and al-
tered frequency of stooling and/or relief of pain upon
defecation [119]. Factors such as younger age, pro-
longed fever, anxiety, depression, and history of child-
hood physical and psychological abuse are often asso-
ciated with the development of this pathology after
acute infectious gastroenteritis [120]. Although IBS is a
highly common functional bowel disorder of unknown
origin and with an intricate pathophysiology, it is
commonly described as a disorder of the brain-gut axis,
including central, spinal cord, peripheral elements, in-
cluding the ENS and the immune system [121, 122]. It
was noticed that psychological stress is a predominant
factor on GI symptoms and exacerbation, likely be-
cause of the significant psychiatric co-morbidities, in-
cluding both anxiety and depression [123]. IBS symp-
toms have been previously linked with visceral hyper-
sensitivity and aberrant serotonin (5-HT) signaling.
Feng and coworker [124] showed a possible correlation
between 5-HT and the endocannabinoid system, in par-
ticular duodenal biopsies from IBS patients exhibited
increased 5-HT and decreased AEA levels, most likely
related to abdominal pain severity. They demonstrated
that the analgesic effect induced by acute intraduode-
nally injection of 5-HT involves vagal 5-HT3R-
mediated duodenal AEA release and downstream CB1
activation [21, 125]. Visceral pain is a common debili-
tating symptom of many disorders, such as GI (colic,
colitis) but also urogenital (interstitial cystitis, endome-
triosis) and thoracic (non-cardiac chest pain, angina)
ailments. Taken together it is clear that IBS has a com-
plex etiology and thus a multifaceted pathophysiology.
Moreover, low levels of NAEs in IBS patients may be
involved in hyperalgesia and in abdominal pain, and
cause alterations in the bowel motility, that could be
improved by direct or indirect CB or PPARs agonists
[126]. Indeed, in IBS patients, a decrease in PEA was
observed in comparison to healthy subjects, and this
reduction was associated with abdominal pain [127].
FAAH inhibitors have been suggested for their analge-
sic action in IBS patients, where visceral pain is one of
the major symptoms [128, 129]. Since FAAH inhibi-
tors act site-specifically in the GI tract, they could be
active both after systemic and topical (enemas) admini-
stration.
Butyrate represents a potential new compound for
IBS therapy. In fact, butyrate plays an important role
due to inhibitation of the signal of proinflammatory
cytokines, restoration of the microbial composition,
and also reduction of visceral pain. Banasiewicz and
coworkers [130] performed a double-blind, random-
ized, placebo-controlled study on patients with IBS,
who received microcapsulated butyric acid or placebo
as an adjunct to standard therapy. Four weeks later, the
patients showed a significant decrease in the frequency
of abdominal pain during defecation.
Recently, the role of sodium butyrate in pain behav-
iour and its derivative has been addressed, the N-(1-
carbamoyl-2-phenyl-ethyl) butyramide (FBA), identi-
fying different and converging genomic and non-
genomic mechanisms of action, which cooperate in
nociception control [94]. In this study, a significant
effect of both butyrate-based compounds was shown on
inflammatory visceral pain and on neuropathic pain.
5. GUT-BRAIN AXIS, CNS DISEASE AND LIP-
IDS
Gut microbiota imbalance is known to influence the
CNS functions and viceversa emotional and physio-
logical stress can influence gut microbiota through gut-
brain axis.
Therefore, it is a key factor understanding how gut
microbes could exert beneficial and therapeutic effect
on neurocognitive behaviors. Lately, a large body of
literature reports that several CNS disorders are related
to gut dysbiosis, accordingly with gut-brain axis hy-
pothesis.
5.1. Autism Spectrum Disorders
Autism spectrum disorder (ASD) is a range of neu-
rodevelopmental disorders characterized by repetitive
and stereotyped behaviours and dysfunction in com-
munication and social interactions skills [131, 132].
In recent years, many studies indicate that active
neuroinflammatory process in different brain regions is
relatively common in children with an ASD. It has
been revealed that they present GI problems and altered
GI flora underlying the pathological role of gut micro-
biota in this disease [133]. Many children with ASD
are also more likely to have IBS, so the effective reduc-
tion of GI symptoms, as diarrhea and bloating, is a
positive result considering the severity of autism. In
details, litterature show both a general gut microbiota
and specific strains alteration in the ASD. The first
study in 1988, exhibitted that Clostridium tetani can
induce autism. However, during the recent years, sev-
eral studies report numerous species under the Clostrid-
8 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Russo et al.
ium genus present in faecal samples of autistic children
[134]. In addition, other phyla as Bacteroidetes and
Firmicutes are implicated in autism [135]. Other human
gut microbiome studies, based on cultures from stool
samples, show that Bifidobacterium, Prevotella, Sut-
terella, Lactobacillus, Ruminococcus genera and Alca-
ligenaceae family are also linked with autism [136,
137].
Nonetheless, special diets or dietary supplementa-
tions may alter microbiota composition. Emerging data
have indicated that polyunsaturated fatty acids (PUFA)
levels in the plasma of children with ASD are signifi-
cantly low, in particular docosahexaenoic acid (DHA)
[138], and patients treated with dietary supplementa-
tions rich in omega-3 fatty acids and linoleic acid, sub-
stantially improve their behavioral symptoms [139].
Indeed, dietary omega-3 contributes to decrease in-
flammation and alter endocannabinoid system related
gene expression, reducing AEA, 2-AG and all the
acylethanolamides, with the exception for PEA [140].
These studies suggest beneficial effects in psychiatric
illness and their link with endocannabinoids [141]. In
particular, Schultz and co-workers [142] have pub-
lished the first study relating endocannabinoid system
and autism. Several studies describe that an abnormal
endocannabinoid signaling might contribute to ASD
symptoms and in particular, to normal social behavior.
Even though the direct activation of CB1 receptors
produces social deficit in rats [143], their suppression
can impair social interaction in a context-dependent
manner [144]. In addition, human studies have found
that marijuana may enhance sociability [145] and a
polymorphism in the CB1 gene modulates social gaze
[146].
In contrast, enhancing the endogenous level of
AEA, through the inhibition of its deactivating enzyme,
FAAH, or FAAH loss of function in mice increases
social interactions in two distinct ASD-related models,
BTBR T+tf/J (BTBR) and fmr1/ mice [147]. Fur-
thermore, substrates of FAAH as NAEs (AEA, OEA
and PEA) are increased after sociability tests, suggest-
ing a behavioral deficit due to reduced AEA tone in
critical brain areas. Interestingly, the down-regulation
of GPR55 and PPAR gene expression supports a role
for these receptors in autism [148]. Moreover, rats sub-
jected to the exposure of valproic acid, which is con-
sidered another murine model of autism, showed ab-
normalities in sociability and nociception tests and al-
terations in distinct elements of endocannabinoid sys-
tem [149].
SCFAs are linked to autism, being the object of
studies in autistic children [150]. Discordant data
shows an increase or decrease in the SCFA in faecal
samples, as the result of poor absorption based on the
increased gut permeability or excessive fermentation.
Interestingly, due to increased gut permeability or ab-
normal microbiota, the elevated level of SCFAs in the
circulatory system, may actually be negative in autistic
children. In particular, between them, propionic acid,
injected both peripherally and centrally in rodents, in-
duces repetitive behaviors and object preference [151],
and also alters basic mitochondrial functions [152]. In
agreement with these studies, prenatal or early postna-
tal exposure to valproate, an anti-epileptic and mood-
stabilizing drug and histone deacetylase inhibitor, like
butyrate, increases the risk of autism which was re-
cently used to induce a mouse model of ASD [153]. On
the other hand, chronic treatment with sodium butyrate
at postnatal period, improved social behavior in a
mouse model of autism [154]. All together, these stud-
ies point out that the time of exposure is crucial to re-
veal the effects of treatments on autism-like behavior.
5.2. Mood Disorders
Among the mental illnesses, depression and anxiety
are the result of a multi-factorial disease caused by be-
havioral disturbance and immunological, metabolic and
neurotransmitter dysregulation, common in people of
all ages [155-157]. They are also frequent conditions in
obesity, IBS patients and people with GI disturbances,
indicating a key role of the gut microbiota and the gut-
brain axis in these disorders [158-160]. Literature
shows three lines of evidence by which the gut micro-
biota is correlated to depression, namely through in-
flammation, the HPA axis or neurotransmitter signaling
pathways [161]. Moreover, early postnatal life repre-
sents an important stage for both the stress response
system and the colonization by gut microbiota, which
can influence the development of brain plasticity. Stud-
ies that use rats show that neonatal stress caused by
maternal separation leads to long-term changes in the
diversity and composition of gut microbiota [162],
which may contribute to alterations in stress-related
behavior persisting throughout life. In support of this,
the use of probiotics during the early stress period has
been shown to normalize basal corticosterone levels,
which are elevated after maternal separation [163]. In
this case, the use of GF mouse model is a useful tool to
study this brain-gut axis. GF mice showed exaggerated
HPA stress response and motor activity and less anxi-
ety-like behavior compared to specific pathogen-free
mice [164]. The modulation of gut microbiota is able to
Role of Lipids in the Gut-brain Axis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 9
reverse this HPA stress response in the GF mice due to
the use of Bifidobacterium infantis [165]. Since 1910,
different data from animal studies have provided the
evidence of this relationship and the important effects
of the use of probiotics on both GI and psychiatric
symptoms [166]. Indeed, species under Lactobacillus
and Bifidobacterium genus have showed anti-
depressant effects in different animal models [167,
168] and healthy volunteers have low score in anxiety
tests and low urinary free cortisol levels [169].
On the other hand, mental illnesses and stress-
related alterations may also affect the microbiota pro-
file [170]. High levels of inflammation markers, like
IL-6, TNF-α, and IL-1β [171], have been found in pa-
tients with depression; thus alteration in gut microbiota
may be linked to depressive symptoms through the in-
flammatory response. Indeed, in both human and ani-
mal studies, obesity and depression have been associ-
ated with low levels of Bacteroidetes [172] and signifi-
cant overgrowth of Acidaminococcaceae family [173].
Across human studies, an increase in Oscillibacter and
Alistipes has been reported in depressed subjects with
abdominal pain in IBS patients with inflammation
[174]. Moreover, a decrease in fecal Faecalibacterium,
known to have anti-inflammatory activity [176], has
been observed in depression [175]. Evidences from
previous studies suggest a role of different inflam-
mogenic enteric pathogenic gram-negative bacteria of
the Enterobacteriaceae family [177]. Although their
presence in normal gut flora results in the increased
permeability of the gut wall in depressed patients,
which may induce their translocation into the systemic
circulation, leading to behavioral and psychological
changes in both animals and humans [178].
In contrast, mice infection with Campylobacter je-
juni or Citrobacter rodentium increases anxiety-like
behaviour, accompanied by an increase in the neuronal
activation marker c-Fos in the CNS [179, 180],
whereas Trichuris muris displays the same effect
through immunological and metabolic mechanisms
[32].
According to the previous animal studies [181],
clinical trials revealed a profound lower expression of
various species of the Lachnospiraceae and Rumino-
coccaceae families, within the phylum Firmicutes, in
stool samples from patients with depression. The Lach-
nospiraceae family has also a role in the breakdown of
carbohydrates into SCFAs. Consequently, low level of
these bacteria leads to a reduction of SCFAs, which in
turn results in intestinal barrier dysfunction [182].
Among SCFAs, butyrate displays antidepressant
profile in animal models of depression and chronic
mild stress [183, 184]. Previous studies indicate an as-
sociation between omega-3 and omega-6 dietary sup-
plementation in people affected by different kind of
depressed mood, major depression, or post-partum de-
pression [185]. Considering that anxiety disorders are
common comorbid of major depression, the diet sup-
plementation may be an effective treatment of anxiety
as well [186, 187]. As for depression disorder treat-
ment, the possible mechanism is associated with re-
duced oxidative stress [188] and pro-inflammatory cy-
tokines [189].
Consistent with the signaling role of endocannabi-
noid/NAE in the regulation of appetite and metabolism,
inflammation, pain and mood disorders, it is interesting
to determine the beneficial effects of this system on
anxiety, as well as on the depressive disorders [190].
Despite the clear role of the endocannabinoid system in
mood disorders, different studies have reported a bi-
modal action in anxiety as in the depressive disorders.
Indeed, CB1 agonists at lower doses are anxiolytic,
while at higher doses are anxiogenic agents [191-193]
and similar bimodal responses were found using CB1
antagonists [194]. Human study revealed high level of
CB1 in post-mortem analysis of brain from patients
with major depression [195] and the use of CB1 an-
tagonists has been associated with an antidepressant-
like activity in several animal models of depression
[196]. By contrast, enhancing the AEA-CB1-receptor
signaling pathway by both CB1 agonists and inhibitors
of FAAH, has evidenced an antidepressant-like and
dose-dependent anxiolytic effects in both rats and mice,
without anxiogenic effects at high dose as happens for
CB1 [197-200]. Moreover, studies on CB1 knockout
mice have evidenced an increase in the depressive be-
havior [201]. In particular, taken together, we can as-
sume that the dose and the duration of treatment and
brain region of interest are important contributing fac-
tors to determine these contrasting results. In addition,
plasma levels of NAE molecules are particularly low in
woman with depression. Among NAEs, the antidepres-
sant-like activity of PEA was recently investigated in
combination with luteolin in a mouse model of anxi-
ety/depressive-like behavior [202]. Instead, exposure to
stress contributes to the increase in inflammatory
markers and the NAE catabolism, resulting in the
down-regulation of PEA and OEA levels. However,
AEA levels do not decline in a similar way to PEA and
OEA, although they share the same catabolic pathway.
The aforementioned studies about the correlation be-
10 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Russo et al.
tween gut microbiota and mood disorders could repre-
sent an important start point for future directions.
5.3. Neurodegenerative Diseases: Parkinson’s dis-
ease (PD), Alzheimer’s Disease(AD) and Multiple
Sclerosis (MS).
5.3.1. Parkinson’s Disease (PD)
Lewy bodies, a physiopathological characteristic of
PD, are constituted by aggregated proteins -mainly al-
pha synuclein and ubiquitin- also found in the ENS in
post mortem cases of early PD. This pathology is char-
acterized by a GI dysregulation that usually appears
several years before its typical symptoms. Braak and
coworkers [203] have hypothesized that this pathology
“begins” in the gut, and then spreads to the CNS via
vagus nerve and spinal cord. In fact, it has been dem-
onstrated that alpha synuclein injected in the gut wall
migrated to the brain via vagus nerve at a rate esti-
mated to be 5-10mm/day in rats [204]. It has been also
observed that colonic biopsies of PD patients have a
low-grade inflammation, with an increased expression
of pro-inflammatory cytokines compared to the control
subjects [205]. To date, the mechanisms involved in
these effects are not clear at all. However, it has been
suggested that matrix metalloproteinase-9, a major
component of the basement membrane, may contribute
to the pathogenesis of PD regulating blood-brain bar-
rier permeability through the release of cytokines and
free radicals and by cleaving vascular basal lamina
and/or tight junctions between cells within the
neurovascular unit [206, 207]. This process may con-
tribute to enhanced permeability and inflammation in
autoimmune encephalitis, hypoxic brain injury, and
other inflammatory diseases of the CNS [208].
It was noted that bacteria from the genera Blautia,
Coprococcus, and Roseburia were significantly lower
in PD patients compared to controls [209]. Moreover,
proteobacteria of the genus Ralstonia were signifi-
cantly more abundant in mucosa of PD than in controls,
which potentially tips the microbial balance within the
colon to a more inflammatory phenotype. Fecal micro-
biota collected from 72 PD subjects and age-matched
controls showed higher counts of Enterobacteriaceae
and reduced Prevotellaceae. Prevotella is known to
metabolize complex carbohydrates, providing SCFAs
as well as thiamine and folate, that promote a healthy
intestinal environment. Decreased Prevotella numbers
are likely to result in reduced production of these im-
portant micronutrients. However, the study did not
evaluate whether or not the patients had a history of GI
disturbances or significant inflammation. The impor-
tance of SCFA is highlighted by the same reports that
show association between PD and the abundance of
certain gut microbiota and show a reduction in fecal
SCFA concentrations [210, 211]. Nevertheless,
changes in the gut microbiome could have a direct ef-
fect on the CNS via the gut-brain axis with a chronic
mild systemic inflammation, possibly driving the
pathogenesis: in fact, microbiota can influence the de-
velopment of normal motor patterns and thus alteration
in its composition, especially if sustained it may poten-
tially lead to sensory-motor dysfunction [212]. PD pa-
tients show both dysmotility and alterations in the mi-
crobiota composition, but which one comes first is not
clear yet. The dysmotility has been proposed to result
from several factors including diet [213], autonomic
dysfunction, direct involvement of the ENS, or as a
side-effect of certain anti-Parkinsonian medications
[214]. An imbalance in the intestinal microbiota can
lead to increased permeability, as well as systemic and
intestinal inflammation, due to the translocation of bac-
terial products and of bacteria themselves [215]. Sev-
eral studies evidence the possibility of GI symptoms
even prior to the development of motor ones of PD
[216-218]. Moreover, recently, it has been showed that
IBS patients have higher hazard of PD compared to
population who are IBS free [219, 220].
Finally, on this basis, butyrate represents an impor-
tant tool not only for its role in the gut inflammation
(IBS and IBD), but also for its therapeutic potential
through histone remodelling, as an inhibitor of HDAC.
Epigenetics, the process by which gene activity is al-
tered without altering genetic information, has long
attracted interest in neurodegenerative disease, due to
the multifactorial origins of this pathology. Epigenetic
factors are thought to contribute to neuronal cell death
in PD [221], and it is suggested that alteration in epige-
netic regulation could hold therapeutic promise against
neurodegeneration [222, 223]. In particular, butyrate
has been shown to improve rotenone-induced models
of PD by preventing the death of dopaminergic neurons
[224]. Moreover, it has recently been shown that
BDNF expression decreases in n-3 PUFA deficient rats
and the upregulation of BDNF and its receptor has
been recognized as a potential mechanism of action of
n-3 PUFA [225, 226]. DHA supplementation in a non-
human primate (MPTP) model reduces levodopa-
induced dyskinesia, suggesting an innovative and safe
approach to improve the quality of life of PD patients
[227].
Increasing evidence suggests a prominent modula-
tory function of the cannabinoid signaling system in the
Role of Lipids in the Gut-brain Axis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 11
basal ganglia. As the cannabinoid signaling system un-
dergoes a biphasic pattern of change during the pro-
gression of PD, it explains the motor inhibition typi-
cally observed in patients with PD. Cannabinoid ago-
nists such as WIN-55,212-2 have been experimentally
demonstrated as neuroprotective agents in PD, with
respect to their ability to suppress excitotoxicity, glial
activation, and oxidative injury that cause degeneration
of dopaminergic neurons. Additional benefits provided
by cannabinoid related compounds, including OEA,
have been reported to possess efficacy against bradyki-
nesia and levodopa-induced dyskinesia in PD. Despite
promising preclinical studies on PD, the use of can-
nabinoids has not been studied extensively at the clini-
cal level [228]. However, a vast body of literature
documents the beneficial effects of exogenously ad-
ministered PEA in the experimental models of PD
[229, 230].
5.3.2. Alzheimer’s Disease (AD)
The mediterranean diet particularly rich in fibers,
anti-oxidants, and natural antimicrobic agents appears
to be able to support the growth of a beneficial micro-
biota and able to prevent the development of putrefac-
tive bacteria characterized by free radicals and toxic
metabolites production [231,232]. The great abundance
of flavonoids and radical scavengers correlate with pro-
tective aspects of the mediterranean diet and the bene-
ficial effects in neurodegenerative diseases, such as AD
[233, 234].
Considerable interest has been emerged in the un-
derstanding of the role of gut microbiota in the context
of AD. Gram-positive facultative anaerobic or mi-
croaerophilic Lactobacillus and other Bifidobacterium
species are copious in the GI tract. They are capable of
metabolizing glutamate to produce gamma-amino bu-
tyric acid (GABA), the major inhibitory neurotransmit-
ter in the CNS. Dysfunctions in GABA-signaling are
also linked to defects in synaptogenesis, and cognitive
impairment, including AD [235-237]. Another impor-
tant example is constituted by BDNF, a neurotrophin
that has pleiotropic effects on neuronal development,
differentiation, synaptogenesis and the synaptic plastic-
ity, underlying circuit formation and cognitive func-
tion. It has been found that BDNF exhibits in brains
and serum in patients with schizophrenia, anxiety and
AD [238]. In experimental infection models that lead to
alterations in the microbiota populations, BDNF ex-
pression is reduced in the hippocampus and cortex of
GF mice, and this reduction is associated with in-
creased anxiety behavior and progressive cognitive
dysfunction [16-239]. Finally, pre-clinical findings
show neurobiological mechanisms in which omega-3
alteration may contribute to the modulation of BDNF
in the hippocampus, the regulation of HPA axis, and in
neuroinflammation; all conditions related to dysbiosis.
It has also been shown that there exists an interac-
tion between microbiota and the N-methyl-D-aspartate
glutamate receptor. This receptor regulates synaptic
plasticity and cognition [240]. In the GI tract, there is a
small number of Cyanobacteria that produce β-N-
methylamino-L-alanine (BMAA), which is elevated,
for example, in the brain of AD and PD patients.
BMAA is an excitotoxin that activates metabotropic
glutamate receptor 5 and induces depletion of glu-
tathione. Thus, neurons and glial cells are unable to
effectively control reactive oxygen species and reactive
nitrogen species production in the brain. BMAA is also
implicated in the aggregation of the amyloid peptide as
seen in the AD, and in facilitating protein misfolding
tipically seen in the PD [241]. Interestingly, BMAA, a
neurotoxic amino acid normally not incorporated into
protein, has been linked with intra-neuronal protein
misfolding and neuroinflammation, that characterize
PD, AD and prion disease [242, 243]. Cyanobacteria
generate other neurotoxins, such as saxitoxin and ana-
toxin-α that may further contribute to neurological dis-
eases, especially during aging when the intestinal
epithelial barrier of the GI tract becomes more perme-
able [244]. Differences in exposure to pathogens and
genetic vulnerability toward microbioma-mediated
autoimmunity may be significant determinants of age-
related neurological disease course and outcome [245,
246]. Finally, it is well known that a sustained inflam-
mation, in gut, as much as in brain, would up-regulate
the expression of already triplicated amyloid precursor
protein gene and contribute earlier to brain amyloid
accumulation.
The endocannabinoids OEA and PEA have been
implicated in the pathology of neurodegenerative dis-
eases. In the particularly case of Alzheimer's disease,
different studies showed their proctective role in neu-
roinflammation, oxidative stress and neurodegeneration
[247, 248]. Recent in vivo evidence shows that fenofi-
brate reduces β-amyloid production in an Alzheimer's
disease transgenic mouse model and also PEA exerts
neuroprotective effect in an experimental model of AD
induced by Ab25-35 [249, 250]. Future investigations
are necessary to understand the possible involvement
of these compounds and the gut brain axis on this dis-
ease.
12 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Russo et al.
5.3.4. Multiple Sclerosis (MS)
MS is a chronic demyelinating inflammatory dis-
ease of CNS. For reproducing human MS, the most
widely and extensively studied animal model of auto-
immunity is experimental autoimmune encephalomye-
litis (EAE). EAE is induced after immunization with
antigens including myelin basic protein, myelin oli-
godendrocyte glycoprotein (MOG) or proteolipid pro-
tein in the presence of bacterial adjuvant, which leads
to myelin-reactive T cells responsible for the pathology
features. Recent studies have begun to underline the
correlation between microbiome and its relevant factors
to MS pathogenesis, with a particular attention on EAE
models [245]. Berer and coworkers [246] have demon-
strated that commensal microbiota is essential for the
development of spontaneous EAE in MOG TCR dou-
ble-transgenic mice, which simulates opticospinal MS.
GF RR mice were protected from EAE because of an
attenuated T helper 17 cells and auto-reactive B cell
responses [246]. EAE can also be induced by commen-
sal microbiota, since GF B6 mice developed this pa-
thology in a less severe manner, characterized by de-
creased interferon gamma and interleukin-17 re-
sponses. Antibiotic therapies could control EAE pro-
gression, modulating gut microbiota. Indeed, the hy-
pothesis that gut microbiome is the potential site of
molecular mimicry, is supported by the fact that with
induction of EAE, both the adjuvant and immunogen
need to be injected simultaneously [251]. However, it
might be a microbial antigen that triggers an inflamma-
tory response in the MS, and the only area of the hu-
man body with sufficient amounts of adjuvants in the
form of bacterial cell walls is the gut [252].
It has already been demonstrated that there is a posi-
tive correlation between the body mass index and the
risk of developing MS, especially at younger ages
[253]. Obesity is characterized by an inadequate accu-
mulation of white adipose tissue (WAT) that can lead
to a state of systemic inflammation called “metaflam-
mation”. WAT is not only involved in energy storage,
but also operates as an endocrine organ secreting pro-
inflammatory cytokine, such as tumor necrosis factor
(TNF)-α, IL-6 or leptin. The latter in particular, deeply
influencing T cell responses in the EAE [254, 255],
enhances phagocytosis and cytokine secretion in
macrophages and promotes CD4+ T cell proliferation
and survival [256]. Both monocytes and T cells are
present in MS lesions and patient-derived cerebrospinal
fluid, highly express leptin and leptin receptor [257,
258]. However, MS incidence is not necessarily ac-
companied by weight gain, so a direct effect of fatty
acids on immunity was supposed. Finally, as reported
above, PEA is able to increase the expression and sig-
naling of leptin receptor in the hypothalamus and these
effects might be related to the suppression of food in-
take and fat accumulation [73].
In MS patients, the levels of Clostridia clusters
XIVa and IV were shown to be reduced [259], both
formed by diverse bacterial species that are able to
produce SCFAs, such as butyrate [260], that displays
anti-inflammatory properties. This probably indicates
that a reduction in these microbes in MS patients may
be associated with disease [261]. Most studies have
demonstrated that the effect of SCFA mechanism in-
volves regulatory T cells (Tregs). In fact, the admini-
stration of butyrate to GF mice mimicked the effect of
Clostridium colonization and increased Treg levels in
colon lamina propria [262]. In the EAE model, SCFA
increases Tregs, while suppresses T helper 17 cells dif-
ferentiation [263], furthermore, butyrate as inhibitor of
HDAC could regulate the differentiation of Tregs in the
gut, producing an improvement of the disease. Indeed,
as reported in several papers, butyrate maintains acety-
lation of genes important for Treg function [264, 265].
To date, the in vivo amelioration of EAE remains un-
fortunately unclear, even if synthetic small inhibitors of
HDAC have already shown to decrease inflammation
in animal models of arthritis, IBD, asthma, diabetes,
cardiovascular diseases, and MS. Hence, SCFA as
naturally occurring nutrients [266] or fermentation
products may have a possible therapeutic use in auto-
immune diseases, such as MS by triggering the produc-
tion of anti-inflammatory Tregs. In fact, a higher per-
centage of MS patients exhibited antibody responses
against GI antigens in contrast to healthy control, indi-
cating a possible alteration in gut microbiome and im-
mune status [267]. Ezendam and coworkers have ob-
served that oral treatment with a single bacterium or
bacteria mixture can modulate EAE; in particular, Bifi-
dobacterium animalis reduced the duration of symp-
toms in a rat EAE model [268]. On the contrary, Lac-
tobacillus casei Shirota exacerbated EAE symptoms in
rats [269]. However, later studies indicated that Lacto-
bacilli, did not enhance but rather suppressed EAE in
rats [270]. This has been supported by other studies
using probiotic mixtures of strains under the Lactoba-
cillus genus. Indeed, Lactobacilli, alone or in combina-
tion with other strains of Bifidobacterium genus, allevi-
ates EAE symptoms in mice regulating pro- and anti-
inflammatory cytokine responses [271-273]. Probiotic
treatment with Bacteroides fragilis and Pediococcus
acidilactici (strain R037) also significantly reduced
mice susceptibility to EAE [274]. Furthermore, engi-
Role of Lipids in the Gut-brain Axis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 13
neered strains, such as Salmonella-CFA/I and Hsp65-
producing Lactococcus lactis can prevent EAE in mice
via Tregs-associated TGFβ and IL-13 signals [275].
Finally, Piccio and coworkers found that high-fat
diet increased EAE severity in mice. In contrast, caloric
restriction diet attenuated EAE symptoms, which was
associated with hormonal, metabolic and cytokine
changes rather than immune suppression [276]. It has
also been illustrated that mice fed with a high-salt diet
developed a more severe form of EAE, in line with the
ability of sodium chloride to activate T helper 17 cells
[277].Therefore, several evidences pointed out a central
role of gut microbiome in linking diet with MS and
EAE. However, endocannabinoids has some potential
to relieve, pain, spasms and spasticity in the MS [278]
showing as in AD and PD, a clear anti-inflammatory
and neuroprotective potential, while until now no stud-
ies have considered a possible link with the microbiota-
brain axis.
CONCLUSION
The concept of a gut-brain axis has been introduced
to describe a recognized integrative physiology be-
tween the GI and the CNS, with particular emphasis on
the key role of microbiota in this bidirectional system.
The interaction between the host and its gut micro-
biome is a complex relationship whose manipulation
could be essential in preventing or treating not only
various gut diseases, like IBS, IBD, but also CNS dis-
orders, such as mood alteration, AD, PD, and autism.
As previously described, dysbiosis can contribute to the
pathogenesis of IBD and IBS, commonly defined as
gut-brain axis disorders, producing a state of malaise
where pain is one of the main symptoms, but in more
than one case, this state of chronic inflammation or
immune activation can also contribute to neurological
and neurodegenerative diseases. Several evidences
suggest that many bioactive lipids (AEA, PEA, OEA,
butyrate) are involved in many physiological processes
directly linked with the maintenance of gut-barrier
function, the regulation of inflammation and pain, and
energy metabolism. In particular, it has been shown
that dysregulation of the endocannabinoid system as
well as PEA or OEA alteration, might play an impor-
tant role in etiopathogenesis of intestinal disorders, in-
cluding IBS and IBD. Recent evidence showed the
possibility to decrease the symptoms of these patholo-
gies through the manipulation of endocannabinoid or
PPARs system, suggesting that these targets could rep-
resent a new therapeutic strategy for these conditions.
Moreover, several evidences underline that mood dis-
orders or neurodegenerative diseases or autism are
characterized by changes in gut microbiota, but there is
a lack of data about lipidomics, CNS disorders and mi-
crobiota . Finally, the modulation of gut microbiota or
the supplementation with postbiotic molecules, restor-
ing normal intestinal integrity, could be beneficial to
peripheral and central disorders related to dysbiosis,
representing a good strategy to prevent the develop-
ment of diseases.
LIST OF ABBREVIATIONS
2-AG = 2-arachidonoylglycerol
5-HT = Serotonin
AD = Alzheimer’s Disease
AEA = Anandamide
ASD = Autism spectrum disorder
BDNF = Brain-derived neurotrophic factor
BMAA = β-N-methylamino-L-alanine
CB = Cannabinoid
CD = Crohn’s Disease
CNS = Central nervous system
DHA = Docosahexaenoic acid
EAE = Experimental autoimmune encepha-
lomyelitis
ENS = Enteric nervous system
FAAH = Fatty acid amide hydrolase
FFAR = Free Fatty Acid Receptor
GABA = Gamma-amino butyric acid
GF = Germ-free
GI = Gastrointestinal
GPR = G-protein-coupled receptor
HDAC = Histone deacetylase
HPA = Hypothalamic-pituitary-adrenal
IBD = Inflammatory Bowel Disease
IBS = Irritable Bowel Syndrome
LPS = Lipopolysaccharide
MCT = Monocarboxylate transporter
MOG = Myelin oligodendrocyte glycoprotein
MS = Multiple Sclerosis
MYD = Myeloid differentiation primary re-
sponse gene
14 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Russo et al.
NAAA = N-acylethanolamine acid amidase
NAE = N-acylethanolamine
NAPE-PLD = N-acyl phosphatidylethanolamine-
specific phospholipase D
OEA) = Oleoilethanolamide
PD = Parkinson’s disease
PEA = Palmitoylethanolamide
PPAR = Peroxisome proliferator-activated
receptors
PUFA = Polyunsaturated fatty acids
SCFA = Short chain acid
Tregs = Regulatory T cells
UC) = Ulcerative Colitis
WAT = White adipose tissue
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
We thank Giuseppe Russo for the English revision
of the manuscript.
REFERENCES
[1] Schloissnig S, Arumugam M, Sunagawa S, Mitreva M, Tap
J, Zhu A, Waller A, Mende DR, Kultima JR, Martin J, Kota
K, Sunyaev SR, Weinstock GM, Bork P. Genomic variation
landscape of the human gut microbiome. Nature,2013,
493(7430):45-50.
[2] Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM,
Knight R, Gordon JI. Thehuman microbiome project. Na-
ture,2007, 449(7164):804-10.
[3] Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO.
Development of the human infant intestinal microbiota.
PLoS biology,2007, 5:e177.
[4] Koren O, Knights D, Gonzalez A, Waldron L, Segata N,
Knight R, Huttenhower C, Ley RE. A guide to enterotypes
across the human body: meta-analysis of microbial commu-
nity structures in human microbiome datasets. PLoS compu-
tational biology, 2013, 9:e1002863.
[5] O'Hara AM, Shanahan F. The gut flora as a forgotten organ.
EMBO reports, 2006, 7:688-693.
[6] Sommer F, Bäckhed F. The gut microbiota--masters of host
development and physiology. NatRev Microbiol., 2013,
11(4):227-38.
[7] Collins SM, Surette M, Bercik P. The interplay between the
intestinal microbiota and the brain. Nat Rev Micro, 2012,
10:735-742.
[8] Montiel-Castro AJ, González-Cervantes RM, Bravo-
Ruiseco G, Pacheco-López G. The microbiota-gut-brain
axis: neurobehavioral correlates, health and sociality.Front
Integr Neurosci.,2013, 7:70.
[9] Berntson GG, Sarter M, Cacioppo JT. Ascending visceral
regulation of corticalaffective information processing. Eur J
Neurosci.,2003,18(8):2103-9.
[10] Li J, Butcher J, Mack D, Stintzi A. Functional impacts of
the intestinal microbiome in the pathogenesis of inflamma-
tory bowel disease. Inflamm Bowel Dis.,2014, 21(1):139-
153.
[11] Lee KN, Lee OY. Intestinal microbiota in pathophysiology
and management of irritable bowel syndrome. World J Gas-
troenterol.2014, 20(27):8886-8897.
[12] Czirr E, Wyss-Coray T. The immunology of neurodegen-
eration. J Clin Invest., 2012, 122(4):1156-63.
[13] Lampron A, Pimentel-Coelho PM, Rivest S. Migration of
bone marrow-derivedcells into the central nervous system
in models of neurodegeneration. J CompNeurol.,2013,
521(17):3863-76.
[14] Caesar R, Tremaroli V, Kovatcheva-Datchary P, Cani PD,
Bäckhed F. Crosstalkbetween Gut Microbiota and Dietary
Lipids Aggravates WAT Inflammation through TLRSignal-
ing. Cell Metab.2015, 22(4):658-68.
[15] Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, Dubu-
quoy L, Dubuquoy C,Merour E, Geboes K, Chamaillard M,
Ouwehand A, Leyer G, Carcano D, Colombel JF,Ardid D,
Desreumaux P. Lactobacillus acidophilus modulates intes-
tinal pain andinduces opioid and cannabinoid receptors. Nat
Med.,2007, 13(1):35-7.
[16] Alhouayek M, Bottemanne P, Subramanian KV, Lambert
DM, Makriyannis A, Cani PD, Muccioli GG. N-
Acylethanolamine-hydrolyzing acid amidase inhibition in-
creases colon N-palmitoylethanolamine levels and counter-
acts murine colitis. FASEB J.,2015, 29(2):650-61.
[17] Kannampalli P, Shaker R, Sengupta JN. Colonic butyrate-
algesic or analgesic? Neurogastroenterol Motil., 2011,
23(11):975-9.
[18] Cannon WB. Organization for physiological homeostasis.
Physiol Rev.1929, 9:399-431.
[19] Foster JA, McVey Neufeld KA. Gut-brain axis: how the
microbiome influences anxiety and depression. Trends Neu-
rosci., 2013, 36:305-312.
[20] Naseribafrouei A, Hestad K, Avershina E, et al. Correlation
between the human fecal microbiota and depression. Neu-
rogastro enterol Motil.,2014, 26:1155-62.
[21] Mangiola F, Ianiro G, Franceschi F, Fagiuoli S, Gasbarrini
G, Gasbarrini A. Gut microbiota in autism and mood disor-
ders. World J Gastroenterol., 2016, 22(1):361-8.
[22] Rhee SH, Pothoulakis C, Mayer EA. Principles and clinical
implications of the brain-gut-enteric microbiota axis. Na-
ture reviews. Gastroenterology & hepatology,2009, 6:306-
314.
[23] Hughes DT, Sperandio V. Inter-kingdom signalling: com-
munication between bacteria and their hosts. Nat. Rev. Mi-
crobiol., 2008, 6:111-120.
[24] Kunze WA, Mao YK, Wang B, Huizinga JD, Ma X, For-
sythe P, Bienenstock J. Lactobacillus reuteri enhances ex-
citability of colonic AH neurons by inhibiting calcium-
dependent potassium channel opening. Journal of cellular
and molecular medicine,2009, 13:2261-2270.
[25] Mao YK, Kasper DL, Wang B, Forsythe P, Bienenstock J,
Kunze WA. Bacteroides fragilis polysaccharide A is neces-
sary and sufficient for acute activation of intestinal sensory
neurons. Nature communications,2013, 4:1465.
[26] Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN,
Kubo C, Koga Y. Postnatal microbial colonization pro-
grams the hypothalamic-pituitary-adrenal system for stress
response in mice. TheJournal of physiology,2004, 558:263-
275.
Role of Lipids in the Gut-brain Axis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 15
[27] Round JL, Mazmanian SK. The gut microbiota shapes in-
testinal immune responses during health and disease.Nature
reviews Immunology,2009, 9:313-323.
[28] Corthésy B. Multi-faceted functions of secretory IgA at
mucosal surfaces.Front Immunol.,2013, 4:185.
[29] Cahenzli J, Balmer ML, McCoy KD. Microbial-immune
cross-talk and regulation ofthe immune system. Immunol-
ogy,2013,138(1):12-22.
[30] Hooper LV, Littman DR, Macpherson AJ. Interactions be-
tween the microbiota and the immune system. Sci-
ence,2012, 336(6086):1268-73.
[31] Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J,
Deng Y, Blennerhassett P, Macri J, McCoy KD, Verdu EF,
Collins SM. The intestinal microbiota affectcentral levels of
brain-derived neurotropic factor and behavior in
mice.Gastroenterology,2011, 141(2):599-609, 609.e1-3.
[32] Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac
HM, Dinan TG, Bienenstock J, Cryan JF. Ingestion of Lac-
tobacillus strain regulates emotionalbehavior and central
GABA receptor expression in a mouse via the vagus nerve.
Proc Natl Acad Sci U S A,2011, 108(38):16050-5.
[33] Cryan JF, Dinan TG. Mind-altering microorganisms: the
impact of the gutmicrobiota on brain and behaviour. Nat
Rev Neurosci.,2012, 13(10):701-12.
[34] Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X,
Deng Y,Blennerhassett PA, Fahnestock M, Moine D,
Berger B, Huizinga JD, Kunze W, McLean PG, Bergonzelli
GE, Collins SM, Verdu EF. The anxiolytic effect ofBifi-
dobacterium longum NCC3001 involves vagal pathways for
gut-braincommunication. Neurogastroenterol Motil.,2011,
23(12):1132-9.
[35] Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G,
Stan TM, FainbergN, Ding Z, Eggel A, Lucin KM, Czirr E,
Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER,
Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA,
Wyss-Coray T. The ageing systemic milieu negatively regu-
lates neurogenesis and cognitive function. Nature,2011,
477(7362):90-4.
[36] Vicario M, Alonso C, Guilarte M, Serra J, Martínez C,
González-Castro AM, Lobo B, Antolín M, Andreu AL,
García-Arumí E, et al. Chronic psychosocial stress induces
reversible mitochondrial damage and corticotropin-
releasing factor receptor type-1 upregulation in the rat intes-
tine and IBS-like gut dysfunction. Psychoneuroendocrinol-
ogy,2012, 37:65-77.
[37] Ewaschuk JB, Diaz H, Meddings L, Diederichs B, Dmy-
trash A, Backer J, Looijer-van Langen M, Madsen KL. Se-
creted bioactive factors from Bifidobacterium infantis en-
hance epithelial cell barrier function. Am J Physiol Gastro-
intest Liver Physiol.,2008, 295:G1025-34.
[38] O’Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen
K, O’Sullivan GC, Kiely B, Collins JK, Shanahan F, et al.
Lactobacillus and bifidobacterium in irritable bowel syn-
drome: symptom responses and relationship to cytokine
profiles. Gastroenterology,2005, 128:541-51.
[39] Ait-Belgnaoui A, Durand H, Cartier C, Chaumaz G, Eu-
tamene H, Ferrier L, Houdeau E, Fioramonti J, Bueno L,
Theodorou V. Prevention of gut leakiness by a probiotic
treatment leads to attenuated HPA response to an acute psy-
chological stress in rats. Psychoneuroendocrinology, 2012,
37(11):1885-95.
[40] O'Mahony SM, Felice VD, Nally K, Savignac HM, Claes-
son MJ, Scully P, Woznicki J, Hyland NP, Shanahan F,
Quigley EM, Marchesi JR, O'Toole PW, Dinan TG, Cryan
JF.Disturbance of the gut microbiota in early-life selectively
affects visceral pain in adulthood without impacting cogni-
tive or anxiety-related behaviors in male rats. Neuroscience,
2014, 277:885-901.
[41] Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG,
Lyte M.Exposure to a social stressor alters the structure of
the intestinal microbiota: implications for stressor-induced
immunomodulation. Brain Behav Immun.,2011, 25(3):397-
407.
[42] De Palma G, Collins SM, Bercik P, Verdu EF.The microbi-
ota-gut-brain axis in gastrointestinal disorders: stressed
bugs, stressed brain or both? J Physiol.,2014, 592(14):2989-
97.
[43] Powell ND, Sloan EK, Bailey MT, Arevalo JM, Miller GE,
Chen E, Kobor MS, Reader BF, Sheridan JF, Cole
SW.Social stress up-regulates inflammatory gene expres-
sion in the leukocyte transcriptome via β-adrenergic induc-
tion of myelopoiesis. Proc Natl Acad Sci U S A., 2013,
110(41):16574-9.
[44] Bailey MT, Dowd SE, Parry NM, Galley JD, Schauer DB,
Lyte M. Stressor exposure disrupts commensal microbial
populations in the intestines and leads to increased coloni-
zation by Citrobacter rodentium. Infect Immun.,2010,
78:1509-1519.
[45] Campos-Rodríguez R, Godínez-Victoria M, Abarca-Rojano
E, Pacheco-Yépez J, Reyna-Garfias H, Barbosa-Cabrera
RE, Drago-Serrano ME. Stress modulates intestinal secre-
tory immunoglobulin A. Front Integr Neurosci.,2013, 7:86.
[46] Rostène W, Kitabgi P, Parsadaniantz SM. Chemokines: a
new class ofneuromodulator? Nat Rev Neurosci.,2007,
8(11):895-903.
[47] Banks WA, Kastin AJ, Broadwell RD. Passage of cytokines
across the blood-brain barrier. Neuroimmunomodulation.
1995, 2(4):241-8.
[48] Kelley KW, Bluthé RM, Dantzer R, Zhou JH, Shen WH,
Johnson RW, Broussard SR. Cytokine-induced sickness be-
havior. Brain Behav Immun.,2003, 17(Suppl 1):S112-8.
[49] Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson
LA, Griffin G, Gibson D,Mandelbaum A, Etinger A, Mech-
oulam R. Isolation and structure of a brainconstituent that
binds to the cannabinoid receptor. Science, 1992,
258(5090):1946-9.
[50] Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Ka-
minski NE, Schatz AR, GopherA, Almog S, Martin BR,
Compton DR, et al. Identification of an endogenous2-
monoglyceride, present in canine gut, that binds to cannabi-
noid receptors.Biochem Pharmacol., 1995, 50(1):83-90.
[51] Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson
NO, Leonova J, ElebringT, Nilsson K, Drmota T, Greasley
PJ. The orphan receptor GPR55 is a novel cannabinoid re-
ceptor. Br J Pharmacol.,2007, 152(7):1092-101.
[52] Ross RA. Anandamide and vanilloid TRPV1 receptors. Br J
Pharmacol.,2003, 140(5):790-801.
[53] Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di
Marzo V, Elphick MR,Greasley PJ, Hansen HS, Kunos G,
Mackie K, Mechoulam R, Ross RA. InternationalUnion of
Basic and Clinical Pharmacology. LXXIX. Cannabinoid re-
ceptors and their ligands: beyond CB and CB. Pharma-
col Rev., 2010, 62(4):588-631.
[54] Izzo AA, Piscitelli F, Capasso R, Aviello G, Romano B,
Borrelli F, Petrosino S, Di Marzo V. Peripheral endocan-
nabinoid dysregulation in obesity: relation to intestinal mo-
tility and energy processing induced by food deprivation
and re-feeding. Br J Pharmacol.,2009, 158(2):451-61.
[55] DiPatrizio NV, Piomelli D. Intestinal lipid-derived signals
that sense dietaryfat. J Clin Invest.,2015 Mar 2;125(3):891-
8.
[56] Troy-Fioramonti S, Demizieux L, Gresti J, Muller T, Ver-
gès B, Degrace P. Acuteactivation of cannabinoid receptors
by anandamide reduces gastrointestinalmotility and im-
proves postprandial glycemia in mice. Diabetes,2015,
64(3):808-18.
16 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Russo et al.
[57] Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm
C, Schubert M, Auer D,Yassouridis A, Thöne-Reineke C,
Ortmann S, Tomassoni F, Cervino C, Nisoli E,Linthorst
AC, Pasquali R, Lutz B, Stalla GK, Pagotto U. The endoge-
nouscannabinoid system affects energy balance via central
orexigenic drive andperipheral lipogenesis. J Clin In-
vest.,2003, 112(3):423-31.
[58] Hoareau L, Buyse M, Festy F, Ravanan P, Gonthier MP,
Matias I, Petrosino S,Tallet F, d'Hellencourt CL, Cesari M,
Di Marzo V, Roche R. Anti-inflammatoryeffect of palmi-
toylethanolamide on human adipocytes. Obesity (Silver
Spring), 2009, 17(3):431-8.
[59] Lam YY, Ha CW, Campbell CR, Mitchell AJ, Dinudom A,
Oscarsson J, Cook DI, Hunt NH, Caterson ID, Holmes AJ,
Storlien LH. Increased gut permeability and microbiota
change associate with mesenteric fat inflammation and
metabolic dysfunction in diet-induced obese mice. PLoS
One, 2012, 7(3):e34233.
[60] Muccioli GG, Naslain D, Bäckhed F, Reigstad CS, Lambert
DM, Delzenne NM, Cani PD. The endocannabinoid system
links gut microbiota to adipogenesis. Mol Syst Biol.,2010,
6:392.
[61] Zhu C, Solorzano C, Sahar S, Realini N, Fung E, Sassone-
Corsi P, Piomelli D. Proinflammatory stimuli control N-
acylphosphatidylethanolamine-specific phospholipase D
expression in macrophages. Mol Pharmacol.,2011,
79(4):786-92.
[62] Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C,
Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C,
Waget A, Delmée E, Cousin B, Sulpice T, Chamontin
B,Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne
NM, Alessi MC, BurcelinR. Metabolic endotoxemia initi-
ates obesity and insulin resistance. Diabetes, 2007,
56(7):1761-72.
[63] Silvestri C, Di Marzo V. The endocannabinoid system in
energy homeostasis and the etiopathology of metabolic dis-
orders. Cell Metab.,2013, 17(4):475-90.
[64] Geurts L, Muccioli GG, Delzenne NM, Cani PD. Chronic
endocannabinoid systemstimulation induces muscle macro-
phage and lipid accumulation in type 2 diabeticmice inde-
pendently of metabolic endotoxaemia. PLoS One,2013,
8(2):e55963.
[65] Alhouayek M, Bottemanne P, Subramanian KV, Lambert
DM, Makriyannis A, Cani PD,Muccioli GG. N-
Acylethanolamine-hydrolyzing acid amidase inhibition in-
creasescolon N-palmitoylethanolamine levels and counter-
acts murine colitis. FASEB J.,2015, 29(2):650-61.
[66] Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C,
Bindels LB, Guiot Y,Derrien M, Muccioli GG, Delzenne
NM, de Vos WM, Cani PD. Cross-talk betweenAkkerman-
sia muciniphila and intestinal epithelium controls diet-
induced obesity. Proc Natl Acad Sci U S A,2013,
110(22):9066-71.
[67] Alhouayek M, Lambert DM, Delzenne NM, Cani PD, Muc-
cioli GG. Increasingendogenous 2-arachidonoylglycerol
levels counteracts colitis and related systemic inflammation.
FASEB J.,2011, 25(8):2711-21.
[68] Everard A, Geurts L, Caesar R, Van Hul M, Matamoros S,
Duparc T, Denis RG,Cochez P, Pierard F, Castel J, Bindels
LB, Plovier H, Robine S, Muccioli GG,Renauld JC,
Dumoutier L, Delzenne NM, Luquet S, Bäckhed F, Cani
PD. Intestinalepithelial MyD88 is a sensor switching host
metabolism towards obesity according to nutritional status.
Nat Commun.,2014 Dec 5;5:5648.
[69] Lo Verme J, Fu J, Astarita G, La Rana G, Russo R, Calig-
nano A, Piomelli D. The nuclear receptor peroxisome pro-
liferator-activated receptor-alpha mediates the anti-
inflammatory actions of palmitoylethanolamide. Mol
Pharmacol.,2005, 67(1):15-9.
[70] Borrelli F, Romano B, Petrosino S, Pagano E, Capasso R,
Coppola D, Battista G,Orlando P, Di Marzo V, Izzo AA.
Palmitoylethanolamide, a naturally occurringlipid, is an
orally effective intestinal anti-inflammatory agent. Br J
Pharmacol.,2015, 172(1):142-58.
[71] Esposito G, Capoccia E, Turco F, Palumbo I, Lu J, Steardo
A, Cuomo R, Sarnelli G, Steardo L. Palmitoylethanolamide
improves colon inflammation through an enteric glia/toll
like receptor 4-dependent PPAR-α activation. Gut, 2014,
63(8):1300-12.
[72] Mattace Raso G, Russo R, Calignano A, Meli R. Palmi-
toylethanolamide in CNS health and disease. Pharmacol
Res.,2014, 86:32-41.
[73] Mattace Raso G, Santoro A, Russo R, Simeoli R, Paciello
O, Di Carlo C, Diano S, Calignano A, Meli R. Palmitoyle-
thanolamide prevents metabolic alterations and restores
leptin sensitivity in ovariectomized rats. Endocrinol-
ogy,2014, 155(4):1291-301.
[74] Piomelli D. A fatty gut feeling. Trends Endocrinol Metab.,
2013, 24(7):332-41.
[75] Igarashi M, Di Patrizio NV, Narayanaswami V, Piomelli D.
Feeding-induced oleoylethanolamide mobilization is dis-
rupted in the gut of diet-induced obese rodents. Biochim-
Biophys Acta.,2015, 1851(9):1218-26
[76] Konturek PC, Kania J, Kukharsky V, Raithel M, Ocker M,
Rembiasz K, Hahn EG, Konturek SJ. Implication of perox-
isome proliferator-activated receptor gamma and proin-
flammatory cytokines in gastric carcinogenesis: link to
Helicobacter pylori-infection. J Pharmaco l Sci.,2004,
96(2):134-43.
[77] Rajaram MV, Brooks MN, Morris JD, Torrelles JB, Azad
AK, Schlesinger LS. Mycobacterium tuberculosis activates
human macrophage peroxisome proliferator-activated re-
ceptor gamma linking mannose receptor recognition to
regulation of immune responses. J Immunol., 2010,
185(2):929-42.
[78] Saubermann LJ, Nakajima A, Wada K, Zhao S, Terauchi Y,
Kadowaki T, AburataniH, Matsuhashi N, Nagai R, Blum-
berg RS. Peroxisome proliferator-activated receptor gamma
agonist ligands stimulate a Th2 cytokine response and pre-
vent acute colitis. Inflamm Bowel Dis.,2002, 8(5):330-9.
[79] Desreumaux P, Dubuquoy L, Nutten S, Peuchmaur M,
Englaro W, Schoonjans K,Derijard B, Desvergne B, Wahli
W, Chambon P, Leibowitz MD, Colombel JF, Auwerx
J.Attenuation of colon inflammation through activators of
the retinoid X receptor (RXR)/peroxisome proliferator-
activated receptor gamma (PPARgamma) heterodimer. A
basis for new therapeutic strategies. J E xp Med., 2001,
193(7):827-38.
[80] Adachi M, Kurotani R, Morimura K, Shah Y, Sanford M,
Madison BB, Gumucio DL, Marin HE, Peters JM, Young
HA, Gonzalez FJ. Peroxisome proliferator activated recep-
tor gamma in colonic epithelial cells protects against ex-
perimental inflammatory bowel disease. Gut., 2006,
55(8):1104-13.
[81] Dubuquoy L, Dharancy S, Nutten S, Pettersson S, Auwerx
J, Desreumaux P. Role of peroxisome proliferator-activated
receptor gamma and retinoid X receptor heterodimer in he-
patogastroenterological diseases. Lancet, 2002,
360(9343):1410-8.
[82] Mattace Raso G, Simeoli R, Russo R, Iacono A, Santoro A,
Paciello O, Ferrante MC, Canani RB, Calignano A, Meli R.
Effects of sodium butyrate and its synthetic amide deriva-
tive on liver inflammation and glucose tolerance in an ani-
mal model of steatosis induced by high fat diet. PLoS
One,2013, 8(7):e68626.
Role of Lipids in the Gut-brain Axis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 17
[83] Fleming SE, Fitch MD, DeVries S, Liu ML, Kight C. Nu-
trient utilization bycells isolated from rat jejunum, cecum
and colon. J Nutr.,1991, 121(6):869-78.
[84] Boren J, Lee WN, Bassilian S, Centelles JJ, Lim S, Ahmed
S, Boros LG, CascanteM. The stable isotope-based dynamic
metabolic profile of butyrate-induced HT29cell differentia-
tion. J Biol Chem.,2003, 278(31):28395-402.
[85] Canani RB, Costanzo MD, Leone L, Pedata M, Meli R,
Calignano A. Potential beneficial effects of butyrate in in-
testinal and extraintestinal diseases. World J Gastroen-
terol.,2011, 17(12):1519-28.
[86] Cook SI, Sellin JH. Review article: short chain fatty acids
in health anddisease. Aliment Pharmacol
Ther.,1998,12(6):499-507.
[87] De Preter V, Arijs I, Windey K, Vanhove W, Vermeire S,
Schuit F, Rutgeerts P, Verbeke K. Impaired butyrate oxida-
tion in ulcerative colitis is due to decreased butyrate uptake
and a defect in the oxidation pathway. Inflamm Bowel
Dis.,2012, 18(6):1127-36.
[88] Thibault R, De Coppet P, Daly K, Bourreille A, Cuff M,
Bonnet C, Mosnier JF,Galmiche JP, Shirazi-Beechey S, Se-
gain JP. Down-regulation of the monocarboxylatetrans-
porter 1 is involved in butyrate deficiency during intestinal
inflammation. Gastroenterology, 2007, 133(6):1916-27.
[89] Lührs H, Gerke T, Müller JG, Melcher R, Schauber J, Box-
berge F, Scheppach W,Menzel T. Butyrate inhibits NF-
kappaB activation in lamina propria macrophages ofpatients
with ulcerative colitis. Scand J Gastroenterol., 2002,
37(4):458-66.
[90] Banasiewicz T, Krokowicz Ł, Stojcev Z, Kaczmarek BF,
Kaczmarek E, Maik J,Marciniak R, Krokowicz P, Walk-
owiak J, Drews M. Microencapsulated sodium butyrater-
educes the frequency of abdominal pain in patien ts with ir-
ritable bowelsyndrome. Colorectal Dis., 2013, 15(2):204-9.
[91] Vinolo MA, Rodrigues HG, Hatanaka E, Sato FT, Sampaio
SC, Curi R. Suppressive effect of short-chain fatty acids on
production of proinflammatory mediators by neutrophils. J
Nutr Biochem., 2011, 22(9):849-55.
[92] Berni Canani R, Di Costanzo M, Leone L. The epigenetic
effects of butyrate:potential therapeutic implications for
clinical practice. Clin Epigenetics, 2012, 4(1):4.
[93] Nøhr MK, Pedersen MH, Gille A, Egerod KL, Engelstoft
MS, Husted AS, SichlauRM, Grunddal KV, Poulsen SS,
Han S, Jones RM, Offermanns S, Schwartz
TW.GPR41/FFAR3 and GPR43/FFAR2 as cosensors for
short-chain fatty acids inenteroendocrine cells vs FFAR3 in
enteric neurons and FFAR2 in entericleukocytes. Endocri-
nology, 2013, 154(10):3552-64.
[94] Russo R, De Caro C, Avagliano C, Cristiano C, La Rana G,
Mattace Raso G, Berni Canani R, Meli R, Calignano A. So-
dium butyrate and its synthetic amide derivative modulate
nociceptive behaviors in mice. Pharmacol Res., 2016,
103:279-91.
[95] Dubuquoy L, Rousseaux C, Thuru X, Peyrin-Biroulet L,
Romano O, Chavatte P,Chamaillard M, Desreumaux P.
PPARgamma as a new therapeutic target ininflammatory
bowel diseases. Gut, 2006, 55(9):1341-9.
[96] Eckmann, L. Animal models of inflammatory bowel dis-
ease: Lessons from enteric infections. Ann. N. Y. Acad. Sci.,
2006, 1072, 28-38.
[97] Yan, F.; Wang, L.; Shi, Y.; Cao, H.; Liu, L.; Washington,
M.K.; Chaturvedi, R.; Israel, D.A.; Cao, H.; Wang, B.; et
al. Berberine promotes recovery of colitis and inhibits in-
flammatory responses in colonic macrophages and epithe-
lial cells in DSS-treated mice. Am. J. Physiol. Gastrointest.
Liver Physiol., 2012, 302, G504-G514.
[98] Baumgart, D.C.; Sandborn, W.J. Crohn’s disease. Lan-
cet,2012, 380, 1590-1605.
[99] Ordas, I.; Eckmann, L.; Talamini, M.; Baumgart, D.C.;
Sandborn, W.J. Ulcerative colitis. Lancet, 2012, 380, 1606-
1619.
[100] Di Sabatino A, Battista N, Biancheri P, Rapino C, Rovedatti
L, Astarita G, Vanoli A, Dainese E, Guerci M, Piomelli D,
Pender SL, MacDonald TT, Maccarrone M, Corazza GR.
The endogenous cannabinoid system in the gut of patients
with inflammatory bowel disease. Mucosal Immunol., 2011,
4(5):574-83.
[101] Franke A, McGovern DP, Barrett JC, Wang K, Radford-
Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts
R, Anderson CA, Bis JC, Bumpstead S, Ellinghaus D,
Festen EM, Georges M, Green T, Haritunians T, Jostins L,
Latiano A, Mathew CG, Montgomery GW, Prescott NJ,
Raychaudhuri S, Rotter JI, Schumm P, Sharma Y, Simms
LA, Taylor KD, Whiteman D, Wijmenga C, Baldassano
RN, Barclay M, Bayless TM, Brand S, Büning C, Cohen A,
Colombel JF, Cottone M, Stronati L, Denson T, De Vos M,
D'Inca R, Dubinsky M, Edwards C, Florin T, Franchimont
D, Gearry R, Glas J, Van Gossum A, Guthery SL, Halfvar-
son J, Verspaget HW, Hugot JP, Karban A, Laukens D,
Lawrance I, Lemann M, Levine A, Libioulle C, Louis E,
Mowat C, Newman W, Panés J, Phillips A, Proctor DD,
Regueiro M, Russell R, Rutgeerts P, Sanderson J, Sans M,
Seibold F, Steinhart AH, Stokkers PC, Torkvist L, Kullak-
Ublick G, Wilson D, Walters T, Targan SR, Brant SR, Ri-
oux JD, D'Amato M, Weersma RK, Kugathasan S, Griffiths
AM, Mansfield JC, Vermeire S, Duerr RH, Silverberg MS,
Satsangi J, Schreiber S, Cho JH, Annese V, Hakonarson H,
Daly MJ, Parkes M. Genome-wide meta-analysis increases
to 71 the number of confirmed Crohn’s disease susceptibil-
ity loci. Nat. Genet., 2010, 42, 1118-25.
[102] Cosnes, J, Gower-Rousseau C, Seksik P, Cortot A. Epide-
miology and natural history of inflammatory bowel dis-
eases.Gastroenterology, 2011, 140, 1785-1794.
[103] Chassaing, B., Darfeuille-Michaud, A. The commensal
microbiota and enteropathogens in the pathogenesis of in-
flammatory bowel diseases. Gastroenterology, 2011, 140,
1720-1728.
[104] Macdonald, T.T. New cytokine targets in inflammatory
bowel disease. GastroenterolHepatol, 2011, 7, 474-476.
[105] Pandey R, Mousawy K, Nagarkatti M, Nagarkatti P. Endo-
cannabinoids and immune regulation.Pharmacol
Res.,2009,60(2):85-92.
[106] Alhouayek M, Muccioli GG.The endocannabinoid system
in inflammatory bowel diseases: from pathophysiology to
therapeutic opportunity. Trends Mol Med., 2012,
18(10):615-25
[107] Sałaga M, Mokrowiecka A, Zakrzewski PK, Cygankiewicz
A, Leishman E, Sobczak M, Zatorski H, Małecka-Panas E,
Kordek R, Storr M, Krajewska WM, Bradshaw HB, Fichna
J. Experimental colitis in mice is attenuated by changes in
the levels of endocannabinoid metabolites induced by selec-
tive inhibition of fatty acid amide hydrolase (FAAH).J
Crohns Colitis, 2014, 8(9):998-1009.
[108] Storr MA, Keenan CM, Emmerdinger D, Zhang H, Yüce B,
Sibaev A, Massa F,Buckley NE, Lutz B, Göke B, Brand S,
Patel KD, Sharkey KA. Targetingendocannabinoid degrada-
tion protects against experimental colitis in mice: involve-
ment of CB1 and CB2 receptors. J Mol Med (Berl)., 2008,
86(8):925-36.
[109] Izzo AA, Sharkey KA. Cannabinoids and the gut: new de-
velopments and emerging concepts. Pharmacol Ther.,
2010, 126:21-38.
[110] Esposito G, Capoccia E, Turco F, Palumbo I, Lu J, Steardo
A, Cuomo R, Sarnelli G, Steardo L. Palmitoylethanolamide
improves colon inflammation through an enteric glia/toll
18 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Russo et al.
like receptor 4-dependent PPAR-α activation. Gut, 2014,
63(8):1300-12.
[111] Butzner JD, Parmar R, Bell CJ, Dalal V. Butyrate enema
therapy stimulates mucosal repair in experimental colitis in
the rat. Gut, 1996, 38(4):568-573.
[112] Roediger WE. The colonic epithelium in ulcerative colitis:
an energy-deficiency disease? Lancet, 1980, 2(8197):712-
715.
[113] Chapman MA, Grahn MF, Boyle MA, Hutton M, Rogers J,
Williams NS.Butyrate oxidation is impaired in the colonic
mucosa of sufferers of quiescent ulcerative colitis. Gut,
1994, 35(1):73-76.
[114] Vernia P, Cittadini M, Caprilli R, Torsoli A.Topical treat-
ment of refractory distal ulcerative colitis with 5-ASA and
sodium butyrate. Dig Dis Sci., 1995, 40(2):305-307.
[115] Vernia P, Monteleone G, Grandinetti G, Villotti G, Di Gi-
ulio E, Frieri G, Marcheggiano A, Pallone F, Caprilli R,
Torsoli A.Combined oral sodium butyrate and mesalazine
treatment compared to oral mesalazine alone in ulcerative
colitis: randomized, double-blind, placebo-controlled pilot
study.Dig Dis Sci., 2000, 45(5):976-981.
[116] Guarner F. What is the role of the enteric commensal flora
in IBD? Inflamm Bowel Dis., 2008, 14Suppl 2:S83-S84.
[117] Chassaing B, Darfeuille-Michaud A. The commensal mi-
crobiota and enteropathogens in th e pathogenesis of in-
flammatory bowel diseases. Gastroenterology, 2011,
140:1720-1728.
[118] Barcenilla A, Pryde SE, Martin JC, Duncan SH, Stewart
CS, Henderson C, Flint HJ. Phylogenetic relationships of
butyrate-producing bacteria from the human gut. Appl Envi-
ron Microbiol., 2000, 66:1654-1661.
[119] Lee BJ, Bak YT. Irritable bowel syndrome, gut microbiota
and probiotics.J Neurogastroenterol Motil., 2011,
17(3):252-66.
[120] Wouters MM, Van Wanrooy S, Nguyen A, Dooley J,
Aguilera-Lizarraga J, Van Brabant W, Garcia-Perez JE,
Van Oudenhove L, Van Ranst M, Verhaegen J, Liston A,
Boeckxstaens G. Psychological comorbidity increases the
risk for postinfectious IBS partly by enhanced susceptibility
to develop infectious gastroenteritis.Gut, 2016, 65(8):1279-
88.
[121] Camilleri M. Physiological underpinnings of irritable bowel
syndrome: neurohormonal mechanisms. J Physiol., 2014,
592(14):2967-80.
[122] Ohman L, Simrén M. Pathogenesis of IBS: role of inflam-
mation, immunity and neuroimmune interactions. Nat Rev
Gastroenterol Hepatol.,2010, 7(3):163-73.
[123] Muscatello MR, Bruno A, Scimeca G, Pandolfo G, Zoccali
RA. Role of negative affects in pathophysiology and clini-
cal expression of irritable bowel syndrome. World J Gas-
troenterol.,2014, 20(24):7570-86.
[124] Feng CC, Yan XJ, Chen X, Wang EM, Liu Q, Zhang LY,
Chen J, Fang JY, Chen SL. Vagal anandamide signaling via
cannabinoid receptor 1 contributes to luminal 5-HT modu-
lation of visceral nociception in rats. Pain, 2014,
155(8):1591-1604
[125] Klooker TK, Leliefeld KE, Van Den Wijngaard RM, Bo-
eckxstaens GE. The cannabinoid receptor agonist delta-9-
tetrahydrocannabinol does not affect visceral sensitivity to
rectal distension in healthy volunteers and IBS patients.
Neurogastroenterol Motil.,2011, 23(1):30-5, e2.
[126] Fichna J, Wood JT, Papanastasiou M, Vadivel SK, Oprocha
P, Sałaga M, Sobczak M, Mokrowiecka A, Cygankiewicz
AI, Zakrzewski PK, Małecka-Panas E, Krajewska WM,
Kościelniak P, Makriyannis A, Storr MA. Endocannabinoid
and cannabinoid-like fatty acid amide levels correlate with
pain-related symptoms in patients with IBS-D and IBS-C: a
pilot study. PLoS One,2013, 8(12):e85073.
[127] Fichna J, Sałaga M, Stuart J, Saur D, Sobczak M, Zatorski
H, Timmermans JP, Bradshaw HB, Ahn K, Storr MA. Se-
lective inhibition of FAAH produces antidiarrheal and anti-
nociceptive effect mediated by endocannabinoids and can-
nabinoid-like fatty acid amides. Neurogastroenterol Mo-
til.,2014, 26(4):470-81.
[128] Sakin YS, Dogrul A, Ilkaya F, Seyrek M, Ulas UH, Gulsen
M, Bagci S.The effect of FAAH, MAGL, and Dual
FAAH/MAGL inhibition on inflammatory and colorectal
distension-induced visceral pain models in Rodents. Neuro-
gastroenterol Motil.,2015, 27(7):936-44.
[129] Finegold SM. State of the art; microbiology in health and
disease. Intestinal bacterial flora in autism. Anaerobe,
2011,17(6):367-368.
[130] Banasiewicz T, Kaczmarek E, Maik J, et al. Quality of life
and the clinical symptoms at the patients with irritable
bowel syndrome treated complementary with protected so-
dium butyrate. Gastroenterol Prakt.,2011, 5:45-53.
[131] Kern JK, Geier DA, Sykes LK, Geier MR. Relevance of
Neuroinflammation andEncephalitis in Autism. Front Cell
Neurosci.,2016, 19;9:519.
[132] Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C,
Tildon JT. Gastrointestinal abnormalities in children with
autistic disorder. J Pediatr.,1999, 135(5):559-563.
[133] Buie T, Campbell DB, Fuchs GJ, III, et al. Evaluation, di-
agnosis, and treatment of gastrointestinal disorders in indi-
viduals with ASDs: a consensus report. Pediatrics.,2010,
125(Suppl 1):S1-S18.
[134] Bolte ER. Autism and Clostridium tetani. Med Hypothe-
ses,1998, 51(2):133-44.
[135] Williams BL, Hornig M, Buie T, Bauman ML, Cho Paik M,
Wick I, Bennett A, Jabado O, Hirschberg DL, Lipkin WI.
Impaired carbohydrate digestion and transport and mucosal
dysbiosis in the intestines of children with autism and gas-
trointestinal disturbances. PloS one, 2011, 6:e24585.
[136] Kang DW, Park JG, Ilhan ZE, Wallstrom G, Labaer J, Ad-
ams JB, Krajmalnik-Brown R. Reduced incidence of
prevotella and other fermenters in intestinal microflora of
autistic children. PloS one,2013, 8:e68322.
[137] Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley
MT, Conlon MA. Increased abundance of Sutterella spp.
and Ruminococcus torques in feces of children with autism
spectrum disorder. Molecular autism,2013, 4:42.
[138] Brigandi SA, Shao H, Qian SY, Shen Y, Wu BL, Kang JX.
Autistic children exhibit decreased levels of essential Fatty
acids in red blood cells. Int J Mol Sci.,2015, 16(5):10061-
76.
[139] Siguel EN, Lerman RH. Prevalence of essential fatty acid
deficiency in patients with chronic gastrointestinal disor-
ders. Metabolism, 1996, 45(1):12-23.
[140] Kim J, Carlson ME, Kuchel GA, Newman JW, Watkins
BA. Dietary DHA reduces downstream endocannabinoid
and inflammatory gene expression and epididymal fat mass
while improving aspects of glucose use in muscle in
C57BL/6J mice. Int J Obes (Lond).,2016, 40(1):129-37.
[141] Mostafa GA, Al-Ayadhi LY. Reduced levels of plasma
polyunsaturated fatty acids and serum carnitine in autistic
children: relation to gastrointestinal manifestations. Behav
Brain Funct.,2015, 11:4.
[142] Schultz ST. Can autism be triggered by acetaminophen
activation of the endocannabinoid system? Acta Neurobiol
Exp (Wars),2010, 70:227-231.
[143] V. Trezza, L.J. Vanderschuren.Bidirectional cannabinoid
modulation of social behavior in adolescent rats. Psycho-
pharmacology,2008, 197 pp. 217-227
[144] Haller J, Varga B, Ledent C, Barna I, Freund TF. Context-
dependent effects of CB1 cannabinoid gene disruption on
Role of Lipids in the Gut-brain Axis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 19
anxiety-like and social behaviour in mice. Eur J Neuro-
sci.,2004, 19(7):1906-12.
[145] CT Tart. Marijuana intoxication: common experiences.
Nature, 1970, 226:701-704.
[146] B Chakrabarti, S Baron-Cohen. Variation in the human
cannabinoid receptor CNR1 gene modulates gaze duration
for happy faces. Mol Autism.,2011, 2:10.
[147] Cassano T, Gaetani S, Macheda T, Laconca L, Romano A,
Morgese MG, Cimmino CS, Chiarotti F, Bambico FR,
Gobbi G, Cuomo V, Piomelli D. Evaluation of the emo-
tional phenotype and serotonergic neurotransmission of
fatty acid amide hydrolase-deficient mice. Psychopharma-
cology (Berl),2011, 214(2):465-76.
[148] D'Agostino G, Cristiano C, Lyons DJ, Citraro R, Russo E,
Avagliano C, Russo R, Raso GM, Meli R, De Sarro G, He-
isler LK, Calignano A. Peroxisome proliferator-activated
receptor alpha plays a crucial role in behavioral repetition
and cognitive flexibility in mice. Mol Metab., 2015,
4(7):528-36.
[149] Kerr DM, Downey L, Conboy M, Finn DP, Roche M. Al-
terations in the endocannabinoid system in the rat valproic
acid model of autism. Behav Brain Res., 2013, 249:124-32.
[150] Macfabe DF. Short-chain fatty acid fermentation products
of the gut microbiome: implications in autism spectrum
disorders. Microb Ecol Health Dis., 2012,
23:10.3402/mehd-v23i0.19260.
[151] MacFabe DF, Cain DP, Rodriguez-Capote K, Franklin AE,
Hoffman JE, Boon F, Taylor AR, Kavaliers M, Ossenkopp
KP. Neurobiological effects of intraventricular propionic
acid in rats: possible role of short chain fatty acids on the
pathogenesis and characteristics of autism spectrum disor-
ders. Behav Brain Res., 2007, 176(1):149-69.
[152] Pons R, Andru AL, Checcarelli N, Vila MR, Engelstad K,
Sue SM, et al. Mitochondrial DNA abnormalities and autis-
tic spectrum disorders. J Pediatr., 2004, 144:81-5.
[153] Kim KC, Kim P, Go HS, Choi CS, Park JH, Kim HJ, Jeon
SJ, Dela Pena IC, Han SH, Cheong JH, Ryu JH, Shin CY.
Male-specific alteration in excitatory post-synaptic devel-
opment and social interaction in pre-natal valproic acid ex-
posure model of autism spectrum disorder. J Neurochem.,
2013, 124:832-843.
[154] Kratsman N, Getselter D, Elliott E. Sodium butyrate attenu-
ates social behaviour deficits and modifies the transcription
of inhibitory/excitatory genes in th e frontal cortex of an
autism model. Neuropharmacology, 2016, 102:136-45.
[155] Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L,
Reim EK, Lanctôt KL. A meta-analysis of cytokines in ma-
jor depression. Biol Psychiatry, 2010, 67(5):446-57.
[156] Jokela M, Hamer M, Singh-Manoux A, Batty GD,
Kivimäki M. Association of metabolically healthy obesity
with depressive symptoms: pooled analysis of eight studies.
Mol Psychiatry, 2014, 19(8):910-4.
[157] Berton O, Nestler EJ. New approaches to antidepressant
drug discovery: beyond monoamines. Nat Rev Neurosci.,
2006, 7(2):137-51.
[158] Fond G, Loundou A, Hamdani N, Boukouaci W, Dargel A,
Oliveira J, Roger M, Tamouza R, Leboyer M, Boyer L.
Anxiety and depression comorbidities in irritable bowel
syndrome (IBS): a systematic review and meta-analysis.
Eur Arch Psychiatry Clin Neurosci, 2014, 264:651-660.
[159] Dinan TG, Cryan JF. Regulation of the stress response by
the gut microbiota: implications for psychoneuroendocri-
nology. Psychoneuroendocrinology, 2012, 37:1369-1378.
[160] Neufeld KA, Kang N, Bienenstock J, Foster JA. Effects of
intestinal microbiota on anxiety-like behavior. Commun In-
tegr Biol., 2011, 4:492-494.
[161] Barden N. Implication of the hypothalamic-pituitary-
adrenal axis in the physiopathology of depression. J Psy-
chiatry Neurosci., 2004, 29(3):185-93.
[162] García-Ródenas CL, Bergonzelli GE, Nutten S, Schumann
A, Cherbut C, Turini M, Ornstein K, Rochat F, Corthésy-
Theulaz I. Nutritional approach to restore impaired intesti-
nal barrier function and growth after neonatal stress in rats.
J Pediatr Gastroenterol Nutr., 2006, 43(1):16-24.
[163] Gareau MG, Jury J, MacQueen G, Sherman PM, Perdue
MH. Probiotic treatment of rat pups normalises corticoster-
one release and ameliorates colonic dysfunction induced by
maternal separation. Gut, 2007,56(11):1522-8.
[164] Diaz Heijtz R, Wang S, Anuar F, Qian Y, Björkholm B,
Samuelsson A, Hibberd ML, Forssberg H, Pettersson S.
Normal gut microbiota modulates brain development and
behavior. ProcNatl Acad Sci U S A,2011, 108(7):3047-52.
[165] Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced
anxiety-like behavior and central neurochemical change in
germ-free mice. Neurogastroenterol Motil,2011, 23:255-
264.
[166] Phillips JGP. The treatment of melancholia by the lactic
acid bacillus. Br J Psychiatry, 1910, 56:422-431.
[167] Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF, Di-
nan TG. Effects of the probiotic Bifidobacterium infantis in
the maternal separation model of depression. Neuroscience,
2010, 170(4):1179-88.
[168] Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac
HM, Dinan TG, Bienenstock J, Cryan JF. Ingestion of Lac-
tobacillus 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(38):16050-5.
[169] 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 Bifidobacterium longum R0175) in rats and human
subjects. Br J Nutr., 2011, 105:755-764.
[170] Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG,
Lyte M. Exposure to a social stressor alters the structure of
the intestinal microbiota: implications for stressor-induced
immunomodulation. Bra in Behav Immun., 2011, 25(3):397-
407.
[171] Lopresti AL, Maker GL, Hood SD, Drummond PD. A re-
view of peripheral biomarkers in major depression: the po-
tential of inflammatory and oxidative stress biomarkers.
ProgNeuropsychopharmacol Biol Psychiatry, 2014,
48:102-11.
[172] Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecol-
ogy: human gut microbes associated with obesity. Nature,
2006, 444: 1022-3.
[173] Jeffery IB, O'Toole PW, Öhman L, Claesson MJ, Deane J,
Quigley EM, Simrén M. An irritable bowel syndrome sub-
type defined by species-specific alterations in faecal micro-
biota. Gut, 2012, 61(7):997-1006.
[174] Naseribafrouei A, Hestad K, Avershina E, Sekelja M, Lin-
løkken A, Wilson R, Rudi K. Correlation between the hu-
man fecal microbiota and depression. Neurogastroenterol
Motil., 2014, 26(8):1155-62.
[175] Jiang H, Ling Z, Zhang Y, Mao H, Ma Z, Yin Y, Wang W,
Tang W, Tan Z, Shi J, Li L, Ruan B. Altered fecal microbi-
ota composition in patients with major depressive disorder.
Brain Behav Immun.,2015, 48:186-94.
[176] Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermúdez-
Humarán LG, Gratadoux JJ, Blugeon S, Bridonneau C,
Furet JP, Corthier G, Grangette C, Vasquez N, Pochart P,
Trugnan G, Thomas G, Blottière HM, Doré J, Marteau P,
Seksik P,Langella P. Faecalibacterium prausnitzii is an anti-
inflammatory commensal bacterium identified by gut mi-
20 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Russo et al.
crobiota analysis of Crohn disease patients. Proc Natl Acad
Sci U S A.,2008, 105(43):16731-6.
[177] Maes M, Kubera M, Leunis JC, Berk M, Geffard M, Bos-
mans E. In depression, bacterial translocation may drive in-
flammatory responses, oxidative and nitrosative stress
(O&NS), and autoimmune responses directed against
O&NS-damaged neoepitopes. Acta Psychiatr Scand.,2013,
127(5):344-54.
[178] Löwe B, Andresen V, Fraedrich K, Gappmayer K, Weg-
scheider K, Treszl A, Riegel B, Rose M, Lohse AW,
Broicher W. Psychological outcome, fatigue, and quality of
life after infection with shiga toxin-producing Escherichia
coli O104. Clin Gastroenterol Hepatol.,2014, 12(11):1848-
55.
[179] Goehler LE, Park SM, Opitz N, Lyte M, Gaykema RP.
Campylobacter jejuni infection increases anxiety-like be-
havior in the holeboard: possible anatomical substrates for
viscerosensory modulation of exploratory behavior. Brain
Behav Immun.,2008, 22(3):354-66.
[180] Lyte M, Li W, Opitz N, Gaykema RP, Goehler LE. Induc-
tion of anxiety-like behavior in mice during the initial
stages of infection with the agent of murine colonic hyper-
plasia Citrobacter rodentium. Physiol Behav.,2006,
30;89(3):350-7.
[181] Davey KJ, Cotter PD, O'Sullivan O, Crispie F, Dinan TG,
Cryan JF, O'Mahony SM. Antipsychotics and the gut mi-
crobiome: olanzapine-induced metabolic dysfunction is at-
tenuated by antibiotic administration in the rat. Transl Psy-
chiatry, 2013, 3:e309.
[182] Vince AJ, McNeil NI, Wager JD, Wrong OM. The effect of
lactulose, pectin, arabinogalactan and cellulose on the pro-
duction of organic acids and metabolism of ammonia by in-
testinal bacteria in a faecal incubation system. Br J Nutr.,
1990, 63(1):17-26.
[183] Sun J, Wang F, Hong G, Pang M, Xu H, Li H, Tian F, Fang
R, Yao Y, Liu J. Antidepressant-like effects of sodium bu-
tyrate and its possible mechanisms of action in mice ex-
posed to chronic unpredictable mild stress. Neurosci
Lett.,2016, 618:159-66.
[184] Valvassori SS, Varela RB, Arent CO, Dal-Pont GC, Bobsin
TS, Budni J, Reus GZ, Quevedo J. Sodium butyrate func-
tions as an antidepressant and improves cognition with en-
hanced neurotrophic expression in models of maternal dep-
rivation and chronic mild stress. Curr Neurovasc Res.,
2014, 11(4):359-66.
[185] Mamalakis G, Tornaritis M, Kafatos A. Depression and
adipose essential polyunsaturated fatty acids. PLEFA, 2002,
67(5):311-318.
[186] Carrie I, Clement M, de Javel D, Frances H, Bourre JM.
Phospholipid supplementation reverses behavioral and bio-
chemical alterations induced by n-3 polyunsaturated fatty
acid deficiency in mice. J Lipid Res., 2000, 41(3):473-480.
[187] Ross BM. Omega-3 polyunsaturated fatty acids and anxiety
disorders. Prostaglandins Leukot Essent Fatty Acids, 2009,
81(5-6):309-12.
[188] Martins JG. EPA but not DHA appears to be responsible for
the efficacy of omega-3 long chain polyunsaturated fatty
acid supplementation in depression: evidence from a meta-
analysis of randomized controlled trials. J Am Coll
Nutr.,2009, 28(5):525-542.
[189] Skouroliakou M, Konstantinou D, Koutri K, Kakavelaki C,
Stathopoulou M, Antoniadi M, Xemelidis N, Kona V, Mar-
kantonis S. A double-blind, randomized clinical trial of the
effect of omega-3 fatty acids on the oxidative stress ofpre-
term neonates fed through parenteral nutrition. EurJ Clin
Nutr.,2010, 64(9):940-7.
[190] Watkins BA, Kim J. The endocannabinoid system: directing
eating behavior and macronutrient metabolism. FrontPsy-
chol.,2015, 5:1506.
[191] Calder PC. n-3 polyunsaturated fatty acids, inflammation,
and inflammatory diseases. Am J Clin Nutr.,2006, 83(6
Suppl):1505S-1519S
[192] Viveros MP, Marco EM, File SE. Endocannabinoid system
and stress and anxiety responses. Pharmacol Biochem Be-
hav.,2005, 81(2):331-42.
[193] Scherma M, Medalie J, Fratta W, Vadivel SK, Makriyannis
A, Piomelli D, Mikics E, Haller J, Yasar S, Tanda G, Gold-
berg SR. The endogenous cannabinoid anandamide has ef-
fects on motivation and anxiety that are revealed by fatty
acid amide hydrolase (FAAH) inhibition. Neuropharmacol-
ogy, 2008, 54(1):129-40.
[194] Lafenêtre P, Chaouloff F, Marsicano G. The endocannabi-
noid system in the processing of anxiety and fear and how
CB1 receptors may modulate fear extinction. Pharmacol
Res., 2007, 56(5):367-81.
[195] Mato S, Rodriguez-Puertas R, González-Maeso J, Meana J,
Sallés J & Pazos A. Receptores centrales para cannabinoi-
des en cerebro humano postmortem: estudio radiométrico
en la depresión mayor. 1a Reunión nacional sobre investi-
gación en cannabinoides Madrid 2000.
[196] Witkin JM, Tzavara ET, Davis RJ, Li X, Nomikos GG. A
therapeutic role for cannabinoid CB1 receptor antagonists
in major depressive disorders. Trends Pharmacol Sci.,2005,
26(12):609-17.
[197] Pistis M, Ferraro L, Pira L, Flore G, Tanganelli S, Gessa
GL, Devoto P. Delta(9)-tetrahydrocannabinol decreases ex-
tracellular GABA and increases extracellular glutamate and
dopamine levels in the rat prefrontal cortex: an invivo mi-
crodialysis study. Brain Res.,2002, 948(1-2):155-8.
[198] Hill MN, Gorzalka BB. Pharmacological enhancement of
cannabinoid CB1 receptor activity elicits an antidepressant-
like response in the rat forced swim test. Eur Neuropsycho-
pharmacol.,2005, 15(6):593-9.
[199] Kathuria S, Gaetani S, Fegley D, Valiño F, Duranti A, Ton-
tini A, Mor M, Tarzia G, La Rana G, Calignano A, Giustino
A, Tattoli M, Palmery M, Cuomo V, Piomelli D. Modula-
tion of anxiety through blockade of anandamide hydrolysis.
Nat Med.,2003, 9(1):76-81.
[200] Patel S, Hillard CJ. Pharmacological evaluation of cannabi-
noid receptor ligands in a mouse model of anxiety: further
evidence for an anxiolytic role for endogenous cannabinoid
signaling. JPharmacol Exp Ther.,2006, 318(1):304-11.
[201] Aso E, Ozaita A, Valdizán EM, Ledent C, Pazos A, Mal-
donado R, Valverde O. BDNF impairment in the hippo-
campus is related to enhanced despair behavior in CB1
knockout mice. J Neurochem.,2008, 105(2):565-72.
[202] Crupi R, Impellizzeri D, Bruschetta G, Cordaro M, Paterniti
I, Siracusa R, Cuzzocrea S, Esposito E. Co-Ultramicronized
Palmitoylethanolamide/Luteolin Promotes Neuronal Rege-
neration after Spinal Cord Injury. Front Pharmacol.,2016,
7:47.
[203] Braak, H., de Vos, R. A., Bohl, J., & Del Tredici, K.Gastric
alpha-synucleinimmunoreactiveinclusions in Meissner's and
Auerbach's plexuses in cases staged for Parkinson's disease-
related brain pathology. Neurosci Lett.,2006, 396, 67-72.
[204] Holmqvist, S., Chutna, O., Bousset, L., Aldrin-Kirk, P., Li,
W., Bjorklund, T., Wang, Z. Y., Roybon, L., Melki, R., &
Li, J. Y. Direct evidence of Parkinson pathology spread
from the gastrointestinal tract to the brain in rats. Acta Neu-
ropathol.,2014, 128, 805-820.
[205] Devos, D., Lebouvier, T., Lardeux, B., Biraud, M., Rouaud,
T.,Pouclet, H., Coron, E., Bruleydes Varannes, S., Naveil-
han, P., Nguyen, J. M., Neunlist, M., &Derkinderen, P.
Role of Lipids in the Gut-brain Axis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 21
Colonic inflammation in Parkinson's disease. Neurobiol
Dis.,2013, 50, 42-48.
[206] Reijerkerk A, Kooij G, van der Pol SM, Khazen S, Dijkstra
CD, de Vries HE.Diapedesis of monocytes is associated
with MMP-mediated occludin disappearance in brain endo-
thelial cells. FASEB J.2006, 20:2550-2.
[207] Verslegers M, Lemmens K, Van Hove I, Moons L. Matrix
metalloproteinase-2 and -9 as promising benefactors in de-
velopment, plasticity and repair of the nervous system.
Prog Neurobiol. 2013, 105:60-78.
[208] Svedin P, Hagberg H, Sävman K, Zhu C, Mallard C. Matrix
metalloproteinase-9 gene knock-out protects the immature
brain after cerebral hypoxia-ischemia. J Neurosci.2007,
27:1511-8.
[209] Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A,
Forsyth CB, Mutlu E., Shannon KM, Colonic bacterial
composition in Parkinson's disease, Mov. Disord.,2015,
1351e1360.
[210] Unger MM, Spiegel J, Dillmann KU, Grundmann D,
Philippeit H, Bürmann J,Faßbender K, Schwiertz A,
Schäfer KH. Short chain fatty acids and gut microbiota dif-
fer between patients with Parkinson's disease and age-
matched controls.Parkinsonism Relat Disord.,2016, pii:
S1353-8020(16)30323-6.
[211] Quigley EM. Microflora modulation of motility. J Neuro-
gastroenterol Motil.,2011, 17(2):140-7
[212] Cassani E, Privitera G, Pezzoli G, Pusani C, Madio C, Iorio
L, Barichella M. Use of probiotics for the treatment of con-
stipation in Parkinson's diseasepatients. Minerva Gastroen-
terol Dietol.,2011, 57(2):117-21.
[213] Heetun ZS, Quigley EM. Gastroparesis and Parkinson's
disease: a systematic review. Parkinsonism Relat Dis-
ord.,2012, 18(5):433-40.
[214] Hyland NP, Quigley EM, Brint E. Microbiota-host interac-
tions in irritable bowel syndrome: epithelial barrier, im-
mune regulation and brain-gut interactions. World J Gas-
troenterol., 2014, 20(27):8859-66.
[215] Ankri S, Mirelman D. Antimicrobial properties of allicin
from garlic. MicrobesInfect.,1999, 1(2):125-9.
[216] Brenes M, Medina E, Romero C, De Castro A. Antimicro-
bial activity of olive oil. Agro Food Industry Hi-Tech,2007,
18, 6-8.
[217] Lebouvier T, Neunlist M, Bruley des Varannes S, et al.
Colonic biopsies to assess the neuropathology of Parkin-
son’s disease, its relationship with symptoms. PLoS
One,2010, 5:e12728.
[218] Pouclet H, Lebouvier T, Coron E, et al. A comparison be-
tween rectal and colonic biopsies to detect Lewy pathology
in Parkinson’s disease. Neurobiol Dis.,2012, 45:305-9.
[219] Singh RK, Rai D, Yadav D, Bhargava A, Balzarini J, De
Clercq E. Synthesis, antibacterial and antiviralproperties of
curcumin bioconjugates bearing dipeptide, fatty acids and
folic acid. Eur J Med Chem., 2010, 45,1078-1086.
[220] Lai SW, Liao KF, Lin CL, Sung FC. Irritable bowel syn-
drome correlates with increased risk of Parkinson's disease
in Taiwan. Eur J Epidemiol.,2014, 29(1):57-62.
[221] Marques SCF, Oliveira CR, Pereira CMF, Outeiro TF. Epi-
genetics in neurodegeneration: A new layer of complexity.
Prog Neuropsychopharmacol Biol Psychiatry,2011,
35(2):348-55.
[222] Abel T, Zukin RS. Epigenetic targets of HDAC inhibition
in neurodegenerative and psychiatric disorders Curr Opin
Pharmacol, 2008, 8(1):57-64.
[223] Konsoula Z, Barile FA. Epigenetic histone acetylation and
deacetylation mechanisms in experimental models of neu-
rodegenerative disorders.J Pharmacol Toxicol Methods,
2012, 66(3):215-20
[224] St Laurent R, O'Brien LM, Ahmad ST. Sodium butyrate
improves locomotor impairment and early mortality in a ro-
tenone-induced Drosophila model of Parkinson's disease.
Neuroscience, 2013, 246:382-90.
[225] Rao JS, Ertley RN, Lee HJ, DeMar Jr JC, Arnold JT,
Rapoport SI, Bazinet RP. N-3 polyunsaturated fatty acid
deprivation in rats decreases frontal cortex BDNF via a p38
MAPK-dependent mechanism. Mol Psychiatry, 2007,
12:36-46.
[226] Bousquet M, Gibrat C, Saint-Pierre M, Julien C, Calon F,
Cicchetti F. Modulation of brain-derived neurotrophic fac-
tor as a potential neuroprotective mechanism of action of
omega-3 fatty acids in a parkinsonian animal model. Prog
Neuropsychopharmacol Biol Psychiatry, 2009, 33:1401-8.
[227] Mahmoudi S, Samadi P, Gilbert F, Ouattara B, Morissette
M, Gregoire L, Rouillard C, Di Paolo T, Lévesque D.
Nur77 mRNA levels and L-Dopa-induced dyskinesias in
MPTP monkeys treated with docosahexaenoic acid. Neuro-
biol Dis, 2009, 36:213-22.
[228] More SV, Choi DK. Promising cannabinoid-based therapies
for Parkinson's disease: motor symptoms to neuroprotec-
tion. Mol Neurodegener., 2015, 10:17.
[229] Esposito E, Impellizzeri D, Mazzon E, Paterniti I, Cuz-
zocrea S. Neuroprotective activities of palmitoylethanola-
mide in an animal model of Parkinson's disease. PLoS One,
2012, 7(8):e41880.
[230] Avagliano C, Russo R, De Caro C, Cristiano C, La Rana G,
Piegari G, Paciello O, Citraro R, Russo E, De Sarro G, Meli
R, Mattace Raso G, Calignano A. Palmitoylethanolamide
protects mice against 6-OHDA-induced neurotoxicity and
endoplasmic reticulum stress: In vivo and in vitro evidence.
Pharmacol Res., 2016, 113(Pt A):276-289.
[231] Gu Y, Luchsinger JA, Stern Y, Scarmeas N. Mediterranean
diet, inflammatory and metabolic biomarkers, andrisk of
Alzheimer’s disease. J Alzheimers Dis.,2010, 22, 483-492.
[232] Aziz, Q., Doré, J., Emmanuel, A., Guarner, F., Quigley, E.
M.Gut microbiota and gastrointestinal health: current con-
cepts and futuredirections.Neurogastroenterol.Motil.,2013,
25,4-15.
[233] Hornig, M. The role of microbes and autoimmunity in the
pathogenesis of neuropsychiatric illness. Curr. Opin.
Rheumatol.,2013, 25, 488-795.
[234] Mandal MD, Mandal S. Honey: its medicinal property and
antibacterial activity.Asian Pac J Trop Biomed., 2011,
1(2):154-60.
[235] Mitew, S., Kirkcaldie, M. T., Dickson, T. C., and Vickers,
J. C. Altered synapses and gliotransmission in Alzheimer’s
disease and AD model mice. Neurobiol. Aging,2013, 34,
2341-2351.
[236] Paula-Lima, A. C., Brito-Moreira, J., and Ferreira, S. T.
Deregulation of excitatory neurotransmission underlying
synapse failure in Alzheimer’s disease. J. Neurochem.,
2013, 126,191-202.
[237] Carlino, D., De Vanna, M., and Tongiorgi, E.Is altered
BDNF biosynthesis a general feature inpatients with cogni-
tive dysfunction? Neuroscientist, 2013, 19, 345-353.
[238] Lakhan, S. E., Caro, M., and Hadzimichalis, N. NMDA
receptor activity in neuropsychiatric disorders. Front. Psy-
chiatry,2013, 4, 52-55.
[239] Brenner, S. R. Blue-green algae or cyanobacteria in the
intestinal micro-flora my produce neurotoxins such as Beta-
N-Methylamino-L-Alanine(BMAA) which may be related
to development ofamyotrophic lateral sclerosis, Alz-
heimer’s diseaseand Parkinsons-Dementia-Complex in hu-
mansand Equine Motor Neuron Disease in horses.
Med.Hypotheses,2013, 80, 103-108.
22 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Russo et al.
[240] He, F., and Balling, R The role of regulatory T cells in neu-
rodegenerative diseases. WileyInterdiscip Rev. Syst. Biol.
Med.,2013, 5, 153-180.
[241] Schwartz, K., and Boles, B. R. Microbialamyloids-
functions and interactions within thehost. Curr. Opin. Mi-
crobiol.2013, 16, 93-99.
[242] Tran, L., and Greenwood-Van Meerveld, B.Age-associated
remodelingofthe intestinal epithelial barrier. J. Gerontol. A
Biol. Sci. Med. Sci.,2013, 68,1045-1056.
[243] Ball, M. J., Lukiw, W. J., Kammerman, E. M., and Hill, J.
M. Intracerebral propagation of Alzheimer’s disease:
strengthening evidence of a herpes simplex virus etiology.
Alzheimers Dement.,2013, 9, 169-175.
[244] Douglas-Escobar, M., Elliott, E., and Neu, J. Effect of intes-
tinal microbial ecology on the developing brain. JAMA Pe-
diatr.,2013, 167, 374-379.
[245] Ochoa-Reparaz J, Mielcarz DW, Begum-Haque S, Kasper
LH. Gut, bugs, and brain: role of commensal bacteria in the
control of central nervous system disease. Annals of neurol-
ogy, 2011, 69:240-247.
[246] Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Joh-
ner C, Wekerle H, Krishnamoorthy G. Commensal micro-
biota and myelin autoantigen cooperate to trigger autoim-
mune demyelination. Nature, 2011, 479:538-541.
[247] Endocannabinoids and beta-amyloid-induced neurotoxicity
in vivo: effect of pharmacological elevation of endocan-
nabinoid levels. van der Stelt M, Mazzola C, Esposito G,
Matias I, Petrosino S, De Filippis D, Micale V, Steardo L,
Drago F, Iuvone T, Di Marzo V. Cell Mol Life Sci., 2006,
63(12):1410-24.
[248] Fidaleo M, Fanelli F, Ceru MP, Moreno S. Neuroprotective
properties of peroxisome proliferator-activated receptor al-
pha (PPARα) and its lipid ligands. Curr Med Chem., 2014,
21:2803-2821
[249] Zhang H, Gao Y, Qiao PF, Zhao FL, Yan Y. Fenofibrate
reduces amyloidogenic processing of APP in APP/PS1
transgenic mice via PPAR-α/PI3-K pathway. Int J Dev Neu-
rosci., 2014, 38:223-231.
[250] D'Agostino G, Russo R, Avagliano C, Cristiano C, Meli R,
Calignano A. Palmitoylethanolamide protects against the
amyloid-β25-35-induced learning and memory impairment
in mice, an experimental model of Alzheimer disease. Neu-
ropsychopharmacology. 2012, 37(7):1784-92.
[251] Root-Bernstein RS, Westall FC. Serotonin binding sites. II.
Muramyl dipeptide binds to serotonin binding sites on mye-
lin basic protein, LHRH, and MSH-ACTH 4-10. Brain Res
Bull.,1990, 25(6):827-41.
[252] Westall FC. Molecular mimicry revisited: Gut bacteria and
multiple sclerosis. J Clin Microbiol, 2006, 44, 2099-2104.
[253] Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Kar-
aoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, Tanoue
T, Imaoka A, Itoh K, Takeda K, Umesaki Y, Honda K,
Littman DR. Induction of intestinal Th17 cells by seg-
mented filamentous bacteria. Cell,2009, 139(3):485-98.
[254] Winer S, Paltser G, Chan Y, Tsui H, Engleman E, Winer D,
Dosch HM. Obesity predisposes to Th17 bias. Eur J Immu-
nol.,2009, 39(9):2629-35.
[255] Lord GM, Matarese G, Howard JK, Baker RJ, Bloom
SR,Lechler RI. Leptin modulates the T-cell immune