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Gut dysbiosis, leaky gut, and intestinal epithelial proliferation in neurological disorders: towards the development of a new therapeutic using amino acids, prebiotics, probiotics, and postbiotics.

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Rev. Neurosci. 2018; aop
Mia Maguire and Greg Maguire*
Gut dysbiosis, leaky gut, and intestinal epithelial proliferation
in neurological disorders: towards the development of a new
therapeutic using amino acids, prebiotics, probiotics, and
Received March 18, 2018; accepted June 21, 2018
Abstract: Here we offer a review of the evidence for a
hypothesis that a combination of ingestible probiotics,
prebiotics, postbiotics, and amino acids will help amelio-
rate dysbiosis and degeneration of the gut, and therefore
promote restoration of nervous system function in a num-
ber of neurological indications.
Keywords: neurodegeneration; postbiotic; prebiotic; pro-
biotic; therapeutic.
In the industrialized Western nations, there is a signifi-
cant increase in total neurological deaths and diseases
– including the dementias – that are starting earlier. This
early manifestation of neurological disease is causing a
profound socioeconomic impact upon patients and their
families, as well as health and social care services, exem-
plified by an 85% increase in deaths due to motor neurone
disease in the UK (Pritchard etal., 2013). Increasing evi-
dence suggests that gut commensal bacteria produce
metabolites that play a major role in host physiology and
the pathophysiology of a number of illnesses, including
neuroimmune disease (Morris et al., 2016), emotional,
cognitive, systemic, central processes (Sarkar etal., 2016),
and neurodegenerative diseases (Fang, 2016). Further, the
integrity of the gut lining depends on commensal bac-
teria, and when the lining is compromised, the nervous
system can then be adversely affected. Mechanistically at
the cellular level, we even have strong evidence in animal
models that the dynamics of maintaining myelination are
dependent on the gut’s microbiota (Hoban etal., 2016).
Hereditable, non-genetic factors that influence
health through microbiome mechanisms have been dem-
onstrated (Stokholm etal., 2018), although elucidation
of the mechanisms for the heredity effect have yet to be
defined. In the Stokholm etal. (2018) study of heredit-
able asthma, maternal asthma status did not affect the
microbial populations of the children and therefore
did not confound their results. Maternal asthma was,
however, a key effect modifier between the microbiome
and asthma risk, pointing to susceptibility of host-micro-
bial interactions specifically for these children. Such
susceptibility could arise from an inborn immune devia-
tion determined by maternal asthma status. Stronger
heritability of maternal over paternal asthma has been
described, consistent with their findings, results that
suggest mechanisms other than genetic effects. If the
non-genetic hereditable effects on the microbiome are
generalized to conditions other than asthma, then the
results of Stokholm etal. (2018) may have implications
for neurological conditions.
In early life, antibiotic exposures, cesarean section,
diet, and a myriad of environmental chemicals may disrupt
establishment of a normal microbiome and adversely
affect health throughout one’s lifespan (Bokulich etal.,
2016). At birth, humans probably enter the world sterile
(Perez-Muñoz etal., 2017) but upon entry to the world are
exposed to a number of different bacteria types including
the mother’s fecal and skin microbiota (Mangiola etal.,
2016). This alters the microbial flora and fauna that does
not become stabilized until the infant is between 6 and
36months (Mangiola etal., 2016). Prolonged exposure to
high doses of antibiotics has been shown to significantly
alter and deplete gut microbiota, which concurrently has
been shown to alter levels of neuromodulators interact-
ing along the gut-brain axis (Desbonnet et al., 2015). In
early life, environmental disturbances to the microbiota,
including the exposure to antibiotics, may affect not
only the immune system but possibly the host’s neuro-
biology as well, interrupting proper brain development
and increasing the risk for a wide range of health issues,
including cognitive deficits, altered dynamics of the tryp-
tophan metabolic pathway, and significantly reduced
brain-derived neurotropic factor (BDNF), oxytocin, and
*Corresponding author: Greg Maguire, BioRegenerative Sciences,
Inc., 11588 Sorrento Valley Rd. #18, San Diego, CA 92121, USA,
Mia Maguire: BioRegenerative Sciences, Inc., 505 Coast Blvd South,
#208, La Jolla, CA 92037, USA
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2 M. Maguire and G. Maguire: Supplement for neurological disorders
vasopressin expression in the adult brain (Desbonnet
etal., 2015).
Furthermore, studies have shown that reducing the
diversity and composition of the microbiome has impact
on health and the ability of the immune system to appro-
priately react to self vs. non-self, and that living in nature
without modern chemical contamination leads to a signif-
icant reduction of chronic inflammatory states and condi-
tions such as Alzheimer’s disease (AD) (Fox etal., 2013;
Schnorr etal., 2014; Clemente etal., 2015).
The push towards exploring the relationship between
gut microbiota and the brain – now referred to as the
gut-brain axis, in any area of developing research – and
the results are pointing to a positive connection between
probiotic therapy and the reduction of particular mood
disorders (Slyepchenko et al., 2014). While the research
on the connection between gut bacteria and neurologi-
cal disorders is more impressive, studies examining the
interplay between psychological health and the microbi-
ome have become an area of increased interest in public
health research. Consumption of fruits and vegetables will
improve the gut’s microbiome composition and result in
improved psychological well-being, even in as little time
as 2weeks (Conner etal., 2017).
In addition to research exploring the efficacy of pro-
biotic therapeutics as a way of treating anxiety symptoms,
mice studies have shown that chronic disturbances in one’s
microbiota, including chronic gastrointestinal (GI) inflam-
mation, can lead to behavioral symptoms that mirror those
of anxiety disorder sufferers. Unsurprisingly, one of the
most common comorbid disorders for those diagnosed
with panic disorder is irritable bowel syndrome. Autism
and Parkinson’s disease (PD) are also frequently accompa-
nied by digestive and GI issues. New studies that examined
the microbiota of hosts with autism found that they have a
different makeup of microbiota when compared to that of
individuals without autism (Fond etal., 2015).
Pre-clinical and clinical trials have also illuminated
the effects of commensal bacteria on the central nervous
system (CNS), offering new perspectives on treating mood
disorders and neurological and psychiatric diseases,
including depression, schizophrenia, and autism. Gut
bacteria influences neurological functioning, through its
ability to modulate and facilitate neuroinflamation, neuro-
transmission, and neurogenesis. Gut bacteria are involved
in synthesizing neurotransmitters and their precursors
(GABA, dopamine, serotonin, and neuroepinephrine)
(Sherwin etal., 2017), important in modulating neurologi-
cal disease.
This connection may be more telling for research-
ers in the field of psychiatric epidemiology, as well as to
psychiatrists who often must rely on faulty ‘trial and error’
treatment phases to find out which medication works best
for the patient. If the fundamental cause could be linked
to say, an abnormality in the gut that was a result of alter-
ing neurotransmitter functioning, then treatment of the
anxiety sufferer with an alternative method, as opposed
to a psychotropic drug, could be administered. Anxiety
disorders are commonly treated with selective serotonin
reuptake inhibitors antidepressant drugs, which work
to treat depression and anxiety by helping to block the
serotonin reuptake process and may be ineffective for
those whose symptoms are not associated with serotonin
uptake processes.
During the last 100 years as a consequence of the
industrial revolution, we have introduced many new
chemicals to the microbiome that did not previously exist
until very recently. For example, newly man-made chemi-
cals such as polychlorinated biphenyls and glyphosate
will cause dysbiosis (Choi etal., 2013; Seneff etal., 2017),
which are associated with disease such as amyotrophic
lateral sclerosis (ALS) (Su etal., 2016; Seneff etal., 2017).
In recent times, we have even seen a proliferation of books
such as Atkins diet, the South Beach diet, and the Paleo
diet, promoting diets that are high in proteins and fats,
serving to induce a number of diseases and dysbiosis
(Russell etal., 2011). I have even seen one physician on
a PBS television program say that dietary cholesterol is
important in order to make proper levels of vitamin D in
our bodies (Perlmutter, 2016). Little does he know that our
cells synthesize their own cholesterol and that we regu-
late our own production of cholesterol depending on how
much cholesterol we consume (Lecerf and de Lorgeril,
2011). Thus, the body makes cholesterol as needed, and
does not directly require dietary sources. Further, the
animal-based high-fat diet that he promotes will have a
number of consequences including dysbiosis (David etal.,
2014), and high levels of serum cholesterol are antedate
to neurodegenerative effects in the brain (Brooks et al.,
2017), while increased dietary saturated fat will likely
degrade the blood-brain barrier (Pallebage-Gamarallage
et al., 2011). Animal-based diets promote a microbiome
with an increased population of Bilophila wadsworthia
that are capable of triggering inflammatory bowel disease
(David et al., 2014). Neu5Gc, a non-human sialic acid
monosaccharide common in red meat, increases the risk
of tumor formation in humans (Samraj etal., 2014) and
inflammation in general (Padler-Karavani et al., 2008).
Neu5Gc will also be found in cow’s milk and in very high
levels in goat’s milk, higher than in cow’s milk (Tang-
voranuntakul et al., 2003). Indeed, high-fat diets have
been shown to create dysbiosis and induce a leaky large
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M. Maguire and G. Maguire: Supplement for neurological disorders3
intestine (Hamilton etal., 2015). Lipopolysaccharide (LPS)
is an endotoxin that is derived from the cell wall of gram-
negative bacteria and circulates at low concentrations in
the blood of healthy individuals. However, in the presence
of a high-fat diet that induces obesity there is a substan-
tial increase in gut pathogenic microbiome and metabolic
endotoxemia, i.e. when LPS concentration is much higher
in the blood in both animals and humans (Brun et al.,
2007; Moreira etal., 2012). Bile acids, synthesized in the
liver and stored in the gall bladder, are secreted into the
intestine where they are involved in dietary fat absorption.
Bile acids have recently been shown to regulate the intesti-
nal microbiome composition; in a reciprocal relationship,
the microbiome of the gut affects bile acid profiles (Ridlon
etal., 2014). High-fat diets increase intestinal Clostridium
species and increase levels of secondary bile acids in the
liver, which then promotes liver cancer (Yoshimoto etal.,
2013). The mechanism underlying the induction of cancer
by a high-fat diet seems to be, at least partially, through
an alteration of T cells, particularly decreased natural
killer (NK) T cells (Ma etal., 2018). Such a fundamental
alteration of T cells by a high-fat diet is likely to affect CNS
Considering the Paleo diet, modern hunter- gatherers
living in desert and tropical grasslands obtain about
29%–34% of their total energy from carbohydrates
(Ströhle and Hahn, 2011), and carbohydrates have been
shown to be important to hominids since early times
(Weiss etal., 2004), including Neanderthals (Henry etal.,
2011, 2014). Remains from 780000years ago in ancient
Israel comprised 55 taxa, including nuts, fruits, seeds,
vegetables, and plants producing underground storage
organs (Melamed etal., 2016). The remains reflect a varied
plant diet, staple plant foods, seasonality, and hominins’
environmental knowledge and use of fire in food process-
ing. As Amanda Henry of the Max Planck Institute for
Evolutionary Anthropology in Leipzig, Germany, has said,
‘Hominins were probably predominantly vegetarians’
(Daley, 2016). That deduction is echoed by Walter Alvarez
at UC Berkeley in his new book, ‘An Improbable Journey’
(Alvarez, 2016). Along with a high-fat, meat-based diet
often comes salt. Salt too has now been shown to alter
the gut-brain axis, where salt consumption was linked
to cognitive impairment through a gut-initiated adaptive
immune response compromising brain function via circu-
lating IL-17 (Faraco etal., 2018) (see Table 1). The evolution
of modern humans and our hominid ancestors took place
in an environment with little, if any, access to salt over a
span of two million years, so that high consumption of
salt is another recent negative change in the human diet
(Heand MacGregor, 2009).
Suggestive to the microbiome’s importance in the
development and maintenance of normal neural com-
plexity is the critical development period in which the
seeding of our core microbiota and the development of
the bacterial community in our gut occurs in parallel
with the growth, maturation, and sprouting of neurons
in the young brain (Borre etal., 2014). A similar profile
is evident in old age where a decline in microbiota com-
plexity and diversity occurs in parallel with a decrease
in neuronal complexity (Biagi etal., 2012). Although this
notion is being debated (Perez-Muñoz etal., 2017), one
recent study suggests that seeding of the gut’s micro-
biome starts in utero (Collado etal., 2016) and is influ-
enced by maternal diet (Chu etal., 2016). Even in those
without disease, probiotics has been shown to enhance
emotional intelligence tasks with an underlying change
in brain activity (Tillisch etal., 2013). Studies in animals
suggest that those with dysbiosis of the gut will benefit
from probiotics when mental tasks are analyzed, but
those without dysbiosis will not benefit from probiotics
(Beilharz etal., 2017). Exercise has been shown to posi-
tively alter the gut microbiota (Allen etal., 2018) and,
while yet to be proven, thus may benefit the nervous
system through a homeostatic renormalization of the
gut’s microbiota.
The wall of the intestine is made up of five principal
anatomical components with integrated and complex
functional attributes: the muscle layer, known as the
muscularis externa, composed of longitudinal and cir-
cular muscle fibers; a submucosal layer; the mucosa; the
gut-associated lymphoid tissue; and the enteric nervous
system (ENS). Signals from commensal bacteria impact
the integrity of these layers and gut function and influ-
ence segmental motility (Schwerdtfeger etal., 2016).
In human tissue, biofilms comprise a community
of sessile bacteria embedded in an adherent extracel-
lular matrix composed of polymeric substances, mostly
polysaccharides. Fungi are also known to form biolfilms
in human infections, making the fungal infection more
resistant to antifungal medications (Chandra etal., 2001).
Over 1000 microbial, mostly bacterial and anaerobic,
species have now been cultured from the human intes-
tine, but the majority of its microbial diversity has yet to
be grown in pure culture (Rajilić-Stojanović and de Vos,
2014). Intestinal biofilms have received only limited study
but have been shown to be associated with inflamma-
tory bowel disease (Swidsinski etal., 2005), and although
animal studies have shown some biofilms to be essential
for health in rodents that have a stomach biofilm consist-
ing of host-specific lactobacilli (Frese et al., 2013), bio-
films can potentially augment amyloid formation given
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4 M. Maguire and G. Maguire: Supplement for neurological disorders
Table 1:Some of the agents acting on the microbiome to affect brain function.
Agent Mechanism Result Reference
Ageing Loss of microbiome complexity Reduced neural complexity Biagi etal. ()
Air pollution Reactive oxygen species, dysbiosis Autism, schizophrenia Brown ()
Amino acid blend Rebuild gut microvilli Reduced GI toxicity from irradiation Yin etal. (a,b)
Antibiotics Dysbiosis in development Neurodegeneration Sampson etal. ()
Bifidobacteria SCFAs Gut homeostasis, reduced protein aggregationZhang etal. ()
Bilophila wadsworthia Inflammation Inflammatory bowel disease, leaky gut David etal. ()
Butyrate Induce Treg and IL- Immune, inflammation regulation, brain
Rose etal. (), Furusawa etal. (),
Arpaia etal. ()
Carnitine (chronic) Metabolized by gut bacteria into
Trimethylamine N-oxide
Increased (neuro)atherosclerosis Koeth etal. ()
Casein protein Slows intestinal transit time Increased inflammation Dalziel etal. ()
Chickpea protein Microbiome modulation Improves leaky gut Monk etal. ()
Emulsifiers (Carboxymethyl
cellulose, polysorbate )
Gut inflammation Metabolic syndrome, colitis Chassaing etal. ()
Escherichia coli Microglia activation Impaired memory Krabbe etal. ()
Escherichia coli Nissle  Increases barrier function Remission of ulcerative colitis Herring etal. (), Kruis etal. ()
Glyphosate (Roundup) Dysbiosis Celiac disease, ALS, PD Samsel and Seneff (, )
High-fat diet Reduced SCFA formation (especially
Increased inflammation Jakobsdottir etal. ()
Mammalian meat and dairy NeuGC Inflammation Samraj etal. ()
Inulin Bacterial fermentation Production of SCFAs, acetate, propionic acid,
Drabińska etal. ()
Greenpea protein Reduced inflammation; increases mucins Improves leaky gut Bibi etal. ()
Salt Dysbiosis, Th cell induction Cognitive impairment, experimental
autoimmune encephalomyelitis
He and MacGregor (), Kleinewietfeld
etal. ()
Pesticide exposure Dysbiosis Parkinson’s disease Ritz etal. ()
Oral propionic acid T-cell regulation Reduced MS symptoms Haghikia etal. (), Haase etal. ()
Oral sodium butyrate Metabolism in brain Increased brain volume, neurogenesis Val-Laillet etal. ()
Staphylococcus aureus PSMαAmyloid secretion Prion-like seeding of proteins cytotoxicty Tayeb-Fligelman etal. ()
Stress Glucocorticoid-mediated increased
intestinal permeability
Penetration of antigens, microorganisms,
toxins into body
Fischer etal. (), Soderheim and
Perdue ()
Vegetables Fermentation of fiber, micronutrients Enhance cognitive function and structure Conner etal. ()
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M. Maguire and G. Maguire: Supplement for neurological disorders5
that the biofilm matrix contains amyloidogenic fibers
(Beckerman, 2006).
The health of the gut has been shown to have direct
consequences in the development of a number of neu-
rodegenerative disorders. Indeed, the gut’s microbiome
is critical to the normal development of the nervous
system (Sharon etal., 2016). Dysbiosis and degeneration
of the gut directly and indirectly affect the health of the
nervous system. Further, recent neurobiological insights
into gut-brain crosstalk have revealed a complex, bidirec-
tional communication system (Schroeder and Bäckhed,
2016) that not only ensures the proper maintenance of GI
homeostasis and digestion but is likely to have multiple
effects on affect, motivation, and higher cognitive func-
tions, including intuitive decision making (Mayer, 2011).
The gut’s microbiome is also involved in the recovery from
stroke (Singh etal., 2016).
Scientists have shown that there are different com-
munities of gut bacteria in persons with PD compared
to those of healthy control, but the studies did not deter-
mine whether these differences were just the byproduct
of the disease or whether those different communities
could actually influence the disease itself. In an animal
model of PD, human gut-derived microbes from patients
with PD were transplanted into healthy control, germ-free
(GF) mice. Microbiota from patients with PD promoted
greater motor dysfunction than microbiota transplanted
from matched controls (Sampson etal., 2016). Wild-type
mice that are not GF did not develop motor dysfunction
in either transplant condition. These data suggest that
PD-associated microbes can promote motor symptoms
in animals where colonization of the dysbiotic microbes
can be established. Epidemiological evidence has linked
specific pesticide exposure to the incidence of PD (Ritz
etal., 2016), with some neurotoxic pesticides (diazinon)
known to perturb microbiome configuration (Gao etal.,
2017). Bacteria in the Prevotella and Clostridiales taxa are
reportedly less abundant in PD patients. These bacteria
secrete short-chain fatty acids (SCFAs), such as butyrate
(four carbons), propionic acid (three carbons), folate, and
thiamine. All of these molecules have been associated
with the reduction of PD pathology.
Amyloid proteins
Amyloid proteins are made by bacteria harbored in the
gut (Hufnagel etal., 2013) and may be an initiating factor
in the disease process of AD, PD, and ALS (Chen et al.,
2016). Most ALS and AD phenotypes cannot be attributed
to hereditary or genetic factors; rather, the diseases occur
at the level of translation and/or post-translation (Cohen
etal., 2016; Horowitz 2016; Walker etal., 2016; Maguire,
2017). Amyloids developed by the Staphylococcus aureus
PSMα3 bacterium differ in secondary structure, exhibit-
ing helices instead of sheets, when compared to amyloids
associated with AD (Tayeb-Fligelman etal., 2017). Whether
the helical amyloids will seed AD-type amyloids with plate
structure is unknown but is likely given that seeding can
occur from fibril formation (Lundmark etal., 2005).
In AD, evidence exists that the aggregation of a
protein other than PrP can be instigated in the human
brain by exogenous seeds, but in neither case was full-
blown AD induced, nor do the findings suggest that AD
can be transmitted from person to person under ordinary
circumstances. Further, Creutzfeldt-Jakob disease patients
who had received PrP prion-contaminated dura mater
transplants many years earlier were also found to have
significantly increased Aβ plaques and cerebral amyloid
angiopathy (Frontzek etal., 2016), suggesting a general-
ized seeding phenomenon for proteins. Seeding could
potentially occur in our gut given that prions have recently
been discovered in bacteria (Yuan and Hochschild, 2017).
Intestinal microbiota contributes to the protective activi-
ties of polyphenol preparations in AD (Wang etal., 2015).
Bifidobacteria have been shown to trigger autophagy
(Lin et al., 2014) and modulate proteasome function, of
which both processes are known to be dysfunctional in
many neurological disorders, including ALS patients
(Sasaki, 2011) and animal models of ALS (Wu etal., 2015).
Autophagy and proteasome function are important to
clearing misfolded proteins. Recent studies suggest that
dysbiosis of the gut microbiota promotes amyloid beta
pathology in a model of AD (Minter etal., 2016), consist-
ent with aberrant autophagy and proteasome activity.
Interestingly, amyloid-β has been shown to have
antimicrobial properties (Kumar etal., 2016). Could it be
that the prion-like proteins in neurological diseases have
evolved to fight infection? If this is true, the chronic para-
inflammatory state associated with many neurodegen-
erative diseases may elicit a spreading prion-like state in
certain proteins, such as amyloid-β (Kumar etal., 2016) or
α-Syn (Sampson etal., 2016), to combat infection associ-
ated with the inflammation, whether the infection is real
or not (Medzhitov, 2008).
ALS patients express significantly more neuronal
transglutaminase 6 (TG6) than do control subjects. The
TG6 antibody titer is dependent on gluten ingestion and is
an indication of a celiac-like gluten sensitivity. Samsel and
Seneff (2013) propose that glyphosate, the active ingre-
dient in the herbicide Roundup, is the most important
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6 M. Maguire and G. Maguire: Supplement for neurological disorders
causal factor in the gluten intolerance epidemic. Some
have suggested that the recent surge in celiac disease is
simply due to better diagnostic tools. However, a recent
study tested frozen sera obtained between 1948 and 1954
for antibodies to gluten and compared the results with
sera collected from a matched sample of people living
today (Rubio-Tapia etal., 2009). The results show a four-
fold increase in the incidence of celiac disease in the
recent cohort compared to the older cohort. Further, the
undiagnosed celiac disease is associated with a fourfold
increased risk of death, mostly due to increased cancer
risk. The authors concluded that the prevalence of undi-
agnosed celiac disease has dramatically increased in
the USA during the past 50 years, coinciding with the
introduction of Roundup to the market. Epidemiological
studies are important to understanding human health
and, when coupled to experimental studies, provide
important coupled data sets for understanding causality.
Glyphosate suppresses 5-enolpyruvylshikimic acid-
3-phosphate synthase, the rate-limiting step in the syn-
thesis of the aromatic amino acids, tryptophan, tyrosine,
and phenylalanine, in the shikimate pathway of bacteria,
archaea, and plants (de María et al., 1996). Glyphosate,
patented as an antimicrobial (Monsanto Technology LLC,
2010), has been shown to disrupt gut bacteria in animals,
preferentially killing beneficial forms and causing an
overgrowth of pathogens. Two other properties of glypho-
sate also negatively impact human health – chelation of
minerals such as iron and cobalt and interference with
cytochrome P450 enzymes, which play many important
roles in the body. Further studies indicate that Roundup
was the most toxic herbicide and insecticide among the
nine tested, and 125 times more toxic than its principal
component glyphosate (Mesnage etal., 2014). The toxic-
ity of Roundup, acting to reduce tissue levels of manga-
nese, has been suggested to be involved in neurological
diseases associated with prion-like protein formation,
including ALS and PD (Samsel and Seneff, 2015).
Fatty acids
Acetate, propionate (PPA), butyrate, and pentanoate,
having respectively two, three, four, and five carbon atoms,
are SCFAs, largely produced by microbial fermentation of
complex polysaccharides in the colon. SCFAs are absorbed
into the colonic epithelium where, primarily, butyrate
is consumed as a preferred fuel source by colonocytes
(Donohoe etal., 2011). SCFAs produced by microbiota enter
the bloodstream through the portal circulation of the host
and the distal colon. Then the SCFAs are transported to
recipient tissues where they are used in a variety of cellu-
lar responses, including the regulation of gene expression
(Alenghat and Artis, 2014) and energy for the brain. So-
called olfactory receptors, Olfr78 and Gpr41, are located in
our kidneys and sense two SCFAs, acetate and PPA, that are
released by commensal bacteria in our guts. Ninety-nine
percent of these two fatty acids in the blood are produced
by the commensal bacteria and are key to regulating blood
pressure. The regulation occurs through Olfr78 leading to
the production of renin to increase blood pressure, whereas
Gpr41 lowers blood pressure. The two act as a push-pull
regulatory system to maintain appropriate pressure; eat
just enough, and pressure is lowered. However, if one eats
too much, then Olfr78 is activated so that pressure does
not continue to lower to dangerous levels. Thus, overeat-
ing may raise blood pressure through a commensal bacteria
mechanism (Pluznick, 2017). Constant constriction of blood
vessels in the brain may contribute to neurodegeneration.
Addition of the SCFA butyrate, produced by bifido-
bacteria, to the drinking water of mice resulted in resto-
ration of intestinal microbial homeostasis, improved gut
integrity, and prolonged life span compared with those of
control mice. At the cellular level, abnormal Paneth cells
– specialized intestinal epithelial cells that regulate the
host-bacterial interactions – were significantly decreased
in the ALS mice treated with butyrate. In both ALS mice
and intestinal epithelial cells cultured from humans,
butyrate treatment was associated with decreased aggre-
gation of the G93A superoxide dismutase 1 mutated
protein (Zhang etal., 2017).
In a mouse model, treatment with SCFAs, PPA most
potently, enhanced differentiation and proliferation of
CD4+CD25+Foxp3+ Treg cells and ameliorated auto-
immune encephalomyelitis disease course. In contrast,
medium chain fatty acid or long chain fatty acid such as
lauric acid or palmitic acid enhanced Th1 and Th17 cell
differentiation and contributed to a more severe course of
experimental autoimmune encephalomyelitis (Haghikia
etal., 2015).
Causes of dysbiosis
Drugmakers sold nearly 30million pounds of antibiotics
for livestock in 2011 – the largest amount yet recorded and
about 80% of all reported antibiotic sales that year (Kessler,
2013). Those antibiotics will then be ingested with the meat
we eat (Sajid etal., 2016; Stępień-Pyśniak etal., 2016).
Stress is a major cause of dysbiosis (Bailey and Coe,
1999) and can be hereditary through transgenerational
epigenetic programming from the father (Rodgers etal.,
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M. Maguire and G. Maguire: Supplement for neurological disorders7
2015) or mother (Weaver, 2007; Franklin etal., 2010). Epi-
demiological studies suggest that gestational exposures
to environmental factors such as stress are strongly asso-
ciated with an increased incidence of neurodevelopmen-
tal disorders, including attention deficit-hyperactivity
disorder, schizophrenia, autism spectrum disorders, and
depression (Brown, 2012).
Circadian disorganization can impact the intestinal
microbiota which may have implications for inflammatory
diseases (Voigt etal., 2014). Ong etal. (2018) are first to
utilize machine learning methods to directly link diet with
gut microbiome populations and brain structure. That is,
high fiber diets will have positive effects on the microbi-
ome and brain structure.
Air pollution (AP) contributes to global burden of
many diseases, including stroke (Feigin etal., 2016). AP
consists of numerous reactive oxygen species (ROS) that
are associated with the development of disease (Tao
etal., 2003). ROS are reactive molecular species with an
unpaired electron in their outer orbit that can easily extract
a second electron from a neighboring molecule. Dysfunc-
tion of mitochondria or NADPH-oxidase and activation
of inflammatory cells to produce ROS and reactive nitro-
gen species are also caused by particulate matter (PM).
Although extracellular ROS can be mitigated or delayed by
antioxidants in biological systems, an overload of ROS is
able to attack local tissues leading to cell injury, including
mitochondrial and DNA damage, and consequently result
in necrotic and apoptotic cell death (Li etal., 2003).
Proteins are extensively oxidized by ROS, and these
oxidized proteins are degraded by proteasome and
autophagic proteolytic systems for bulk degradation.
Approximately 90% of damaged proteins are degraded
into small peptides by the ubiquitin-proteasome pathway
(Rock etal., 1994).
In addition to the ubiquitin-proteasome pathway,
autophagy is also an essential pathway to degrade
oxidized proteins. Autophagy is a regulated cellular
mechanism for degrading proteins that is mediated by
lysosomal-dependent processing. The autophagosome
then fuses with and delivers its contents to the lysosome.
Lysosomal enzymes subsequently facilitate degradation
to regenerate metabolic precursor molecules (Mizushima
and Komatsu, 2011).
Many factors will influence neuroinflammation, includ-
ing diet and environmental chemical exposure, and even
environmental enrichment will reduce inflammation (Xu
et al., 2016). Feeding mice a Western diet, comprising
high-calorie, high-fat, low-fiber, and fast food, led to sig-
nificant inflammatory changes after just 1 month. The
experimental group of mice showed changes throughout
their bodies that are similar to the strong inflammation
reactions that occur in bacterial infections (Christ etal.,
2018). The acute inflammation response was quelled after
the Western diet mice were fed their normal cereal diet for
4 weeks. However, switching to the more healthful diet
failed to reverse the fundamental alterations in the innate
immune system, and many of the genes that had been
activated by the Western diet stayed active. As previously
shown, this is another example that the innate immune
system has a form of memory (Sun etal., 2014) and is
another means for establishing chronic para-inflamma-
tion. AP, including diesel particulate, is another means for
inducing neuroinflammation, microglia activation, and
neurodegeneration (Block and Calderón-Garcidueñas,
2009) leading to significant changes in human electroen-
cephalograms, for example (Crüts etal., 2008; Levesque
etal., 2011).
Induction of a very low grade endotoxemia by injec-
tion of Escherichia coli endotoxin can impair memory in
humans (Krabbe etal., 2005), and epidemiological inves-
tigations have demonstrated an association between low-
grade peripheral inflammation and age-related decline in
cognitive function (Engelhart etal., 2004). Inflammatory
responses occurring at the site of pathology have been
linked to neurodegeneration in CNS disorders such as
AD (Wyss-Coray and Rogers, 2011) and PD (Hirsch etal.,
At the cellular level in the CNS, glaucoma has been
associated with oral dysbiosis, thought to be associated
with a parainflammatory state in the retinal ganglion cells
and optic tract as demonstrated in a mouse model (Asta-
furov etal., 2014).
Damage to the lining of the intestinal tissue, the intro-
duction of pathogenic microbes, or exposure to molecules
that induce immune reactions can increase the inflamma-
tory state of the intestinal environment. In turn, enteric
inflammation can induce a number of effects that ulti-
mately alter CNS function and the neuroinflammatory
In the CNS, the microglia are the innate sentinel
immune cells that can detect subtle changes in mole-
cules in their locality (Kim and de Vellis, 2005; Tremblay
etal., 2011) and ultimately are responsible for neuroin-
flammatory processes (Kettenmann etal., 2011; Yama-
saki et al., 2014; Ransohoff etal., 2015). Immune cells
can directly communicate with neurons (Pavlov and
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8 M. Maguire and G. Maguire: Supplement for neurological disorders
Tracey, 2015). The extent of the functional impact of
neuro-immune synapses is not known, but it is clear that
activated immune cells can modulate neuronal activity
via the release of neurotransmitters and cytokines. In
a mouse model, host bacteria vitally regulate microglia
maturation and function, whereas microglia impairment
can be partially rectified by complex microbiota (Erny
etal., 2015). A diverse GI microbiota is necessary for the
maintenance of microglia in a healthy functional state.
In contrast, the absence of a complex host microbiota
led to increased microglial populations with defects in
microglia maturation, activation state and differentia-
tion, and alterations to microglia morphology. A com-
promised immune response to bacterial or viral infection
was also demonstrated (Erny etal., 2015). Inhibition of
microglia formation is neuroprotective in a mouse model
(Tikka and Koistinaho, 2001).
A recent study conducted by Cattaneo et al. (2017)
found that the Escherichia and Shigella bacterial genera
were increased in Alzheimer’s patients compared to that
of the control group. This type of bacteria is associated
with facilitating inflammation (Sherwin etal., 2017). DNA
sequences for bacteria have also been found in the brain
of Alzheimer’s patients (Emery etal., 2017). Inflammation
and abnormality in the GI system have been linked with
the development of neurological disorders like autism and
dementia, as well as neuropsychiatric disorders like schiz-
ophrenia and bipolar disorder (Mangiola et al., 2016).
While autism and Alzheimer’s have been the most studied
diseases when it comes to the influence of the gut, studies
exploring microbiota’s connection to other disorders are
becoming more and more telling.
Evidence suggests that inflammation promotes the
selective survival of pathogenic microbes possessing
mechanisms for preventing or tolerating proinflamma-
tory host immune responses, characteristic features of
pathogens (Scher etal. 2015). Thus, under inflammatory
conditions, intestinal bacteria typically exhibit more path-
ogenic and less commensal activity, further exacerbating
inflammation and increasing the likelihood of persistent
immune responses in the intestine.
Amino acids, transit time, and
Amino acids are important to maintaining gut health,
but we will see that amino acids derived from plants
have advantages over those derived from animals. For
example, hydrolyzed casein slowed GI transit compared
with hydrolyzed soy (Dalziel etal., 2017). This is important
for autophagy, where slowed transit time in the GI reduces
autophagy (Kim et al., 2017). Molecular components of
the autophagy pathway are involved in the digestion and
transport of lipids across the intestinal epithelium (Khal-
doun etal., 2014), the secretion of cargo from specialized
cell types (Dupont etal., 2011; Cleyrat et al., 2014; Van-
dussen et al., 2014; Bel et al., 2017; Kimura etal., 2017;
Liu et al., 2015), and microbial containment and clear-
ance, called antimicrobial autophagy (Wild et al., 2011;
LaRock etal., 2015; Schwerd etal., 2016). Thus, intrinsic
autophagy in the gut is necessary for the control of inflam-
mation and the immune response to adventitious agents,
and also in the maintenance of intestinal stem cells and
for intestinal regeneration following irradiation (Asano
etal., 2017).
Microvilli and intestinal cells
Studies of rats (Keelan etal., 1985) and humans (Warren
etal., 1978) have shown age-related losses in villous and
enterocyte heights (Höhn etal., 1978), and aged rats dem-
onstrated altered rates of the uptake of saturated fatty
acids in the jejunum (second section of small intestine).
Environmental regulation of the cells in the intestine
includes factors such as zinc intake (Duff and Ettarh,
2002). Irradiation, even at low doses, during cancer treat-
ment is also another factor that diminishes microvilli size,
structure, and function (Wróblewski etal., 2002).
The composition of the microbiota largely determines the
levels of tryptophan in the systemic circulation and, hence,
indirectly, the levels of serotonin in the brain (O’Mahony
etal., 2015). Some microbiota synthesize neurotransmit-
ters directly, e.g. γ-amino butyric acid (Barrett etal., 2012),
while modulating the synthesis of neurotransmitters,
such as dopamine, norepinephrine, and BDNF.
Furthermore, the neurotransmitter and hormone
5-hydroxytryptamine (5-HT) not only helps to synthesize
serotonin production, but it also greatly impacts the GI
system. Ninety percent of 5-HT is produced in the gut and
activates a number of different 5-HT receptor subtypes
and immune cells. Recent GF mice studies have shown
that gut microbes influence the level of 5-HT in the blood
and in the colon (Yano etal., 2015). Imbalances in sero-
tonin have been associated with the presence of certain
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M. Maguire and G. Maguire: Supplement for neurological disorders9
mood disorders, including major depressive disorder and
a range of anxiety disorders.
One study found that animals brought up in a sterile
environment presented an increased hypothalamic pitui-
tary adrenal response to psychological stressors (Dinan
and Cryan, 2012) suggesting that overexposure to antibi-
otics or over-sterilization of an environment in early life
could lead to anxiety-like behavior and perhaps even an
anxiety disorder.
Leaky gut
Intestinal microbiota regulate expression of proteins that
build the tight junction (Al-Asmakh and Hedin, 2015) and
many proinflammatory cytokines secreted by activated
immune cells. The secreted cytokines include TNF, IL-1β,
and IL-6 that act on tight junctions to increase barrier
permeability (Al-Sadi and Ma, 2007; Capaldo and Nusrat,
2009) so that additional immune cells and components
from circulation can be recruited to the sites express-
ing an inflammatory state. Although weakening of the
intestinal barrier facilitates a wider engagement of the
immune system, a compromise in the containment of gut
contents, especially the molecules that microbes release,
will result. Leakage from the intestine into the peritoneal
cavity and into the circulation can then occur, eliciting a
systemic proinflammatory immune response (Al-Asmakh
and Hedin, 2015). Many microbial pathogenic secretions
or components such as LPS that enter the circulation fol-
lowing increased intestinal permeability are immuno-
genic and can trigger systemic inflammatory responses.
Proinflammatory cytokines and oxidative stress have been
causally linked to neuron death, including dopaminergic
neurons, and neuroinflammation is now considered a key
factor in numerous neurodegenerative diseases. However,
if the source of the immune induction is rapidly cleared,
proinflammatory responses usually terminate, and then
the gut barrier function can be restored. However, unique
features of the intestine render the gut particularly sus-
ceptible to the development of a chronic inflammatory
state and resultant barrier dysfunction. Many of the result-
ing diseases, such as PD, are associated with aging, and
given that intestinal inflammation and forms of intesti-
nal permeability have been shown to increase with age
(Man etal., 2015), immune mediation of gut-brain inter-
actions may be particularly relevant in the pathology of
neurodegenerative diseases of aging. For example, under
physiological conditions αSYN is mostly localized in
synapses. However, a portion of αSYN is secreted to the
extracellular space, where it must be sequestered. If not
sequestered, inflammatory responses in neighboring cells
could be induced, where activation of pro-inflammatory
TLR4 pathways occurs in astrocytes (Ranniko etal., 2015).
Further, over-expression of αSYN has been shown to
produce αSYN aggregation in the intestines and brains
of mice and humans (Hallett etal., 2012). We hypothesize
that one way the αSYN is not properly sequestered in the
tissue surrounding neurons is because of the breakdown
in matrix caused by inflammation due to a leaky gut. Here
the leaky gut is causing a ‘leaky matrix’. The same ‘leaky
structure’ may follow for other forms of matrix, including,
for example, perineuronal nets that are so critical to neu-
ronal function and possibly to preventing neurodegenera-
tion (e.g. Maguire, 2017). Another way that the disrupted
epithelial lining can lead to toxicity of cells is through the
resulting absence of ciliary signaling of flow. Normally,
the flow of fluids through the gut, such as milk from a
neonatal diet, generates a shear stress on the unilaminar
epithelium lining the lumen, thereby inducing mechani-
cal autophagy (Kim etal., 2017).
Again, the luminal surface of the intestine limits the
access of pathogenic microorganisms to the underlying
gut tissues. Protection of the surface derives from mucous
and a single layer of epithelial cells bound by tight junc-
tions. Within the villus epithelium and follicle-associated
epithelium (FAE) of the Peyer’s patch are microfold cells
(M cells), a unique form of epithelial cell that special-
izes in the transepithelial transport of macromolecules
and particles. M cells enable the host’s immune system
to sample the intestinal lumen and mount an appropri-
ate immune response. However, some pathogenic micro-
organisms exploit M cells and use them to gain entry
into mucosal tissues (Kraehenbuhl and Neutra, 2000).
M cells have been shown to actively transcytose prions
to the basolateral side of the epithelium, and studies in
mice suggest that prions might likewise be translocated
across the FAE by M cells in vivo (Foster and Macpherson,
2010). Here again, we see another form of leaky gut that
may be induced by microorganisms to translocate their
malformed proteins to the host organism. The actin-rich
microvilli of the epithelial cells sense the flow of intestinal
fluid, inducing macroscopic transport of fluids across the
cells and activating a noncanonical autophagy (Kim etal.,
2017). Without autophagy, the cells will not be able to clear
debris and toxins. Thus, the potentially destructive debris
and toxins may spread as the cells are known to expunge
internal molecules when autophagy is inoperable.
Stress acting through cortisol is another means by
which increases in intestinal permeability occur (Vanuyt-
sel et al., 2014), allowing bacterial translocation from
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10 M. Maguire and G. Maguire: Supplement for neurological disorders
the gut to distant sites. Given that the leprosy bacterium,
Mycobacterium leprae, reprograms through dedifferentia-
tion the Schwann cells to mesenchymal-like stem cells by
downregulating lineage determinants and upregulating
endothelial-mesenchymal transition genes (Masaki etal.,
2013), it is clear that bacteria can have profound direct
effects on the nervous system. Dedifferentiation has been
considered as a reversal to an earlier developmental stage
in the Schwann cell (SC) lineage (Chen etal., 2007), until
a recent study challenged this view. The study demon-
strated that dedifferentiated SC upregulate a specialized
repair-promoting transcriptional program orchestrated
by c-jun and suggested that injury reprograms cells into
‘repair cells’ (Arthur-Farraj etal., 2012). Additional work of
Clements etal. (2017) supports this idea and confirms that
dedifferentiated SCs are more closely related to embryonic
stem cells than their developmental progenitors.
Fortunately, probiotics can reduce cortisol levels
in response to stress (Bravo etal., 2011), and in a clini-
cal study E. coli Nissle 1917has been shown to maintain
remission of ulcerative colitis (Kruis etal., 2004), acting,
at least partially, through increasing the barrier function
of epithelial cells (Hering et al., 2014). Circulating LPS
is found in ALS and major depression patients, and PD
patients early in the sequelae (Maes etal., 2008; Zhang
et al., 2009; Forsyth et al., 2011), an indication of leaky
gut occurring early in these conditions. Human studies
have shown that through mucociliary transport inhaled
PM are quickly cleared from the lungs and translocated
into the intestine (Möller etal., 1985). Furthermore, pol-
lutant PM contaminates both our food and water supply
in significant amounts. Hence, pollutant PM can account
for additional oral route exposure (Beamish etal., 2011).
Short-term treatment of wild-type mice with PM altered
immune gene expression; enhanced pro-inflammatory
cytokine secretion in the small intestine; increased gut
permeability, oxidative stress, and disruption of tight
junctions; and induced hyporesponsiveness in spleno-
cytes (Mutlu etal., 2011; Kish etal., 2013).
The composition of the microbiota determines the
levels and nature of tryptophan catabolites which in
turn has profound effects on aryl hydrocarbon recep-
tors, thereby influencing epithelial barrier integrity and
the presence of an inflammatory or tolerogenic environ-
ment in the intestine and beyond. The composition of the
microbiota also determines the levels and ratios of SCFAs
such as butyrate and PPA. Butyrate is a key energy source
for colonocytes. Dysbiosis leading to reduced levels of
SCFAs, notably butyrate, therefore may have adverse
effects on epithelial barrier integrity, energy homeosta-
sis, and the T helper 17/regulatory/T cell balance (Vinolo
et al., 2011). Moreover, dysbiosis leading to reduced
butyrate levels may increase bacterial translocation into
the systemic circulation. Fermentation of fiber making
propionic acid by gut bacteria will also have a profound
effect on regulating T cells. Linker’s lab has shown that
fermentation of fiber into propionic acid downregulates
Th1 and Th17 cells, upregulates Treg cells in animal
models and humans, and leads to a reduction of symp-
toms in multiple sclerosis (MS) patients (Haghikia etal.,
2015; Duscha etal., 2017).
Because NK cells and cytotoxic T lymphocytes depend
on a well-orchestrated process to specifically deliver their
lytic granules to target cells without delivery to surround-
ing healthy cells (Hsu etal., 2016), we suggest that dysbio-
sis may interrupt the specificity of lytic granule targeting
and lead to destruction of the cells in the gut’s lining
through non-specific delivery of lytic granules to healthy
Proper gut function in the prevention of neurode-
generative disease is highlighted by a study showing that
middle-aged men who defecated less than once a day had
an over fourfold increased risk for PD diagnosis over the
next 24years compared to men with regular bowel move-
ments (Abbott etal., 2001).
Blue arrows indicate psychobiotic processes and
effects, while red arrows indicate processes associated
with leaky gut and inflammation (Figure 1). Probiotics
directly introduce beneficial bacteria such as Lactobacilli
and bifidobacteria into the gut. Prebiotics (e.g. inulin)
support the growth of such bacteria. The following are
Postbiotics, including SCFAs and gut hormones. Both
probiotics and prebiotics increase production of
SCFAs, which interact with gut mucosal enteroendo-
crine cells and catalyze the release of gut hormones
such as cholecystokinin, peptide tyrosine tyrosine,
and glucagon-like peptide-1. Prebiotics may have
stronger effects in this regard in comparison to pro-
biotics. SCFAs and gut hormones enter circulation
and can migrate into the CNS. Gut hormones are also
secreted by tissues other than enteroendocrine cells.
Neurotransmitters. Psychobiotics enhance neurotrans-
mitter production in the gut, including dopamine,
serotonin (5-HT), noradrenaline, and γ-aminobutyric
acid (GABA), which likely modulate neurotransmis-
sion in the proximal synapses of the ENS.
Vagal connections. The vagus nerve synapses on enteric
neurons and enables gut-brain communication.
Stress, barrier function, and cytokines. Barrier dys-
function is exacerbated through stress-induced
glucocorticoid exposure. This enables migration of
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M. Maguire and G. Maguire: Supplement for neurological disorders11
bacteria with pro-inflammatory components, increas-
ing inflammation directly and also triggering a rise
in pro-inflammatory cytokines via the immunogenic
response. These cytokines impair the integrity of the
blood-brain barrier and permit access to potentially
pathogenic or inflammatory elements. Pro-inflam-
matory cytokines (red circles) also reduce the integ-
rity of the gut barrier. Psychobiotic action restores
gut barrier function and decreases circulating con-
centrations of glucocorticoids and pro-inflammatory
cytokines. They also increase concentrations of anti-
inflammatory cytokines (blue circles) that enhance
integrity of the blood-brain barrier and the gut barrier
and reduce overall inflammation. Cytokines cluster-
ing at the brain represent cytokine interaction with
the blood-brain barrier. SCFAs can pass the blood-
brain barrier as an energy source for the brain.
Central lymphatic vessels. Cytokines may interact
more directly with the brain than previously appre-
ciated through the recently discovered central lym-
phatic vessels (taken with permission from Sakar
etal., 2016).
Immune system, leaky gut,
andstem cell function
Without proper immune system function, stem cell func-
tion (at least transplanted stem cell function) does not have
Figure 1:Overview of some important pathways in brain-gut connection.
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12 M. Maguire and G. Maguire: Supplement for neurological disorders
therapeutic benefit (Galleu etal., 2017). Maintenance and
repair of gut lining is highly dependent on stem cell func-
tion, probably mostly from intrinsic stem cells and not those
from bone marrow (Leibowitz etal., 2014; Yin etal., 2016).
Although nonsteroidal anti-inflammatory drugs (NSAIDs)
reduce inflammation, and many had hoped they would
prove useful for neurodegenerative diseases, NSAIDs can
cause ulcers and probably leaky gut (Thiéfin and B eaugerie,
2004), and we suggest that this is, at least partially, a reason
why NSAIDs fail to have positive effects in human neurode-
generative diseases (Schwartz and Shechter, 2010).
Animal-based food
Meat and meat proteins increase the risk of neurodegener-
ation, including ALS (Pupillo etal., 2017). Increased death
risk primarily associated with red meats, eggs, and dairy
is not found among those with healthy lifestyle in which
plant protein is consumed (Giovannucci et al., 2016).
Among women with a history of gestational diabetes, a
low-carbohydrate dietary pattern, particularly with high
protein and fat intake mainly from animal-source foods,
is associated with higher type 2 diabetes risk, whereas a
low-carbohydrate dietary pattern with high protein and fat
intake from plant-source foods is not significantly associ-
ated with risk of type 2 diabetes (Bao etal., 2015). Here we
have provided evidence of why adding some dietary plant
ingredients to your diet is healthful. The proliferation of
books by those without scientific training promoting a diet
rich in fat and little or no grains is helping to cause a long-
term health crisis. The Atkins diet, the South Beach diet,
Grain Brain, and the Paleo diet, promoting diets that are
high in proteins and fats and devoid of or highly reduced in
grains, are serving to induce a number of diseases and dys-
biosis (Ornish, 2004; Russell etal., 2011; Fung etal., 2015).
Animal-based diets promote a gut microbiome with an
increased population of B. wadsworthia that are capable of
triggering inflammatory bowel disease (David etal., 2014).
Indeed, high-fat diets have been shown to create dysbiosis,
induce a leaky large intestine (Hamilton etal., 2015), and
increase oxidative stress and inflammation (Barbaresco
et al., 2013; Montonen et al., 2013; Ley et al., 2014). Red
meat and chicken are also associated with an increased
risk of type 2 diabetes (Talaei etal., 2017).
These results change previous notions of the Paleo
diet and shed light on hominin abilities to adjust to new
environments and exploit different flora, facilitating
population diffusion, survival, and colonization beyond
Africa. A vegetarian diet provides all of the essential
amino acids (McDougall, 2002), and while vitamin B12
is a concern, that may be supplied by the bacteria in our
guts (Albert etal., 1980) and some fermented foods and
seaweed (Rizzo etal., 2016). However, given modern steril-
ity, and the dysbiosis of our guts, vegans are recommended
to supplement their diet with vitamin B12 (McDougall and
McDougall, 2013). The whole idea of eating a fatty diet and
excluding whole grains is therefore unfounded. Organic
food is advised given the food supply is tainted with many
toxins, antibiotics, and pesticides such as glyphosate
(Samsel and Seneff, 2015). Inclusion of a plant-based diet
with whole grains will even lead to healthier DNA, induc-
ing increased levels of telomerase and lengthening the
telomeres (Ornish etal., 2013), the protective caps at the
ends of DNA strands (Blackburn and Epel, 2017). The ben-
efits of a plant-based diet are many-fold, including their
antiangiogenic effects (Li etal., 2012), and an increase in
their consumption includes a rapid increase in the feeling
of well-being and happiness (Mujcic and Oswald, 2016).
A primary means by which the intestine is protected
from its microbiota is via multi-layered mucus structures
that cover the intestinal surface, thereby allowing the
vast majority of gut bacteria to be kept at a safe distance
from epithelial cells that line the intestine. Thus, agents
that disrupt mucus-bacterial interactions might have the
potential to promote diseases associated with gut inflam-
mation. Carboxymethylcellulose and polysorbate-80have
been shown to induce dysbiosis, low-grade inflammation,
and obesity/metabolic syndrome in wild-type mice and
promoted colitis (Chassaing etal., 2015).
Exosomes and extracellular vesicles
Bacteria send signals throughout the body by releas-
ing extracellular vesicles, which are exosome-like nano-
particles (Maguire, 2016). In somatic cells, the content,
including microRNA, and functional characteristics of
exosomes on other cells has been shown to be regulated
by environmental inputs (Lo Cicero et al., 2015). Outer
membrane vesicles released from bacteria are similar to
exosomes (Sjöström etal., 2015), and therefore, this is an
important area for future research.
In the 1920s, the psychiatrist Henry Cotton performed
colectomies to treat psychiatric problems, believing,
without evidence, that the agent causing the neurological
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M. Maguire and G. Maguire: Supplement for neurological disorders13
condition was the colon in a state of dysbiosis (Skull,
2005). Others during that time recognized that the dysbio-
sis underlying the psychiatric condition could be treated
with probiotics (Phillips, 1910). The emergence of over-
whelming data in humans, and animal models, indicate
that dysbiosis can be overcome by changing one’s diet
(David et al., 2014). Meat can induce dysbiosis (David
etal., 2014), and a diet rich in vegetables and low in meat
and dairy may even increase brain volume (Gu etal., 2015).
To treat neurodegenerative diseases, several strate-
gies involving the gut are proposed: (1) Introduce bacteria
to the gut that supply beneficial metabolites, (2) recolonize
the gut with commensal bacteria, (3) provide prebiotics
that feed the endogenous and exogenous commensal bac-
teria but not the pathogenic bacteria, (4) supply the gut
with amino acids that are known to be beneficial to build-
ing the integrity of the intestinal lining and in rebuilding
the microvilli of the gut’s epithelial cells, and (5) provide
the gut and hence the circulation and brain with postbi-
otic anti-inflammatory molecules.
Arguments have been put forth to develop therapeu-
tics in a non-reductionist manner, incorporating multiple
molecules to target the multiple pathways that underlie
the condition (Maguire, 2014). Likewise, similar argu-
ments have been offered for the development and analysis
of nutrients (Campbell, 2014).
The gut has gained momentum in public health dis-
course recently, with a shift towards understanding the
gut and brain as symbiotic and bi-directional rather than
isolated entities when it comes to overall health and dis-
eases prevention. Now, research is beginning to discover
convincing findings, which will hopefully bring to light
the reciprocal relationship between neurological, physio-
logical, and psychological health and the gut, to help
guide physicians and mental health care providers with
an expanded range of treatment options.
Our approach based on current evidence is to deliver
as a supplement a combination of prebiotics, probiotics,
and postbiotics, along with amino acids to rebuild the gut
wall and to restore homeostasis to the gut. Restoration of
homeostasis to the gut and repaired gut wall to eliminate
leaky gut syndrome will then lead to brain homeostasis,
especially proteostasis, and help restore normal function
to the nervous system. We now highlight what is included
in the proposed supplement.
According to the International Scientific Association for
Probiotics and Prebiotics (ISAPP), probiotics are defined
as ‘live microorganisms that, when administered in ade-
quate amounts, confer a health benefit on the host’ (Hill
etal., 2014).
Butyrate has potent anti-inflammatory properties so
it probably also has tumor-suppressive properties that are
not cancer cell autonomous. For example, butyrate ame-
liorates the inflammation associated with colitis in both
rodent models and human patients (Hamer etal., 2008).
Some of these effects are probably due to histone deacety-
lase inhibition and epigenetic regulation of gene expres-
sion, but there is also evidence that it can signal through
G-protein-coupled receptors to stimulate the expansion of
Treg cells (Smith etal., 2013).
Scientists have identified more than 200 human
milk oligosaccharides (HMOs) which are prebiotic
(Karav etal., 2016). The risk of MS is reduced in those
who were breast fed (Conradi etal., 2013). How does
this protection arise? Bifidobacterium longum infantis
digests HMOs, and in turn releases SCFAs, which feed
an infant’s gut cells. Through direct contact, B. infantis
also encourages gut cells to make adhesive proteins that
seal the gaps between them, keeping microbes out of the
bloodstream. Anti-inflammatory molecules are also pro-
duced. These changes only happen when B. infantis feeds
on HMOs; if it feeds on lactose instead, it survives but
does not engage in any symbiosis with the baby’s cells.
In other words, the microbe’s full beneficial potential is
unlocked only when it feeds on breast milk. Likewise,
for a child to reap the full benefits that milk can provide,
B.infantis must be present in the gut. Probiotics are those
products that can survive in the human gut and impact
microbes which colonize the gut. However, many pro-
biotic strains do not colonize the gut and are no longer
recoverable in stool 1–4weeks after stopping their con-
sumption. For example, a fermented milk product with
probiotic strains matching the commercially available
Activia was recently studied (McNulty etal., 2011). The
study showed that the probiotic product did not change
the gut’s bacterial composition, but instead altered
gene expression patterns relevant to carbohydrate
metabolism in the host’s resident gut microbes. These
changes in the human fecal gut function were confined
only to the time of probiotic consumption. Thus, a sus-
tained benefit and colonization of the bacteria was not
achieved. These data show that babies require mother’s
breast milk for optimal health, and that the bacteria
in milk, but not the milk itself, is beneficial to adult
health. In a model of childhood malnutrition using gno-
tobiotic mice, certain long-term dietary practices may
impair responses to dietary interventions, necessitating
the introduction of diet-responsive bacterial lineages
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14 M. Maguire and G. Maguire: Supplement for neurological disorders
present in other individuals and identified as beneficial
(Wagner etal., 2016).
Below will summarize some of the important bacteria
to human health.
1. Ruminoccus brummi breaks down resistant starch and
feeds other bacteria (a keystone bacterium).
2. Faecalibacterium prausnitzii has been shown to
respond to prebiotic supplementation using a mixed
chain length fructan supplement. Faecalibacterium
prausnitzii is also able to use pectin for growth which
may enable a more targeted approach to boosting
numbers of this bacterial species. Reduced numbers
of F. prausnitzii are present in Crohn’s disease patients,
and since this bacterium has also been shown to have
an anti-inflammatory effect, it is a strong target for
disease therapy (Scott etal., 2015).
3. Bifidobacterium animalis subsp lactis (strain number
I-2494 in the French National Collection of Cultures
of Micro-organisms, Paris, France) is referred to as
DN-173 010. Tillisch etal. (2013) has shown this bacte-
rium to modulate brain activity.
4. Lactobacillus rhamnosus JB-1, an effective modula-
tor of the gut microbiota, was proved to be able to
increase GABA (Aα2) in the hippocampus of mice
(Bravo etal., 2011).
5. Oxalobacter formigenes ferments oxylates, which are
toxic if not broken down (Noonan and Savage, 1999).
6. Lactobacillus reuteri clade II strain 6475 attenuates
colonic inflammation (Gao etal., 2015).
7. Lactobacillus GG alleviates the intestinal inflamma-
tion and pulmonary exacerbations rate in cystic fibro-
sis patients (Bruzzese etal., 2004).
8. The acetate-producing Bifidobacterium species
have been shown to promote gut epithelial integrity
(Fukuda etal., 2011).
9. Prevotella and a lower proportion of Bacteroides are
associated with a higher production of SCFAs, such as
butyrate (Ou etal., 2013).
10. Consider the independent contribution of gut micro-
biota-derived metabolites versus metabolites derived
directly from food, such as tryptophan metabolites
and ω-3 fatty acids. Indole-3-aldehyde, one trypto-
phan metabolite produced by lactobacilli, is an aryl
hydrocarbon receptor (AhR) agonist (Zelante et al.,
2013). AhR-dependent gene expression includes
genes involved in the production of mediators impor-
tant for gut homeostasis (Li etal., 2011).
11. A study conducted at the University of Toronto
found a significant decrease in anxiety symptoms in
patients who took the probiotic Lactobacillus casei
after 60days (Rao etal., 2009).
12. Escherichia coli Nissle 1917modulates natural immu-
nity in the gut (Trebichavsky etal., 2010).
13. Bacillus coagulans is a very well studied probiotic in
the spore family that has a profound effect on inflam-
matory conditions such as irritable bowel syndrome
and Crohn’s disease. Bacillus coagulans offers an
expanded effect of controlling these common inflam-
matory bowel conditions in addition to its potent
immune-boosting activity. Bacillus coagulans has the
unique attribute of producing lactic acid and spe-
cifically the L+ optical isomer of lactic acid, which
has been shown to have a more profound effect on
immune stimulation and gut defense than the other
forms of lactic acid produced by conventional probiot-
ics. Bacillus coagulans is also a tremendous colonizer
and thus assures proper colonization, which in turn
will produce the beneficial effects required. Bacillus
coagulans also plays a key role in digestion of food and
absorption of nutrients. Bacillus coagulans can digest
incoming fat to reduce the uptake of cholesterol. Bacil-
lus coagulans adds another dimension given its potent
ability to fight inflammatory conditions, aid in diges-
tion, and prevent the growth of harmful bacteria.
14. Bacillus subtilis HU58 is one strain that has been
shown in studies to actually alter the GI flora when it
colonizes (Tam etal., 2006).
15. NCFM strain of Lactobacillus acidophilus, developed
at North Carolina State University from a human intes-
tinal tract, L. acidophilus HMF, and the L. acidophilus
DDS-1strain produce a number of positive benefits for
the host (Sanders and Klaenhammer, 2011).
16. Faecalibacterium prausnitzii has a protective role in
inflammatory bowel disease (Underwood, 2014).
1 7. VLS#3 has been shown to attenuate the signs and
symptoms of colitis (Mencarelli et al., 2011) and
contains the following bacteria: Streptococcus
thermophiles, Bifidobacterium breve, B. longum, Bifi-
dobacterium infantis, L. acidophilus, Lactobacillus
plantarum, Lactobacillus paracasei, and Lactobacillus
delbrueckii subsp. bulgaricus.
Amino acids
The amino acids and carbohydrates in food help the bac-
terial spores move from their dormant (spore state) to their
active (vegetative state) form in the GI. There are tremen-
dous immune benefits if the spores are made to germinate
into their vegetative state in the upper GI itself, and so
taking a supplement just after a meal (10–60min after)
is ideal.
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M. Maguire and G. Maguire: Supplement for neurological disorders15
Multiple elements of tryptophan catabolism facilitate
gut homeostasis (Thorburn etal., 2 014). Tryptophan builds
barrier function by regulating the expression of tight junc-
tion proteins in intestinal epithelial cells (Alvarez etal.,
N-acetylcysteine improves the microbiota compo-
sition and barrier function in the gut (Oz et al., 2007;
Xu et al., 2016) and prevents premature senescence of
endothelial cells (Khan et al., 2017). N-acetylcysteine
reduced ROS while increasing growth and ATP production
in the fibroblasts of patients with mitochondrial disease
(Douiev et al., 2016). Oral administration can improve
brain function in a number of neurodegenerative indica-
tions (Shahipour etal., 2014).
However, an overabundance of amino acids, includ-
ing N-acetylcysteine and tryptophan, can lead to inflam-
mation (Rieber and Belohradsky, 2010; Koeth etal., 2013;
Zhenyukh etal., 2017). mTORC1mediates pro-oxidant and
pro-inflammatory activation of blood cells by branched-
chain amino acids (BCAAs), leucine, isoleucine, and
valine. Daily BCAA supplementation could reach elevated
blood levels around 3–6mmol/l concentrations used in
the in vitro studies showing the BCAAs to have pro-oxi-
dant and pro-inflammatory effects (Zhenyukh etal., 2017).
Prebiotics are defined according to the ISAPP as ‘a selec-
tively fermented ingredient that results in specific changes
in the composition and/or activity of the GI microbiota,
thus conferring benefit(s) upon host health’ (Gibson etal.,
2010). Fibers, such as starches, are composed mostly of
many sugar units bonded together. However, unlike most
starches, the bonds in fiber cannot be broken down by
digestive enzymes and therefore pass relatively intact
into the large intestine. Fiber is fermented by commensal
bacteria to produce large quantities of acetate, PPA, and
butyrate (~40, 20, and 20 m, respectively) (Tan etal.,
2014). Dietary fiber is listed on the Nutrition Facts panel,
and 25 g of dietary fiber is the currently recommended
amount in a 2000-kcal diet. Manufacturers are allowed to
call a food item a ‘good source of fiber’ if it contains 10%
of the recommended amount (2.5g/serving) and an ‘excel-
lent source of fiber’ if the food contains 20% of the recom-
mended amount (5g/serving). Dietary fiber on food labels
includes both dietary fiber and functional fiber. Most
people in the United States do not consume adequate
amounts of fiber, and 80% are nutrient deficient (Marriott
etal., 2010).
Gum arabic is a soluble fiber that promotes healthy
gut and enhances neurological function (Binjumah etal.,
2016). It acts as a prebiotic to increase Lactobacilli and
Bacteroides, and the numbers of Bifidobacteria, Lacto-
bacilli and Bacteroides were significantly higher for gum
arabic than for inulin (Calame etal., 2008).
Inulin-type fructans, arabinose, and arabinoxylan-oli-
gosaccharides are prebiotics that stimulate both bifidobac-
teria and the production of butyrate (Falony et al., 2009;
De Vuyst and Leroy, 2011; De Vuyst et al., 2014; Rivière
et al., 2014). Green pea and chickpea-supplemented diet
alters the gut microbiome and enhances gut barrier integ-
rity in mice (Bibi etal., 2017; Monk etal., 2017).
Here I define postbiotics as those molecules released by
bacteria and other microorganisms that when adminis-
tered in adequate amounts confer health benefits to the
host. Tryptophan metabolites, including tryptamine and
indole-3-propionic acid, have been shown to rebuild the
gut lining (Jennis etal., 2017). Fermented foods are great
for the GI, but the benefits do not typically derive from the
microorganisms colonizing the gut; rather the benefits
derive from the ferment itself. The many nutrients the
bacteria make, what I call the postbiotics, while ferment-
ing the foods, are what are beneficial to the GI and the
immune system.
Enhancing gut epithelial
Amino acids have been shown to increase electrolyte
absorption and improved mucosal barrier functions
(Yinetal., 2016). Enterocytes are absorptive cells, formed
as simple columnar epithelial cells that are found in the
small intestine. The brush border on the apical surface
of enterocytes is a highly specialized structure well
adapted for efficient digestion and nutrient transport,
while at the same time providing a protective barrier for
the intestinal mucosa. The brush border is constituted of
a densely ordered array of microvilli, protrusions of the
plasma membrane, which are supported by actin-based
microfilaments and interacting proteins and anchored in
an apical network of actomyosin and intermediate fila-
ments, the so-called terminal web. The highly dynamic,
specialized apical domain is both an essential partner
for the gut microbiota and an efficient signaling platform
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16 M. Maguire and G. Maguire: Supplement for neurological disorders
that enables adaptation to physiological stimuli from
the external and internal milieu. Nevertheless, inherited
alterations or various pathological stresses, such as infec-
tion, inflammation, and mechanical or nutritional altera-
tions, can jeopardize this equilibrium and compromise
intestinal functions.
Lactobacillus reuteri treatment substantially counter-
acted the detrimental effects of E. coli and preserved the
barrier function. Lactobacillus johnsonii and Lactobacil-
lus GG also achieved barrier protection, partly by directly
inhibiting enterotoxigenic E. coli attachment. Specific
strains of Lactobacillus can enhance gut barrier func-
tion through cytoprotective heat shock protein induction
and fortify the cell protection against an E. coli challenge
through tight junction protein modulation and direct
interaction with pathogens (Liu etal., 2015).
The proposed supplement should be taken about 1h fol-
lowing a meal. This allows the food to clear well enough
for the amino acids to interact with the gut and also allows
for the pH of the stomach to become more alkaline due to
the food, thus allowing better translocation of the probiot-
ics through the acidic stomach (Lawrence, 1998).
Future trends
Synthetic biology is hugely promising for developing
therapeutics; however, the technology is currently used
to engineer bacteria and yeast for the secretion of a par-
ticular molecule (Eisenstein, 2016), representing the con-
tinuation of a reductionist approach for treating disease
(Maguire, 2014). Another promising methodology for the
production of therapeutics are cell-free expression and
purification of proteins (Sullivan etal., 2016) using lysates
of bacteria and yeast. However, such approaches may not
benefit from the synergistic properties of the systems ther-
apeutic where a broader collection of therapeutic mole-
cules are included (Maguire, 2014), and the packaging of
the molecules into exosomes that provide protection and
delivery properties to the molecules is present, as well as
possible important post-translational modifications made
within the exosome (Maguire, 2016). Because bacteria
secrete molecules and exosomes, using the secretome
of commensal bacteria may provide a much more useful
therapeutic. In the diagnostic realm, scientists and engi-
neers at Massachusetts Institute of Technology have now
developed an ingestible sensor of various compounds
(Mimee et al., 2018). Using a bioengineered bacterium
that fluoresces coupled with a sensor to measure the
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in the gut, including heme to quantify GI bleeding. These
sensors could be engineered to measure many types of
molecules in the gut depending on the bacterial construct
used in their micro-bio-electronic device. This is one pos-
sible means to help develop personalized gut medicine
potentially leading to specific supplements for the ame-
lioration of patient-specific neurological diseases.
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18 M. Maguire and G. Maguire: Supplement for neurological disorders
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... In addition, were observed associate with neuroinflammation and cognitive dysfunction [6] and brain health and correlated diseases [7]. However, it has been advocated that the negative impacts of westernized diets consumption on intestinal health and microbial composition may be minimized by consuming components such as amino acids, prebiotics, probiotics, and postbiotics [8], fiber and oligosaccharides [9] increasing the population of beneficial microorganisms (e.g, bifidobacteria and lactobacilli) in the gut environment. ...
... Heat stress induces intestinal disturbance and microbial dysbiosis . In contract, beneficial bacteria (probiotics), such as those composed of the synbiotic, modify the gut microflora by inducing the production of immunoglobulins ( Bauer et al., 2006;Gupta and Garg, 2009); decreasing gut pH through the breakdown of indigestible carbohydrates (Kabir, 2009); preventing adherence of pathogenic bacteria to the intestinal epithelia through competitive exclusion (Ferket, 2011); and reducing intestinal barrier permeability (Leaky gut) via increased gut integrity and epithelial defense response (Maguire and Maguire, 2019;Nagpal and Yadav, 2017). ...
Full-text available
The aim of this study was to examine the effect of a dietary synbiotic supplement on the cecal microflora, antioxidant status, and immune response of broiler chickens under heat stress (HS). A total of 360 one-day-old male Ross 708 broiler chicks were randomly distributed among 3 dietary treatments containing a synbiotic (PoultryStar consists of Bifidobacterium animalis, Enterococcus faecium, Lactobacillus reuteri, Pediococcus acidilactici, and fructooligosaccharides) at 0 (control), 0.5 (0.5X), and 1.0 (1.0X) g/kg. Each treatment contained 8 replicates of 15 birds each housed in floor pens. Heat stimulation was at 32°C for 9 h daily from day 15 to 42. Heat stress-induced changes of cecal bacteria were detected using bacteria-specific agars, and spleen protein concentration and mRNA expression of interleukins and antioxidants were examined using ELISA and real-time PCR, respectively. Under the HS condition, synbiotic fed broilers regardless of dose had lower cecal enumerations of Escherichia coli and coliforms, and a lower heterophil/lymphocyte (H/L) ratio (P < 0.05) compared to controls. 1.0X group also had higher cecal enumerations of Bifidobacterium spp. and Lactobacillus spp., spleen glutathione peroxidase (GPx), and plasma nuclear factor erythroid 2-related factor 2 (Nrf-2), and a lower H/L ratio compared to both control and 0.5X groups (P < 0.05). However, there were no treatment effects on the levels of Enterococcus spp., the circulating monocytes, eosinophils, and basophils, Toll like receptor-4 (TLR-4), interleukin-6 (IL-6), interlukin-10 (IL-10), and their mRNA expression, as well as plasma Kelch-like ECH-associated protein 1 (Keap-1) (P > 0.05). These results suggest that the synbiotic could inhibit the negative effects of HS on broiler health through the reduction of cecal pathogens, regulation of stress reactions, and improvement of antioxidant status.
... Different studies on boilers have suggested that when these boilers were fed with chicory fructans, there was an increase in the lactobacilli counts and decrease in the Campylobacter and Salmonella in the gastrointestinal tract [4]. Various experimental studies have been proved that prebiotics can help in reducing the severity of particular diseases such as diabetes, IBS, neural disorders and other infectious diseases [5]. Prebiotics are necessary to study as they are related not only with the health aspects but in the food industries; health professionals, scientists, regulators as well as consumers have a great interest in exploring the other beneficial effects of them. ...
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Prebiotics are non-digestible carbohydrates which can be used as prime source of energy for gut microflora. These can be naturally occurring in fruit and vegetables or can be made synthetically by enzymatic digestions. New versatile sources of prebiotics had been found nowadays for economic commercialization. This review will decipher on highlighting the importance of prebiotics in immunomodulation and nutrient absorption abilities of gut, as it is important for the anti-effective capacity of the organism especially in the neonatal period. Moreover, new prebiotics transmission strategies with higher penetrating capacity such as microencapsulation and immobilization have been discussed. In addition to this, literature had shown the modulation of gut microflora by the continuous use of prebiotics in many disorders so here, the role of prebiotics in health-related issues such as diabetes and inflammatory bowel disease (IBS) have been explained.
Background Excessive free radicals, generated from the metabolic reaction in organisms, have been implicated in many human diseases as well as aging process. Nowadays, many synthetic substances have been developed as anti‐oxidation cosmetic ingredients. However, man‐made antioxidants often have certain toxicity and side effects, which make their application under strict control. Therefore, more and more researchers focus on natural antioxidants because of their advantages. Aims In this study, CE obtained from natural Chinese medicine was used to investigate whether it had antioxidant effect in vitro and repair effect on HaCaT cell damage caused by UVB. Methods UV‐Vis and HPLC were adopted for qualitative and quantitative analysis of CE. We investigated the antioxidant potential of CE by assessing its ABTS⁺, DPPH•, hydroxyl (OH•), and superoxide anions () free‐radical quenching ability. The safety of CE was studied by CCK‐8 assay. To evaluate the anti‐oxidation effect of CE on UVB‐induced damage on HaCaT cells, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) content were tested. Results Experiment data showed that the CE displayed high scavenging ability: ABTS⁺, DPPH•, OH•, and quenching rates were 88%, 64%, 94%, and 58%, respectively. Furthermore, after UVB radiation (30 mJ/cm²), adding CE (50‐500 μg/mL) could increase the SOD activity in HaCaT cells and reduce the MDA contents. Conclusions All results illustrate that the CE shows significant antioxidant effect on scavenging free radicals in vitro. Besides, the CE can repair UVB‐induced oxidant damage by improving SOD activity and reducing MDA content.
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Celiac disease (CD) is associated with intestinal microbiota alterations. The administration of prebiotics could be a promising method of restoring gut homeostasis in CD. The aim of this study was to evaluate the effect of prolonged oligofructose-enriched inulin (Synergy 1) administration on the characteristics and metabolism of intestinal microbiota in CD children following a gluten-free diet (GFD). Thirty-four paediatric CD patients (mean age 10 years; 62% females) on a GFD were randomized into two experimental groups receiving Synergy 1 (10 g/day) or placebo (maltodextrin; 7 g/day) for 3 months. The quantitative gut microbiota characteristics and short-chain fatty acids (SCFAs) concentration were analysed. In addition, side effects were monitored. Generally, the administration of Synergy 1 in a GFD did not cause any side effects. After the intervention period, Bifidobacterium count increased significantly (p < 0.05) in the Synergy 1 group. Moreover, an increase in faecal acetate and butyrate levels was observed in the prebiotic group. Consequently, total SCFA levels were 31% higher than at the baseline. The presented trial shows that Synergy 1 applied as a supplement of a GFD had a moderate effect on the qualitative characteristics of faecal microbiota, whereas it stimulated the bacterial metabolite production in CD children.
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Butyrate (BT) is a ubiquitous short-chain fatty acid (SCFA) principally derived from the enteric microbiome. BT positively modulates mitochondrial function, including enhancing oxidative phosphorylation and beta-oxidation and has been proposed as a neuroprotectant. BT and other SCFAs have also been associated with autism spectrum disorders (ASD), a condition associated with mitochondrial dysfunction. We have developed a lymphoblastoid cell line (LCL) model of ASD, with a subset of LCLs demonstrating mitochondrial dysfunction (AD-A) and another subset of LCLs demonstrating normal mitochondrial function (AD-N). Given the positive modulation of BT on mitochondrial function, we hypothesized that BT would have a preferential positive effect on AD-A LCLs. To this end, we measured mitochondrial function in ASD and age-matched control (CNT) LCLs, all derived from boys, following 24 and 48 h exposure to BT (0, 0.1, 0.5, and 1 mM) both with and without an in vitro increase in reactive oxygen species (ROS). We also examined the expression of key genes involved in cellular and mitochondrial response to stress. In CNT LCLs, respiratory parameters linked to adenosine triphosphate (ATP) production were attenuated by 1 mM BT. In contrast, BT significantly increased respiratory parameters linked to ATP production in AD-A LCLs but not in AD-N LCLs. In the context of ROS exposure, BT increased respiratory parameters linked to ATP production for all groups. BT was found to modulate individual LCL mitochondrial respiration to a common set-point, with this set-point slightly higher for the AD-A LCLs as compared to the other groups. The highest concentration of BT (1 mM) increased the expression of genes involved in mitochondrial fission (PINK1, DRP1, FIS1) and physiological stress (UCP2, mTOR, HIF1α, PGC1α) as well as genes thought to be linked to cognition and behavior (CREB1, CamKinase II). These data show that the enteric microbiome-derived SCFA BT modulates mitochondrial activity, with this modulation dependent on concentration, microenvironment redox state, and the underlying mitochondrial function of the cell. In general, these data suggest that BT can enhance mitochondrial function in the context of physiological stress and/or mitochondrial dysfunction, and may be an important metabolite that can help rescue energy metabolism during disease states. Thus, insight into this metabolic modulator may have wide applications for both health and disease since BT has been implicated in a wide variety of conditions including ASD. However, future clinical studies in humans are needed to help define the practical implications of these physiological findings.
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A diet rich in salt is linked to an increased risk of cerebrovascular diseases and dementia, but it remains unclear how dietary salt harms the brain. We report that, in mice, excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on expansion of TH17 cells in the small intestine, resulting in a marked increase in plasma interleukin-17 (IL-17). Circulating IL-17, in turn, promotes endothelial dysfunction and cognitive impairment by the Rho kinase-dependent inhibitory phosphorylation of endothelial nitric oxide synthase and reduced nitric oxide production in cerebral endothelial cells. The findings reveal a new gut-brain axis linking dietary habits to cognitive impairment through a gut-initiated adaptive immune response compromising brain function via circulating IL-17. Thus, the TH17 cell-IL-17 pathway is a putative target to counter the deleterious brain effects induced by dietary salt and other diseases associated with TH17 polarization.
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The composition of the human gut microbiome matures within the first years of life. It has been hypothesized that microbial compositions in this period can cause immune dysregulations and potentially cause asthma. Here we show, by associating gut microbial composition from 16S rRNA gene amplicon sequencing during the first year of life with subsequent risk of asthma in 690 participants, that 1-year-old children with an immature microbial composition have an increased risk of asthma at age 5 years. This association is only apparent among children born to asthmatic mothers, suggesting that lacking microbial stimulation during the first year of life can trigger their inherited asthma risk. Conversely, adequate maturation of the gut microbiome in this period may protect these pre-disposed children.
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Altered gut microbiome populations are associated with a broad range of neurodevelopmental disorders including autism spectrum disorder and mood disorders. In animal models, modulation of gut microbiome populations via dietary manipulation influences brain function and behavior and has been shown to ameliorate behavioral symptoms. With striking differences in microbiome-driven behavior, we explored whether these behavioral changes are also accompanied by corresponding changes in neural tissue microstructure. Utilizing diffusion tensor imaging, we identified global changes in white matter structural integrity occurring in a diet-dependent manner. Analysis of 16S ribosomal RNA sequencing of gut bacteria also showed changes in bacterial populations as a function of diet. Changes in brain structure were found to be associated with diet-dependent changes in gut microbiome populations using a machine learning classifier for quantitative assessment of the strength of microbiome-brain region associations. These associations allow us to further test our understanding of the gut-brain-microbiota axis by revealing possible links between altered and dysbiotic gut microbiome populations and changes in brain structure, highlighting the potential impact of diet and metagenomic effects in neuroimaging.
Biomolecular monitoring in the gastrointestinal tract could offer rapid, precise disease detection and management but is impeded by access to the remote and complex environment. Here, we present an ingestible micro-bio-electronic device (IMBED) for in situ biomolecular detection based on environmentally resilient biosensor bacteria and miniaturized luminescence readout electronics that wirelessly communicate with an external device. As a proof of concept, we engineer heme-sensitive probiotic biosensors and demonstrate accurate diagnosis of gastrointestinal bleeding in swine. Additionally, we integrate alternative biosensors to demonstrate modularity and extensibility of the detection platform. IMBEDs enable new opportunities for gastrointestinal biomarker discovery and could transform the management and diagnosis of gastrointestinal disease.
Primary liver tumors and liver metastasis currently represent the leading cause of cancer-related death. Commensal bacteria are important regulators of antitumor immunity, and although the liver is exposed to gut bacteria, their role in antitumor surveillance of liver tumors is poorly understood. We found that altering commensal gut bacteria in mice induced a liver-selective antitumor effect, with an increase of hepatic CXCR6⁺ natural killer T (NKT) cells and heightened interferon-γ production upon antigen stimulation. In vivo functional studies showed that NKT cells mediated liver-selective tumor inhibition. NKT cell accumulation was regulated by CXCL16 expression of liver sinusoidal endothelial cells, which was controlled by gut microbiome-mediated primary-to-secondary bile acid conversion. Our study suggests a link between gut bacteria–controlled bile acid metabolism and liver antitumor immunosurveillance.
Long-term epigenetic reprogramming of innate immune cells in response to microbes, also termed "trained immunity," causes prolonged altered cellular functionality to protect from secondary infections. Here, we investigated whether sterile triggers of inflammation induce trained immunity and thereby influence innate immune responses. Western diet (WD) feeding of Ldlr-/- mice induced systemic inflammation, which was undetectable in serum soon after mice were shifted back to a chow diet (CD). In contrast, myeloid cell responses toward innate stimuli remained broadly augmented. WD-induced transcriptomic and epigenomic reprogramming of myeloid progenitor cells led to increased proliferation and enhanced innate immune responses. Quantitative trait locus (QTL) analysis in human monocytes trained with oxidized low-density lipoprotein (oxLDL) and stimulated with lipopolysaccharide (LPS) suggested inflammasome-mediated trained immunity. Consistently, Nlrp3-/-/Ldlr-/- mice lacked WD-induced systemic inflammation, myeloid progenitor proliferation, and reprogramming. Hence, NLRP3 mediates trained immunity following WD and could thereby mediate the potentially deleterious effects of trained immunity in inflammatory diseases.
Background: The gut microbiome as well as dietary habits have recently been established as environmental contributors to the pathogenesis of multiple sclerosis (MS), a T-cell-mediated autoimmune disease of the central nervous system (CNS). Objective: To summarize recent findings on the Janus-faced effects of dietary short-chain fatty acids (SCFAs) and long-chain fatty acids (LCFAs) on T-cell immunity with a special focus on the gut and the microbiome as an interface linking diet and T-cell responses during MS. Methods: Review article. Results: The autoimmune basis of MS most likely stems from an imbalance between pro-inflammatory T helper cell (Th)1 and Th17 cells and anti-inflammatory or regulatory mechanisms including regulatory T cells (Treg). Hence, the rationale of currently available therapeutic interventions is to either suppress pathogenic Th1/Th17 and/or to foster Treg responses. Dietary fatty acids are often discussed for their detrimental role in MS. However, recent studies investigating saturated fatty acids in animal models of MS revealed harmful as well as beneficial effects depending on their aliphatic chain length. Conclusion: Dietary SCFAs constitute interesting candidates as safe and potent add-on therapy in the immunomodulatory treatment armamentarium for relapsing-remitting MS.