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REVIEW
KEY WORDS: D-lactic acid endotoxin microbial endocrinology microbiome prebiotics probiotics short-chain
fatty acids trimethylamine oxide (TMAO)
A study of germ-free (GF) mice found that the vast majority of chemicals circulating in blood are dependent on the
microbiome for their synthesis, although many are subsequently modified by the host.8 These chemicals have a
profound effect on mammalian behavior and neuroendocrine responses. This review will focus on research done in
humans, but work done with GF rodents signals the evolutionary importance of the microbiome in shaping mammalian behavior, with important implications for human health.
The developmental abnormalities found in GF mice are
totally reversible by colonization with intestinal bacteria
early in life but not in adulthood, suggesting that the microbiome influences brain development.9,10
When compared with conventional mice, GF mice show
greater exploratory activity in an open-field activity box,
suggesting less vigilance and caution.11 Similar behavioral
changes are produced in conventional mice by administration of a mixture of nonabsorbed antibiotics for 7 days.12
Although some researchers have attributed these behavioral
changes to diminished anxiety, elevation of striatal norepinephrine, dopamine, and serotonin turnover in the brains of
GF mice11 and elevated plasma levels of adrenal corticotrophic hormone and corticosterone in response to restraint
stress13 demonstrate heightened stress reactivity in GF mice,
an effect also seen in GF rats, who are, however, less active
and more cautious than conventional rats.14 It appears that
INTRODUCTION
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Adaptive immunity
The adaptive immune system responds to specific microbes
with antibodies or antigen-specific cellular immune responses
and can produce CNS dysfunction through auto-immune reactions caused by molecular mimicry between bacterial and
self proteins. Although this is an area of ongoing investigation, there is presently little evidence for a link between the
gut microbiome, the adaptive immune system, specific autoimmunity, and disorders of the CNS in humans.43,44 However,
in a laboratory model of multiple sclerosis, mice sensitized to
the autoantigen, myelin oligodendrocyte glycoprotein, only
developed experimental autoimmune encephalitis in the
presence of commensal bacteria.45
Celiac disease (CD) is a notable exception, although the
mechanism is indirect. Alterations in the gut microbiome
may play a primary role in the pathogenesis of CD,46 a
gluten-sensitive disease in which the adaptive immune
system damages not only the gut but also the brain. The most
common CNS manifestations of CD are ataxia (with or
without myoclonus), headache, and cognitive dysfunction.
Gastrointestinal symptoms are often absent in neurologic
CD, as are the usual marker of intestinal CD, transglutaminase (TG) antibodies. The autoimmune target in neurologic gluten sensitivity is TG6 rather than TG2, which is the
target for autoantibodies measured in commercial tests.47
Most studies, but not all,48 have found significant differences between healthy children and children with CD in the
duodenal49,50 and oral51 microbial populations. Some of these
differences are the result of inflammation and disappear during a gluten-free diet, but reduced levels of Bifidobacterium
species, a replicable finding, do not become normal with a
gluten-free diet.52,53 Infants at high risk of developing CD
because of family history and personal genotype show a
reduction in Bifidobacteria before the onset of illness.54
Bifidobacteria protect human intestinal cells from the toxic
effects of gliadin peptides, the inflammatory triggers of
CD, by altering their structure.55 They also induce an antiinflammatory response in stimulated human mononuclear
cells in tissue culture.56 Destruction of protective Bifidobacteria can explain the association between incident CD
and previous antibiotic exposure.57 Loss of Bifidobacteria
may play a pathogenetic role in CD and contribute to its
rising prevalence. Administration of Bifidobacterium long-
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(FOS) favor acetate over lactate as an end-product of carbohydrate metabolism. Horses who had barley added to their
diets experienced a change in fecal flora characterized by
increased concentrations of lactic acid bacteria belonging to
the genera Lactobacillus and Streptococcus, associated with
an increase in D-lactate concentration in the stool. These
changes were prevented by administration of FOS.72
Ammonia
Ammonia is a well-known neurotoxin, produced in the
intestinal tract from urea by the action of bacterial ureases.
Gut-derived ammonia is taken up by the liver and consumed
in the urea cycle. By creating portosystemic shunts, cirrhosis
allows absorbed ammonia to escape hepatic metabolism,
increasing blood ammonia, which contributes to the pathogenesis of hepatic encephalopathy (HE).61 In addition to
direct neurotoxic injury, ammonia alters function of the
bloodbrain barrier, impairing intracerebral synthesis of
serotonin and dopamine and producing abnormal neurotransmitters such as octopamine.73
Minimal HE (MHE) is a common neurocognitive disorder that occurs in 80% of cirrhotic patients74 and often
evades diagnosis.75 It is characterized by subtle intellectual
deficits and psychomotor abnormalities that have a significant negative impact on health-related quality of life, impair
motor vehicle operation, and increase the incidence of vehicular accidents.76 Failure to diagnose MHE in apparently
normal patients with chronic liver disease is considered a
medical error.77
Cognitive dysfunction in patients with cirrhosis is associated with altered composition of the gut microbiome,
which differs between cirrhotics with or without HE.78,79
Levels of urease-producing bacteria are positively associated with cognitive dysfunction in cirrhotic patients.80 The
nonabsorbed antibiotic rifaximin, when added to conventional therapy with lactulose, increases the rate of total
reversal of HE from 51% to 76% and reduces mortality
from 49.1% to 23.8%,81 demonstrating the importance of
gut flora in HE pathogenesis. Changing the gut microbiome
with synbiotics has also been shown to alleviate cognitive
dysfunction in patients with cirrhosis. A combination of B.
longum and FOS82 or a cocktail of four freeze-dried, nonurease-producing bacteria (Pediacoccus pentoseceus, Leuconostoc mesenteroides, Lactobacillus paracasei ssp. paracasei,
and Lactobacillus plantarum) mixed with beta glucan, inulin,
pectin, and resistant starch83 had similar effects. Each regimen
reduced serum ammonia and improved cognitive performance
when compared with placebo. Administration of synbiotics
has been proposed for all patients with cirrhosis as a way to
prevent MHE.82
Short-chain fatty acids
Volatile fatty acids with a chain length of two to four
carbon atoms (acetate, propionate, and butyrate) are produced in abundance through bacterial fermentation of indigestible carbohydrate in the normal colon. Health benefits of
high fiber consumption have been linked to increased syn-
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measured. Unlike pharmacologic agents, however, gut microbes exist in a series of interconnected and highly structured living communities. Administering a probiotic does
more than just introduce a new bacterial species, which may
or may not be able to establish a niche in the community. It
may change community structure in unexpected ways, and
these changes may or may not alter community function.138
Human studies have unveiled substantial differences in the
gut microbial composition among individuals139141 that
depend on age, genetic background, physiological state,
microbial interactions, environmental factors, and diet.142144
Moreover, the microbiota of the effluent from the ileum is
both simpler and less stable than colonic fecal microflora and
is dominated by different bacterial phyla.145 This complexity
implies that the application of clinical and laboratory research on the health effects of manipulating the microbiome
will need to be tailored to specific characteristics of each
individual patient.146
DIET AND THE GUT MICROBIOME
Since diet has a significant impact on composition and
function of the human gut microbiome, dietary patterns
should be considered in attempts to understand the impact
of gut microbes on the brain, especially when interventions
are designed. Sequence analysis of amplified microbial ribosomal RNA-encoding genes (16S ribosomal DNA) reveals that the human adult microbiota consists of five
bacterial phyla: Firmicutes and Bacteroidetes predominate,
with Actinobacteria, Proteobacteria, and Verrucomicrobia
comprising just 2% of organisms. Most belong to the genera
Faecalibacterium, Bacteroides, Roseburia, Ruminococcus,
Eubacterium, Coprabacillus, and Bifidobacterium.147 A diet
high in animal protein and fat favors abundance of Bacteroides. A vegetarian diet or one high in monosaccharides
favors abundance of Prevotella species.148 High consumption of oligosaccharides favors growth of Bifidobacteria,
which is the dominant genus of breast-fed infants, who receive most of their carbohydrate in the form of breast milk
oligosaccharides.149
The impact of diet on the microbiome is an area of intense
study at present, with most research focused on metabolic
effects as they relate to obesity, diabetes, and cardiovascular disease. A systematic discussion is outside the scope
of this review. There is almost no published research that
describes actual diet > microbiome > CNS effects in
humans, just allusions to such an effect. A role for dietary
restriction in the treatment of D-lactic acidosis was previously mentioned. In a single case report, restriction of
monosaccharides and sucrose was shown to decrease Dlactate production in a patient with short bowel syndrome,
preventing neurotoxicity.150
Several aspects of the diet/microbiome relationship deserve further research for their potential importance to brain
health in the care of individual patients:
(1) Bacteria can feed or inhibit the growth of each other.
Metabolic interactions among components of the
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(2)
(3)
(4)
(5)
(6)
(7)
in food-associated biofilms produce unique signaling molecules and may represent a new dimension
in the relationship between food, microbes, and
human health.160
CONCLUSION
Experimental studies with human volunteers and with
small mammals demonstrate effects of commensal intestinal
bacteria on behavior and brain function that are contextually
meaningful and which appear to be biologically significant.
Gut bacteria influence reactivity of the HPA axis and the
induction and maintenance of nREM sleep. They may influence mood, pain sensitivity and normal brain development.
Clinical studies have demonstrated distinct pathological
CNS effects of commensal gut bacteria in hepatic cirrhosis
and short bowel syndrome and have led researchers to
speculate on possible adverse effects of gut microbes in alcohol dependence, CFS, fibromyalgia, RLS, ASD, schizophrenia, mood disorders, and degenerative or autoimmune
neurologic disease. Adverse effects have been attributed to
alterations in bacterial community structure (dysbiosis),
SIBO, and increased intestinal permeability.
Several mechanisms, none mutually exclusive, may enable commensal gut bacteria to influence function or dysfunction in the CNS: (1) stimulation of host immune
responses leading to diverse patterns of systemic cytokine
activation; (2) synthesis of absorbable neuroactive metabolites, including neurotransmitters; and (3) alterations in
neuronal circuitry by direct microbial effects on the ENS,
with CNS transmission through vagal and other routes. The
only mechanisms with a high level of proof in humans are
the neurotoxic effects of ammonia in HE and of D-lactic
acid in short bowel syndrome.
CNS and neuroendocrine activity, stress responses in
particular, may, in turn, influence the composition of the gut
microbiome by differentially altering the growth of bacterial
species and the production of bacterial virulence factors.
Enterobacteriaceae, a family that includes most of the
aerobic Gram-negative pathogens, is especially well tuned
to exploiting host stress responses for enhancing bacterial
growth and virulence.
Dietary patterns also modify microbiome composition
and function, in complex ways that vary among individuals
and cultures and are the subject of intense ongoing research.
Prebiotics, probiotics, and fermented foods such as yogurt
may influence the impact of the gut microbiome on the CNS
and have shown significant effects on brain function in a
number of experimental trials and clinical studies. Along
with diet, these functional food components may offer future opportunities for altering the microbiome to enhance
cognitive or emotive function and prevent or treat neurologic disorders.
AUTHOR DISCLOSURE STATEMENT
No competing financial interests exist.
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