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Infectious Disease and Neurocognition
than in other areas of the brain (Anglin et al., 2015). As described in a review, such
communication has been shown to impact psychiatric- like behavior in germ- free
mice, who show more anxious- like traits and cognitive impairment than mice with
typical gut microbiota (Anglin et al., 2015; Wang & Kasper, 2014).
Most human studies are association studies, but there is mounting evidence
from the studies that exist that the human gut and brain communicate and inuence health. One small human study indicates that Bacteroidetes, Firmicutes,
Proteobacteria, and Verrucomicrobia dier between cognitively impaired and unimpaired older adults. Cognitive impairment was measured using the Mini- Mental
State Exam, several assessments of executive functioning (e.g., Trail Making Test,
Stroop Color Word Test), two standardized memory assessments, and a verbal uency assessment (Manderino et al., 2017).
Another player in the microbiota– gut– brain axis is the HPA axis, which develops
partly in response to gut microbiota and mediates stress responses, which are involved in neuropsychiatric conditions. Evidence includes research in which germfree mice have an exaggerated stress response (Golubeva et al., 2015; Robertson
et al., 2017; Sudo et al., 2004), implying that reduced biodiversity of the gut triggers
increased susceptibility to neuropsychiatric conditions.
Inammation plays a role in the connection between the gut and brain, too. In
one scenario, pathogens in the gut decrease gut permeability and pass through the
intestinal wall to signal the immune system to release cytokines, which active the
vagus nerve to change the host’s behavior (Selkoe, 2001). Inammation appears
to play a role in the connection between the gut and autism (Azhari et al., 2019;
Carissimi et al., 2019; Inoue et al., 2016) as well as between the gut and Alzheimer’s
disease (Liu et al., 2021; Selkoe, 2001), poststroke cognitive impairment (Wang et al.,
2022), chemotherapy- related cognitive impairment (Deleemans et al., 2019), diet
(Robertson et al., 2017), and the aging brain (Verdi et al., 2018). However, research
sometimes fails to nd a link between gut microbiota and cognition (Deshpande
et al., 2019).
Inammation is associated with increased blood– brain barrier permeability
(Braniste et al., 2014) and a disruption in gut microbiota. Dysbiosis can impair immune function, which, in turn, induces anxiety and depression and related cognitive impairments independent from the inuence of gut microbiota on cognition
(Deleemans et al., 2019). Inammatory biomarkers likely induce microglial cells,
alter brain development, and associate with the extent of autism traits (Azhari et al.,
2019; Inoue et al., 2016). Cognitive function is also associated with gut composition in otherwise healthy older adults and poststroke patients and may be related
to the inammation they experience (Manderino et al., 2017; Wang et al., 2022).
Supporting this idea is that rats on an omega- 3- rich diet had higher expression of a
microglial anti- inammatory marker (Robertson et al., 2017).
One gene product, mammalian target of rapamycin (mTOR), is a protein complex that regulates processing nutrients for energy. It is activated by amino acids,
growth factors, and insulin in various cells. In a murine model of autism, mTOR a
Microbiome and Brain Function 429
protein involved in regulating inammation, caused hyperconnectivity and autismlike traits that were rescued by inhibition of mTOR (Pagani et al., 2021; Weichhart
et al., 2015). Dysregulation in mTOR has also been implicated in faulty memory formation (Hasebe et al., 2021).
Metabolites present another mechanism by which various partners in the gut–
brain axis exert inuence over distant partners. SCFAs, p- cresol, and indoles are
metabolites from gut microbiota. SCFAs are the product of food fermentation in
the gut (Aw & Fukuda, 2015; Lei et al., 2016). One SCFA, acetate, is produced by
Akkermansia muciniphila, Bacteroides spp., Bidobacterium spp., Lactobacillus spp.,
Prevotella spp., Ruminococcus spp., and Streptococcus spp. (Fernández et al., 2016;
Louis et al., 2014). SCFAs can inuence the brain because they can pass through the
blood– brain barrier and act as a signal for the production of neurotransmitters such
as serotonin and dopamine (Song et al., 2004). Altering diet by increasing consumption of foods that can be converted to SCFAs can also lead to altered metabolites and
improved cognitive function (Li et al., 2017; Liu et al., 2021), providing further evidence for their inuence. In mice, neonatal antibiotic administration disrupted gut
metabolites into adulthood and led to behavioral alterations such as impaired performance on cognitive tasks and anxious- like behavior (Keogh et al., 2021).
P- cresol is a byproduct of C. dicile, Clostridium scatologenes, Lactobacillus spp.,
and Pseudomonas spp. and is a toxin in various metabolic processes (Song et al.,
2004). P- cresol can increase lipid peroxidation in the brain, which causes extensive
cellular damage (Calderón- Guzmán et al., 2005; Goodhart et al., 1987). Its presence
is higher in fecal and urine samples collected from individuals diagnosed with ASD
than in samples from neurotypical control individuals (Altieri et al., 2011; de Angelis
et al., 2013; Gevi et al., 2016; Yang et al., 2018). In contrast, indole mostly has benets for the host’s intestinal function. Indole is produced from the decomposition
of tryptophan, and indole derivatives have antiviral, anti- inammatory, and other
protective properties. Tryptophan is the precursor of serotonin, and contributes
to phenotypic traits, including cognition (Ding et al., 2017; Fiore & Murray, 2021;
Srikantha & Mohajeri, 2019).
e mechanisms of inammation and metabolite inuence are closely related because metabolites escape the intestine when there is gut inammation. Metabolites
created by gut microbiota act as signaling agents with direct and indirect inuence
over the central nervous system, including cognitive function (Guo et al., 2020; Heiss
& Olofsson, 2019). Of course, these pathways are not isolated. Neurobehavioral development is dependent on substances such as omega- 3, and enhancing, restricting,
and restoring its availability will alter cognitive, anxious- like, and social behaviors in
mice (Robertson et al., 2017).
e reverse is also true. Metabolites escaping the gut can lead to inammation,
and the metabolites can cross the blood– brain barrier, which causes microglial
dysregulation and neuroinammation, leading to altered neural activity (Azhari
et al., 2019). For example, individuals with ASD can experience altered gut microbiota composition, overproduction of bacterial metabolites, and increased intestinal
Infectious Disease and Neurocognition
permeability (Azhari et al., 2019; Srikantha & Mohajeri, 2019). ese processes
likely alter cognition in ASD from early brain development.
Microglia also play a role in brain development and cognition, including synaptic pruning. Interestingly, activation of microglia is partly dependent on signals
from gut microbiota, and several conditions (e.g., ASD, Alzheimer’s disease, and
Parkinson’s disease) have both altered gut microbiota composition and increased
microglial activation (Heiss & Olofsson, 2019). In addition, germ- free mice have
impaired microglial function (Cryan & Dinan, 2015; Erny et al., 2015), providing
evidence that microglia do not function properly when gut microbiota are inadequate. If gut microbiota control the homeostasis of microglia, then it is not surprising that loss of this balance may be associated with neurocognitive diseases such
as Alzheimer’s disease (Liu et al., 2021).
Gut microbiota aect myelination in the prefrontal cortex, hippocampus, cerebellum, amygdala, and striatum, as demonstrated with germ- free mice (Guida et al.,
2018; Heiss & Olofsson, 2019; Hoban et al., 2016; Needham et al., 2022). Altered
myelination impacts the mice throughout their lives. Similarly, antibiotic treatment
in the neonatal period induces a gut microbiota decient state early in life. Germfree status in humans can be approximated with early life antibiotic administration
and implies that antibiotics can alter cognition as well as cause gut dysbiosis (Dash
et al., 2022; Keogh et al., 2021). Ampicillin and gentamicin administration early in a
human infant’s life tends to decrease abundance of Actinobacteria and Lactobacillus
spp. (Fouhy et al., 2012). Dysbiosis, neuroinammation, and neurodevelopmental
disruption may follow (Lu & Claud, 2019; Warner, 2019). is early decit gut microbiota state may lead to disrupted cognitive development. is includes memory
formation and cognition generally (Keogh et al., 2021). Germ- free mice also have
increased neurogenesis and decreased pruning in adulthood (Ganguly & Poo, 2013;
Guida et al., 2018; Heiss & Olofsson, 2019; Möhle et al., 2016; Sawada et al., 2018).
e research I have reviewed suggests several possible future directions to foster
well- being and lead to better neurocognitive outcomes. In most cases, intervention
needs to begin early. Possible ways to intervene when gut microbiota are inadequate are to examine the individual’s antibiotic use history, current and past diet,
history of infections, and history of stressful events (Carissimi et al., 2019; C. Chen
et al., 2022). Assessing inammatory response, perhaps with a high- sensitivity Creactive protein test and white blood cell count (Carissimi et al., 2019), may also
prove useful for more individualized medical decision- making. If restoring a healthy
gut microbiome is important, as most research supports, then we need improved
methods to maintain the longevity of a fecal transplantation (Y. J. Chen et al., 2021;
Leung & uret, 2015). Other therapeutics may be developed, but those will need
to be studied for long- term cognitive eects. We also need to determine the longterm eects of the current commercial products that are advertised to improve gut
health (Ticinesi et al., 2018). Of course, we still need to clarify more precise pathways
for gut– brain interaction (Y. J. Chen et al., 2021; Gonzalez- Santana & Heijtz, 2020).
Doing so will help determine which interventions or therapeutics are most likely to
Microbiome and Brain Function 431
be successful. e next steps would be targeting gut microbiota that need to be adjusted and nding methods to do so.
Conclusion
In closing, I emphasize the bidirectional nature of the microbiota– gut– brain axis.
Bacteria have metabolites that inuence the immune response, metabolism, blood–
brain permeability, and the production of precursors to neurotransmitters. In like
manner, the brain can inuence gut microbiota through cortisol, mucin production, and changing gut motility, all of which change the environment for gut microbiota and alter its composition. e HPA axis releases cortisol, which inuences
intestinal motility and integrity. Neural pathways regulate mucin secretion from
intestinal epithelial cells, which exert control over microbial populations within
the gut.
Likewise, the gut microbiota inuence the brain through mechanisms such as
neural, endocrine, immune, and metabolic pathways. While researchers have likely
not elucidated all the mechanisms yet, we do know that the gut inuences the brain
through peptides and other metabolites, which loop back to control satiation and
therefore inuence dietary choices and that the brain inuences the gut through
host behaviors such as choosing environments and nutrients.
Acknowledgments
I would like to thank Matthew Hatch, Hojae “Vivian” Lee, and Deneb Burgoyne for
their help in manuscript preparation.
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