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Reyes et al. Neuroimmunol Neuroinflammation 2020;7:215-33 I http://dx.doi.org/10.20517/2347-8659.2020.13 Page 217
[19]
[20]
the development of neuropsychiatric disorders later in life . Another study by Thion et al. found that
mice born from GF maternal mice expressed changes in genes regulating LPS recognition and processing
in utero and continued to exhibit sex-specific alterations in microglial-related gene expressions postnatally.
It is important to note that the timeframe when the human GMB begins to stabilize and resemble an
adult composition, i.e., around three years of age, also overlaps with critical periods of CNS development,
synaptic pruning, and neural remodeling [21-23] . These observations support the assertion that a complex
commensal microbiota ecosystem and their metabolites are integral to the early programming of key host
physiological systems.

Continuous microbiota-gut-brain axis communication may also play an important role during progression
of neurological disorders occurring later in life. Clinical analyses have revealed common comorbidities and
correlations between neurological symptoms and GI dysfunction, such as anxiety levels corresponding with
[25]
[24]
irritable bowel syndrome symptoms and GI-related symptoms associated with Parkinson’s disease .
Furthermore, “sickness behavior” is a phenomenon descriptive of subjective changes in mood and
[26]
behavior commonly found in humans and animal models of infection and illness . These relationships
highly suggest that GI activity, immunity and microbiome are linked to the CNS function and psychiatric
disorders.

There are various methods to modulate the microbiome in order to study its direct impact on health and
diseases, ranging from GF, sterile bred rodent models with overt developmental aberrations to antibiotic
treatment and fecal matter transplantation (FMT) [27,28] . FMT studies have begun to reveal potential causal
and therapeutic roles for the GMB through its ability to endow phenotypes from donor subjects to
recipients, such as transferring anxiety-like behaviors and depressive symptoms within rodent models [29,30] .
Furthermore, within the past 6 years, FMT has become a standard of care for patients suffering from
recurrent C. difficile infections who were unresponsive to antibiotic treatments but responded favorably to
[31]
the induction of healthy donor microbiota cultures . Colonic samples from healthy donors were also able to
improve GI and behavioral symptoms in a small (n = 18) cohort of children diagnosed with autism spectrum
[32]
disorders . Although the exact mechanisms directing microbiota-gut-brain axis influences in neurological
disorders are still being investigated, communication pathways and components have been identified which
are related to the systemic immune system, vagus nerve signaling, and neuroendocrine system .
[33]
THE MICROBIOTA-GUT-BRAIN AXIS AND IMMUNE SYSTEM
The gut microbiota, intestinal immune tolerance and homeostasis
Due to lifelong cohabitation with the intestinal microbiota, mucosal immune tolerance becomes important
[34]
in differentiating between commensal and pathogenic bacteria . The GMB is not hidden from immune
[35]
systems but is instead active in maintaining homeostasis through “tolerogenic” signaling . Toll-like
receptors (TLRs) on the membrane of epithelial cells and lymphoid cells are responsible for recognizing
different broad microbe-associated patterns, including bacterial membrane components, endotoxins such
[36]
as LPS, and bacterial DNA . TLR stimulation releases nuclear factor kappa-light-chain enhancer of
activated B cells (NF-κβ) and involves activation of signaling chemokines, cytokines, and other effector
proteins of humoral immune activity . TLR signaling is decreased during the early weeks of development
[37]
while the GMB ecosystem is being established, and immune-tolerance of bacteria is achieved when
recognition of commensal bacteria-produced antigens inhibits inflammatory activation . Specifically, TLR
[38]
activation on the apical, microbiota-exposed membrane of epithelial cells, rather than on the basolateral
membrane, inhibits the inflammatory cascade and limits immune response to microbial antigens found
[39]
within the GI lumen . Incorrect or incomplete immune-tolerance development can lead to autoimmune
diseases, chronic inflammation, and tissue damage. The importance of the GMB in promoting immune
homeostasis opens the possibility of microbiota-targeted therapeutics to reduce inflammation in response
to GI diseases, such as colon cancer and colitis .
[40]