




































The Role of the Gut Microbiome in Neuromodulation Therapies as a Potential Treatment Adjunct for Multiple Sclerosis


Berkeley
Pharma Tech
Journal of Medicine

Correspondence: 
Pipertonne@gmail.com

Keywords:
Gut-brain axis
Gut microbiome
Immune system
Multiple sclerosis 
Neuromodulation

Submitted June 28, 2021 
Accepted July 20, 2021
Published December 17, 2021

Full Open Access

Creative Commons Attribution 
License 4.0

Abstract
Gut microbiome research has surged in popularity over the past decade. These 
studies have found local and distal effects of micro organisms such as fungi and 
bacteria on human physiology, including the nervous, immune, and endocrine 
systems. A number of studies have demonstrated the potential for gut microbiota to 
combat classical diseases such as clinical depression and autism spectrum disorder. 
The impact of gut-produced metabolites on the secretion of various cytokines has 
presented a new-found opportunity for future disease therapy through these 
micro-organisms. This review examines recent evidence for the use of gut 
bacteria in neurological rehabilitation, specifically for Multiple Sclerosis (MS) 
patients. Available data has shown overwhelming support for microbiota-based 
MS therapy, but the lack of comprehension regarding the specific physiological 
mechanisms of these microbiota suggests that clinical trials may be far off. 
Furthermore, there has been minimal research investigating the consequences of 
using microbiotic therapy in tandem with current therapies such as 
neurostimulation or drug therapy. Factors including the mechanisms and 
restorative capability of specific species of microbiota must be studied in 
depth in order to successfully manipulate the gut microbiome for the treatment of 
neurological disorders. 

The Role of the Gut Microbiome in 
Neuromodulation Therapies as a Potential 
Treatment Adjunct for Multiple Sclerosis
By: Piper Tonne, Deondre Do, Nabeeha Hasan, Sravya Gundapaneni, Ariya Reddy, 
Saadhana Sridharan, and Sierra Richardson

The axon of the neuron, pictured on the right side, begins to degrade following the onset of multiple sclerosis. 
Image Credits: N/C



Introduction
In recent years, the accessibility and prevalence of research regarding the gut
microbiome has increased tremendously. It is common knowledge that the
human gut plays an important role in regulating health. The question that
remains to be asked is, just how much in�uence does the gut microbiome
hold? Newfound curiosity regarding the e�ects of manipulation of the
bacterial population residing in the gut prompts the scienti�c community
to expand research on ways to harness the power of the gut microbiome.
Research on the gut microbiome has advanced considerably since its
discovery decades ago with the development of technologies such as 16S
rRNA sequencing to assist in mapping the human microbiome (Choileain,
2020; Jangi, 2016; Takewaki, 2020; Zuo, 2018). Furthermore, with
advancements in microbiome-related engineering and technology,
researchers have come far closer to understanding the speci�c genes and
mechanisms behind microbial functions in the gut and beyond (Azad,
2018; Cani, 2018). However, with a collective human genome including
tens of thousands of genes, discovering speci�c causation from gut-related
studies has proven to be exceedingly challenging. A large number of papers
studying the human microbiome within the past decade have covered its
immense potential to impact human health. However, none have been able
to specify the mechanisms, much less the genes behind these
microorganisms, which mainly consist of bacteria (Cani, 2018; Han, 2018;
Strandwitz, 2018).

In this review, recent evidence showing the impact of general probiotics and
speci�c bacterial implants on human neurophysiology will be examined.
The various e�ects of the gut microbiome on the neuroimmune system will
be discussed along with a scrutinization of the current neuromodulatory
therapies. This paper explores the possibility of using gut therapy
speci�cally for the clinical treatment of Multiple Sclerosis (MS) patients.
Before jumping into this discussion, it is imperative to know the
background of this disease and the organisms that may assist in its
treatment.

The Gut Microbiome
The term gut microbiome refers to the trillions of microbes living within the
tract of humans and other animals. Although incredibly small, the microbes
in the gut play a huge role in human metabolism, physiology, and immune

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system development (Azad, 2018). The gut microbiome encompasses a large 
scope of symbiotic functions in the body including vitamin synthesis and 
GI hormone release, the latter of which protects the body from pathogen 
colonization (Collins, 2012). One aspect of this symbiosis investigated in 
this review is the e�ects on the human central nervous system (CNS), where 
alterations of neuronal signaling by the gut, especially in the brain, have 
piqued scholarly interest. Particularly, there has been extensive research on 
microbial impact on the GI tract, as well as its impact on human physiology. 
Within the past decade, research on the gut microbiome has seen an 
exponential increase due to the metagenomic revolution - the study of 
genomes of bacterial species in a speci�c environment rather than pure 
laboratory cultures.

One reason the GI tract is an area of interest is due to its key role in the 
complex mechanisms of immunoregulation (Joscelyn, 2014; Kirby, 2018; 
Mangalam, 2017; Ochoa-Repáraz, 2014,2018; Shahi, 2019; 
Velasquez-Mano�, 2015). At �rst, interest in the role of the microbiome led 
researchers to look for any associations regarding innate and adaptive 
immunity within the human body. For example, gut-associated lymphoid 
tissue (GALT) represents almost 70% of the entire immune system, and the 
GI tract hosts around 80% of plasma cells, such as immunoglobulin A 
(IgA)-bearing cells (Vighi, 2008). This research has since dramatically 
expanded with the upsurge of discoveries correlating bacteria, such as 
Akkermansia muciniphila or Prevotella Copri, with various disease 
pathologies including: obesity, type II diabetes, and multiple sclerosis 
(Cani, 2018). For example, researchers now understand that the function of 
the overall human immune system is deeply in�uenced by bacteriophages, 
viruses that parasitize bacteria by infecting them and reproducing inside 
them. Research indicates that bacteriophages, such as Caudovirales, can be 
manipulated in order to provide relief to patients su�ering from 
Clostridium Difficile infection through successful fecal microbiota 
transplantation. By administering fecal matter from a donor into the 
intestinal tract of a recipient, the recipient experiences relief of infection 
symptoms as a result of the change in their gut microbial composition (Zuo, 
2018). Furthermore, with the increasing interest in elucidating the potential 
manipulation of the gut microbiome, there has been an increase in research 
highlighting its connection with the central nervous system, and its role in 
maintaining homeostasis (Ochoa-Repáraz, 2009; Wang, 2014; Wang & 
Kasper, 2014; Winter 2018). However, although research is extensive, there

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is an inadequate understanding of the speci�c mechanisms of the gut on
human physiology.

It is widely accepted that the development of the GI microbiome begins at
birth. The GI tract is rapidly colonized after childbirth and is impacted
throughout life by various external factors such as: illness, antibiotic
treatment, and changes in diet (Rodríguez, 2015). It is imperative to
acknowledge the consequences of certain lifestyle choices on the gut
microbiome, as any shifts in one’s microbial genome could a�ect their entire
physiology (Figure 1).

Diet is a major lifestyle choice that in�uences gut health. Both short and
long-term alterations in diet can impact microbial pro�les, and infant
nutrition may have lifelong consequences through microbial modulation of
the immune system (Harmsen, 2000). In conjunction with the prevalence
of malnourishment, with the most common representation being obesity,
diet is an ever-growing area of concern within medical research (Manichanh,
2006). Gut microbes produce a large number of bioactive compounds that
can be bene�cial, such as vitamins. Bacteria, such as Bifidobacterium, can
generate crucial vitamins such as: vitamin K, B12, biotin, folate, and
thiamine (Nicholson, 2012). In addition, digestion is in�uenced by many
enzymes produced by microbes. The microbial diversity in the human gut is

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Figure 1. The gut microbiome plays an important role in maintaining host immunity 
and homeostasis via the gut-brain axis. Since the axis is bidirectional, factors such as 
hunger, anxiety, stress, and depressive disorders, in addition to lifestyle choices such as 
diet and exercise, can reshape the gut bacteria's composition and exert an influence on 
immune function and health.



attributable to the spectrum of microbial enzymatic capacity needed to
degrade nutrients, particularly the many forms of complex polysaccharides
that are consumed by humans (Cantarel, 2012). Nourishing the body
properly through a balanced diet is the best way of maintaining a healthy
gut microbiota population. The gut microbiome is a complex ecosystem
that cycles nutrients between the microbiota and their host cells. This
cycling of nutrients dictates the body’s immune response to foreign invaders
(Azad, 2018). However, the bidirectional nature of this relationship should
be noted. Changes in chemical, nutritional, and immunological pathways of
the body have also been shown to in�uence the density and composition of
the gut microbiome (Thursby, 2017).

Research has already shown that the gut microbiome is largely dominated
by rapidly growing probiotic bacteria because they have the capability to
survive in harsh conditions. Some of the most common genera of gut
bacteria in adults are Bifidobacterium, Lactobacillus, Bacteroides,
Clostridium, Escherichia, Streptococcus, and Ruminococcus (Conlon, 2014).
In order to protect the integrity of the gut, some researchers have explored
gut modulation by probiotic species, which may be able to improve and
restore the gut �ora if certain bacterial species of the gut were ever eradicated
(Azad, 2018). Two crucial microbial strains discovered for gut microbiome
regulation were Lactobacillus and Bifidobacterium. These quintessential
probiotics are target bacterial groups made from short-chain nondigestible
carbohydrates (inulin-type fructans, fructo-oligosaccharides [FOS], and
galacto-oligosaccharides [GOS]) (Loo, 2009). As it stands, gut regulation is
essential in isolating speci�c bacterial species for clinical therapy, especially
for neurological disorders like multiple sclerosis (MS), whose causes are still
unknown.

Multiple Sclerosis
MS has cell-mediated pro-in�ammatory e�ects (also known as type IV
hypersensitivities) that result in demyelination of neurons and autoimmune
pathogenesis of the disorder, leading to disruptions in brain-body
communication. In MS patients, autoreactive T and B lymphocytes enter
the CNS, induce in�ammation, and undermine the blood-brain barrier
(BBB) via cytokine secretion (Ghasemi, 2017). These cytokines begin a
signaling cascade that results in oligodendrocytic death and thus, the
destruction of neuronal myelin sheaths in the CNS (Ghasemi, 2017). The
resultant CNS lesions disturb proper communication between neurons,

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and lead to various cortical dysfunctions within MS patients such as
modulations to resting motor threshold, short interval cortical inhibition,
and central motor conduction time (Ghasemi, 2017). Although microbial
therapy holds promise, its implementation as a universal MS therapy
remains far o� because of the lack of understanding behind the speci�c
mechanisms of gut-brain interactions and early research into this �eld
(Figure 2).

While the speci�c origin of MS still eludes scientists, most postulate that a 
combination of genetic and environmental factors plays a signi�cant role in 
pathogenesis. Environmental elements such as geography, vitamin D 
de�ciency, obesity, diet, smoking, and physical or emotional stress have been 
shown to be relevant in MS progression (Gianfrancesco, 2016;
Ochoa-Repáraz, 2014; Rosso, 2019; Sintzel 2018). When these factors 
collaborate with adverse genetics, the health of MS patients can quickly 
deteriorate. One of the most salient genetic factors is sex, with MS diagnosis 
showing an astounding 2:1 male-to-female ratio (Reynolds, 2018). Women 
are also diagnosed with an irreversible disability at older ages than men 
(Confavreux, 2006). Another important genetic factor is the 
HLA-DRB1*15 gene haplotype. The DR2 haplotype HLA-DRB1*15 gene 
encodes a protein important in T-lymphocyte reactivity and is also 
associated with MS disease progression, age at onset, and atrophy of 
subcortical gray matter (Isobe, 2016).

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Figure 2. A neuron is made up of a cell body, an axon, and dendrites. The 
protective coating of the axon, the myelin sheath, are damaged in patients with 
Multiple Sclerosis. The immune system attacks the myelin sheath and causes 
injury and inflammation. Neural deficits ensue.



Types of Multiple Sclerosis
MS patients are categorized into four subtypes including:
relapsing-remitting (RRMS), secondary progressive (SPMS), primary
progressive (PPMS), and progressive-relapsing (PRMS). RRMS is the most
common subtype, a�ecting approximately 87% of the patient population
(Ghasemi, 2017). Autoimmune in�ammatory attacks on the nervous
system among patients of this subtype occur months or years apart followed
by a period of remission, leading to a progressive increase in irreversible
disability. This neural damage eventually manifests as vision loss, muscle
weakness, and impaired coordination (Weiner, 2008). During periods of
remission, patients revert to relatively normal neurological activity
(Høglund, 2014). This subtype of MS shows the greatest promise of
therapy because intervention is possible during remission periods.
Unfortunately, within the population of RRMS patients, around 70%
develop SPMS (Kirby, 2018). However, what facilitates the progression
from RRMS to SPMS remains unclear. SPMS is characterized by a minimal
to complete lack of relapse activity, leading to a constant increase in
irreversible neural damage (Høglund, 2014). Although the underlying
mechanisms of the progression from RRMS to SPMS are currently unclear,
most likely a combination of environmental and genetic factors, SPMS
di�ers from RRMS in that demyelination is restricted to short lengths of
disrupted myelin located in aggregates of microglial cells (Prineas, 2001).
Patients in this category have a mean age of about 44-63 years at SPMS onset
(Confavreux, 2006). PPMS patients see similar e�ects, but their
pathogenesis is slightly di�erent. PPMS patients compose approximately
10-15% of all MS patients and tend to have less brain atrophy but increased
spinal cord atrophy (Ghasemi, 2017). In PPMS, regression does not occur.
Patients instead experience a steady increase in the debilitating e�ects of MS
(Reynolds, 2018). Lastly, PRMS is the subtype of MS with the fastest
increase of disability over time due to periodic immune system attacks along
with a steady increase in disability. PRMS is the most devastating subtype,
and it comprises approximately 5% of the MS population (Ghasemi, 2017).

MS symptoms are similar among patients, with many resulting from plaque
formation after demyelination. These symptoms are notoriously di�cult for
physicians to predict due to di�ering plaque locations between patients
leading to di�erent symptoms (Kister, 2013). However, common symptoms

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in those a�ected include vision loss, decreased mobility, bowel/bladder
dysfunction, sensory loss, impaired coordination, decreased energy, and
spasticity (Kister, 2013). Patients often experience chronic pain from
conditions such as trigeminal neuralgia (pain triggered by oral activity),
dysesthetic pain, back pain, and painful spasms (Solaro, 2004). These
conditions are often comorbid with mental health disorders such as
depression, further confounding diagnostic e�orts (Chwastiak, 2007;
Kister, 2013; Vattakatuchery, 2011). Thus, it is critical to pinpoint the
speci�c causes of MS in order to establish a framework for the development
of e�ective microbial therapies.

Multiple Sclerosis Pathogenesis
It is still unclear whether an overactive immune system and acute
in�ammation are the incipient causes of MS, or if pathogenesis stems from a
radically di�erent cause. Similarly, there is still ambiguity regarding
autoreactive immune cell leakage into the CNS. The current literature
demonstrates that T helper (Th) lymphocytes and various cytokines play a
primary role in MS pathogenesis (Williams, 2020; Choileain, 2020; Berer,
2011).

Th17 is the most studied T helper cell, and it is considered by many to play a
large role in the in�ammation observed in MS patients. (Choileáin, 2020;
Reynolds, 2010; Mangalam, 2017; Tahmasebinia, 2017). Many studies
support the role of Th17 in producing pro-in�ammatory interleukins (IL)
such as IL-17, IL-17A, IL-17F, IL-21, IL-22, and IL-26 (Ghasemi, 2017;
Xu, 2020; Reynolds, 2010). This increased in�ammatory response is
aggravated further when the normal negative feedback response becomes
impaired.

MS patients have displayed a reduced ability to produce T regulatory cells,
which normally mediate the in�ammatory e�ects of Th cells that occur as a
result of leakiness of the blood-brain barrier (BBB) (Cekanaviciute, 2017).
The blood-brain barrier is a semipermeable border composed of endothelial
cells (ECs), pericytes, astrocytes, and an extracellular matrix (Abbott, 2010).
Recent studies indicate that MS patients have circulating factors and the
BBB engages in crosstalk that is mediated by endothelial cells (ECs) and
adjustment of astrocytic expression (Williams, 2020; Setiadi, 2019;
Zivadinov, 2016). MS patients are further characterized by lymphocytes

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undermining BBB permeability by inducing oxidative stress in ECs and
enhancing leukocyte transmigration by producing various facilitative
proteins: P-glycoprotein, intercellular cell adhesion molecule 1(ICAM-1),
and vascular cell adhesion molecule 1 (VCAM-1) (Sheikh, 2020). VCAM-1
and ICAM-1 expression is directly correlated to levels of IL-17 and TNF-α,
suggesting another mechanism of the enhanced in�ammation seen in MS
patients (Gao, 2017). By modifying BBB immuno-tra�cking, autoreactive
cells are readily able to cross into the CNS and cause further damage.

This leakage of immune cells is exacerbated as MS lesions begin increasing B
cell transcription ten-fold through promoting the production of B
cell-activating factor (BAFF) (Krumbholz, 2005; Kannel, 2015).
Furthermore, once pathogen-associated molecules bind to toll-like receptors
(TLR) on these lymphocytes, autoreactive T cells are signaled to produce
cytokines that induce additional cell di�erentiation (Reynolds, 2010). MS
patients reportedly possess high levels of TLR2 and TLR4 among others,
with TLR2 being associated with the defective remyelination seen in MS
(Hasheminia, 2014; Wasko, 2020). Microbial manipulation of the immune
system gives scientists hope for gut-based therapies, albeit speci�c causation
has not been established.

Current Treatment Options for MS
Due to its complex neurological pathogenesis, MS is currently an incurable
disease. Treatment options for patients with MS are divided into three
categories: acute relapse management, slowing of disease progression, and
treatment of related symptoms (Hart, 2016). Glucocorticoids are the drugs
of choice for an acute attack because they downregulate molecules
associated with in�ammation in the body, such as cytokines and
chemokines, and upregulate anti-in�ammatory proteins. Therapy with
glucocorticoids such as high-dose methylprednisolone should be considered
in patients whose relapse is of moderate to severe severity (Doshi, 2016).
Ultimately, glucocorticoids are used to shorten the duration of a relapse or
acute attack.

It has become increasingly important to focus on slowing disease
progression in order to improve the quality of life of MS patients.
Disease-modifying treatments (DMTs) have become a key component of
comprehensive MS care for this reason (Hart, 2016). RRMS is the most

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treatable subtype of MS. Drugs such as beta-interferons, glatiramer acetate,
teri�unomide, dimethyl fumarate, and �ngolimod have moderate e�cacy
but are a safer option in patients with RRMS. The human body already
produces beta-interferons as a natural response to in�ammation. The
man-made drug further aids in the downregulation of in�ammation and
decreases the damage to the nerves in the body. However, since other DMTs
can have life-threatening adverse e�ects, it is necessary to monitor clinical
conditions and conduct frequent MRI scans. Alemtuzumab and
natalizumab, targeted cancer drugs, have a higher e�cacy but present
serious side e�ects such as progressive multifocal leukoencephalopathy
(PML). PML, an illness that leads to brain damage, severe disabilities, and
death, can develop in patients that are on natalizumab treatment for more
than two years with a prior history of chemotherapy or immunosuppression
(Doshi, 2016) (Figure 3).

It is recommended that DMTs are started as soon as possible to increase the
likelihood of slowing the progression of the disease before severe
neurological de�cits can arise. Unfortunately, there is not enough current
research indicating that DMTs can aid in slowing progressive MS and there
is still a lack of cohesive understanding about DMTs in the research
community. More studies are necessary in order to understand the e�cacy
and safety of drugs while simultaneously slowing the progression of the
disease.

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Figure 3. The mechanism of action of the DMT IFNβ. This drug targets immune 
cells. It decreases T cell activation, B cell proliferation and promotes anti-
inflammatory cytokine production.



Symptomatic treatment of MS is just as important as slowing the 
progression of the disease or treating an exacerbation. Patients often 
complain of fatigue, depressive symptoms, urinary frequency, sexual 
dysfunction, constipation, pain, ataxia, and more (Doshi, 2016). Not all 
symptoms necessarily require medication. However, it is important that 
physicians recognize the heterogeneity of this disease when creating a 
treatment plan for their patients.

MS can largely impact one’s functionality, and patients typically struggle 
with adapting to the changes in their daily life. Thus, patients are often 
recommended to start cognitive therapy alongside their medication. Pain 
and depression are symptoms that have long been overlooked in individuals 
with MS. One study showed that more than 88% of people with MS 
experience pain in more than one bodily area (Gromisch, 2020). 
Another study reported that 22.8% of patients with MS struggle with 
lifetime major depression (Wang, 2000). Studies have shown that using 
cognitive behavioral therapy as an adjunct treatment for MS can improve 
mental health and quality of life in patients (Gromisch, 2020).

Neurostimulation technologies are recent medical advancements that are 
rapidly being researched as potential symptomatic treatment options for 
neurologic and psychiatric disorders. An increased understanding of neural 
circuitry and neurotechnologies has shown promising therapeutic results in 
patients with neuropsychiatric conditions. These therapies include invasive 
and noninvasive approaches that target a speci�c nerve or anatomical region 
in the body. Some examples include brain temperature control, magnetic 
stimulation, deep brain stimulation, spinal cord stimulation, and vagus 
nerve stimulation (Edwards, 2017). Research has shown that gut bacteria 
communicate with neurons of the enteric nervous system to send signals to 
the brain via the vagus nerve (Galland, 2014). Currently, an FDA-approved 
implantable vagus nerve stimulator called LivaNova can treat drug-resistant 
epilepsy. In addition, vagus nerve stimulation has been used to treat 
drug-resistant depression (Edwards, 2017). Researchers at the Texas 
Biomedical Device Center have developed a technology called the RePair 
System that rewires neural circuitry through stimulation of the vagus nerve, 
focusing on targeted plasticity therapy. The �rst human trials involved 
stroke patients and focused on improving upper and lower limb motor

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de�cits following a brain injury or disease (Darrow, 2020). Symptoms of
MS often include muscle weakness and motor imbalance, leading
researchers to believe that this therapy has the potential to change how
physicians approach the treatment of MS and other neurological disorders.
Another clinical trial tested vagus nerve stimulation in three MS patients in
an e�ort to reduce cerebellar tremor and dysphagia. Symptoms were
improved over a period of two to three months and the involvement of the
nucleus tractus solitarius, a key visceral component of the vagus nerve, was
further studied (Marrasu, 2007). To date, the underlying mechanisms of
neuromodulation therapies are not well understood, which is why they are
not primary treatment options for most neuropsychiatric diseases.
However, a better understanding of neural circuitry in the human body has
led to promising technological advancements that may signi�cantly reduce
symptoms in patients su�ering from various neurological conditions.

Microbial Links to Human Physiology
Lactobacillus is a genus of bene�cial gut bacteria that have gained an
increasing amount of scholarly attention (Esber, 2020; Zhou, 2015).
Speci�c species of Lactobacillus including L. acidophilus, L. casei, L.
rhamnosus, and L. helveticus have been linked to the prevention of disease in
humans and animals (Azad, 2018). Lactobacillus can alter the population of
microorganisms in the gut microbiome by producing lactic acid, preventing
harmful bacteria from colonizing the intestines. A study using a mouse
model of hyperlipidemia explored the impact of modulating the gut
microbiome by introducing probiotic feeding of Lactobacillus into the
mice’s diet. Signi�cant changes in the microbiota composition were found,
including an increased abundance of Bacteroidetes and Verrucomicrobia and
a reduced ratio of Firmicutes (Chen, 2014). L. acidophilus has even displayed
the ability to maintain a homeostatic concentration of in�ammatory
cytokines, Th17, and regulatory T (Treg) cells (Park 2018). Furthermore, L.
acidophilus suppressed proin�ammatory cytokines such as IL-6, tumor
necrosis factor-α (TNF-α), and IL-1β in colon tissues.

Similar to Lactobacillus, there has been a research focus on the probiotic
genus Bifidobacterium. Bifidobacterium assists the human body in
performing essential functions such as digestion, improving gastrointestinal
barrier integrity, preventing harmful bacterial colonization, and suppressing
proin�ammatory cytokines (Ganz, 2002). It maintains immune homeostasis

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by altering the function of dendritic cells in order to protect against foreign
bacteria and pathogens (Azad, 2018). Moreover, bi�dobacteria increase the
proportion of bene�cial bacteria in the gut microbiota through
cross-feeding, allowing other bacteria to live o� of their metabolic products.
Bifidobacterium bifidum has shown signi�cantly increased metabolic
activity when cocultured with Bifidobacterium breve (Turroni, 2015). This
co-culture of probiotic bacteria a�ected the metabolic shift in the gut
microbiota by increasing the production of short-chain fatty acids,
suggesting Bifidobacterium could play a role in cognitive function via
hormonal signaling (Savignac, 2013). This can lead to improved memory
function, including the growth of brain-derived neurotrophic factor
(BDNF) and N-methyl-D-aspartate receptor expression (Savignac, 2013).

The prophylactic role of this bacterial species among other probiotic strains
was further explored in a mouse model of β-lactoglobulin allergy, �nding
that the administration of Bifidobacterium longum subsp. infantis (B.
infantis) LA308 for 3 weeks modi�ed the composition of the gut
microbiota, signaling a connection between probiotics and the diversity of
gut microbiota (Azad, 2018). There was a signi�cant change in forkhead
box P3 (FOXP3), transforming growth factor-beta (TGF-β), and IL-10 ileal
gene expression, as well as plasma metabolomic alterations in the
tryptophan (Trp) pathway. The study concluded that probiotic
introduction to the human body led to alterations in immune responses,
tolerogenic energy induction, and anti-in�ammatory responses (Esber,
2020).

Human Gut-Immune Interactions
The immune system plays a pivotal role as the intermediary between the gut
microbiome and CNS, especially in the regulation of autoimmune
responses. The presence or absence of several components of the gut
microbiota regulates T and B cell activation within the brain, leading to the
enhanced in�ammatory response associated with autoimmune diseases like
MS. For instance, the presence of gut-residing bacteria Faecalibacterium
prausnitzii caused various symptoms in patients with Crohn’s disease, an
autoimmune disease characterized by heightened in�ammation in the
digestive tract (Velasquez-Mano�, 2015). Patients who lacked this bacteria
experienced in�ammatory bowel syndrome and asthma, while those
possessing them displayed a negative correlation with in�ammatory

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autoimmune diseases (Velasquez-Mano�, 2015). The potential therapeutic
applications of this bacteria's anti-in�ammatory nature are currently under
research for autoimmune disorders (Figure 4) (Velasquez-Mano�, 2015).

Human-Gut Immune Interactions - Metabolites
Further studies on gut-immune interactions have emphasized modi�cations
to in�ammatory cytokine pathways. These interactions vary from
cytokine-speci�c to stimulant-speci�c responses or sometimes, both
concurrently. Studies revealed that 10% of the variability of cytokine
responses associated with in�ammation can be accounted for by variations
in the gut microbiome (Schirmer, 2016). Moreover, the interaction between
the bacterial component of the gut microbiome and immune cells does not
occur directly, but through metabolites, small molecules referring to the
intermediates or end products of a metabolic pathway (Wirthgen, 2018).

One such pathway leads to the formation of tryptophol, a metabolite and
common inhibitor of TNF-α. The degradation of the essential amino acid
Trp to tryptophol is negatively associated with the interferon gamma (IFNγ)
in�ammatory pathway (Schirmer, 2016). Several other Trp-derived
metabolites, particularly the TRYP-6 neuroactive compounds kynurenine,
quinolinate, serotonin, indole, and indole derivatives, may have a critical
role in bacterial signaling (Kaur, 2019). Low levels of these compounds are
associated with disorders like major depression, autism spectrum disorder,

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Figure 4. The presence of bacteria F. Prausnitzii in the gut maintains the integrity of the 
epithelial gut lining and inhibits the T cell inflammatory response. The absence of this 
materia creates leaky cell junctions in the gut lining, which allow for opportunistic microbes 
and toxins to enter and activate the inflammatory response.



and Parkinson's disease. Researchers have seen extensive modulation of
these metabolic pathways from several genera of gut bacteria which break
down Trp like Clostridium, Burkholderia, Streptomyces, Pseudomonas, and
Bacillus (Kaur, 2019).

In addition, it is believed that gut microbiota contribute to the availability
of Trp and the neurotransmitter 5-hydroxytryptamine, which regulates
neuroendocrine signaling (Martin, 2018). 5-hydroxytryptamine, also known
as serotonin, is important in combating the comorbidities that often
accompany MS. Namely, major depression and anxiety disorder (Kelly,
2016; Zheng, 2016; Winter, 2018). However, there are a multitude of
additional disorders that may be associated with gut microbiota including
obesity, diabetes mellitus, schizophrenia, and autistic disorders (Evrensel,
2015). Changes in gut microbiota are relevant to mood states due to their
contribution to the production of neurotransmitters (Mittal, 2017).
Regulation of this pathway appears to be extremely important for the
development of gut-based MS therapy.

However, while the formation of Trp metabolites is a key pathway, there are
various other important metabolites that should be considered. Secondary
bile acids (2BAs) are strongly in�uenced by microbial activity and activate
the intestinal L cell’s surface G protein-coupled bile acid receptors (Martin,
2018). 2BAs derived from spore-forming bacteria of the gut regulate a
signi�cant percentage of 5-HT synthesis and release from enterochroma�n
cells, introducing another intriguing connection between gut metabolites
(Yano, 2015).

Short-chain fatty acid (SCFA) synthesis is another metabolic pathway that is
a�ected by gut bacteria, often through bacterial fermentation or host
protein glycosylation. Microbial fermentation (primarily by Bacteroidetes)
leading to SCFA production in the colon and blood is believed to play a
critical role in immunoregulation (Choileáin, 2020). Furthermore, the
biochemical conversion of nutrients into SCFAs and other amino
acid-derived metabolites like 5-HT are often conducted by intestinal
microbes (Hemarajata, 2013). These peptides function as
immunomodulators through mechanisms including (Park, 2019):
1. metabolic integration, or the integration of two or more metabolites
2. microbiota regulation

3. histone deacetylase (HDAC) inhibition, which is involved in epigenetic

Berkeley Pharma Tech Journal of Medicine | 78



or non-epigenetic regulation of cancer cells
4. G-protein coupled receptor (GPCRs) activation that plays a role in the
cellular signal transduction pathway

The proin�ammatory cytokines tumor necrosis factor-alpha (TNF-α) and 
IL-1β even see an increased level after SCFA induction of the gut-immune 
system (Galland, 2014). SCFAs have been shown to upregulate or 
downregulate primary immune cells such as CD4+ e�ector cells and IL10+ 
Tregs in mice with experimental autoimmune encephalitis (EAE), a disease 
with pathogenesis similar to MS (Höftberger, 2015). Some SCFAs can 
contribute to the anti-in�ammatory response by stimulating IL-10 
production while others, for example, the G-protein coupled receptors 
GPR41 and GPR43, may initiate a pro-in�ammatory response. However, 
further research must occur to determine the exact relationship between 
SCFAs and related immune cells, as well as the pathways through which this 
in�ammation occurs (Park, 2019).

Gut-Immune Interactions - Proteins
An important part of gut-immune interactions is the e�ect that they have 
on toll-like receptors (TLRs). A few studies have suggested there is a 
connection between TLR2, and its signaling pathway, that ties MS to the 
microbiome (Wang, 2014; Wasko, 2020). TLR2 can be stimulated by 
bacterial lipopeptides. In murine models of MS, microbial injections 
inducing TLR2 tolerance have shown inhibition of CNS in�ammation 
while improving remyelination (Wasko, 2020). Another protein, TLR4, has 
also displayed responses to lipopolysaccharides (LPS) from gram-negative 
bacteria (Park, 2009). In practice, lack of exposure to LPS from gut bacteria 
resulted in a lack of TLR4 tolerance, resulting in de�cient regulation of 
innate immune TLR responses and enhanced autoimmunity (Wasko, 
2020).

Gut-Immune Interactions - Cytokines
When researching the gut-brain axis relationship, it is important to
understand how each micro or macromolecule a�ects both sides of this 
a�liation. With the importance of cytokines in the formation of MS 
lesions, these proteins are particularly important in understanding how the 
gut can impact the brain. Numerous studies have found that dysbiosis of 
the gut may induce proin�ammatory responses, suggesting a potential 
avenue for gut-based MS treatment (Choileáin, 2020; Galland, 2014;

Berkeley Pharma Tech Journal of Medicine | 79



Monteleone, 2011; Martin, 2018; Adamcyzk-Sowa, 2017; Shahi, 2017). 
Proin�ammatory interleukins such as IL-6 and IL-17 have shown evidence 
of being a�ected by microbial modi�cations in the gut. Interestingly, 
mesenteric lymph nodes (MLN) of antibiotic-treated animals produced less 
IL-6 while signi�cantly increasing levels of the anti-in�ammatory IL-13 and 
IL-10 compared to controls (Ochoa-Repáraz, 2009). Furthermore, research 
regarding the gut-brain axis has shown that arti�cial activation of aryl 
hydrocarbon receptor (AhR) ligands, a part of the tryptophan metabolite 
pathway, decreased the concentration of IFN-γ while up-regulating 
proin�ammatory IL-22 in the gut of in�ammatory bowel disease patients 
(Monteleone, 2011). These gut-based cytokine alterations are only 
compounded with the modi�cations to peripheral blood mononuclear cells 
(PBMCs) within the body.

Gut-Immune Interactions-Peripheral Blood 
Mononuclear Cells
PBMCs such as T cells among others all see concentration adjustments due 
to the gut. Exposure of healthy PBMCs to Parabacteroides distasonis, a 
common gut bacteria, signi�cantly increased the percentage of IL-10 
expressing CD4+CD25+ T cells and IL10+FoxP3+ Tregs within the 
CD4+CD3+ population (Cekanaviciute, 2017). Furthermore, treatment of 
mice with Prevotella histicola also showed an increase in CD4+FOXP3+ 
Tregs in addition to a decrease in proin�ammatory Th1 and TH17 immune 
cells (Mangalam, 2017). These correlations display bacterial importance in 
the regulation of CD4+ and CD8+ T cells; which have shown an increased 
expression of CXCR3+ in MS patients, contributing to greater leakage in 
the blood-brain barrier (Choileáin, 2020). Protection of this barrier will be 
crucial in the development of gut-based MS therapies in order to combat 
the reduced expression of regulatory proteins seen in RRMS patients such 
as occludin and vascular endothelial cadherin (Sheikh, 2020).

While T lymphocyte regulation is extremely important in achieving this 
goal, so are other PMBCs like NK cells and B cells, the latter of which is 
believed to be involved with MS because of their association with 
immunoglobulin presence (Høglund, 2014). MS usually involves the 
depletion of B cell numbers and an increase in T lymphocytes (Krumbholz, 
2012). NK cells are important in their role of target cell lysis and can also be 
a therapeutic target due to their role in cytokine and chemokine secretion 
(Høglund, 2014). Additionally, they have the ability to modify or lyse T

Berkeley Pharma Tech Journal of Medicine | 80



cells, an interaction that can be investigated in the future to improve the
understanding of the dysregulation of immune systems in MS patients
(Høglund, 2014).

The gut-immune relationship is a two-way street. In the future, research
must take into account that the gut does not a�ect human physiology
unidirectionally. While the composition of the gut microbiome heavily
in�uences the autoimmune response by regulating the interactions between
immunoregulatory cells and metabolites, the immune system is also critical
in cultivating healthy bacteria and destroying harmful bacteria in our gut
(Velasquez-Mano�, 2015). The key players in shaping the gut microbiome
are nucleotide-binding and oligomerization domain-like receptors (NLRs
or NOD-like receptors). For instance, the NOD2 bacterial sensor regulates
in�ammation caused by the growth of the commensal Bacteroides vulgatus
(Ramanan, 2014). This regulation promotes epithelial stem cell survival and
regeneration in the gut. Furthermore, NLRs that assemble into
multiprotein complexes, known as in�ammasomes, activate in�ammatory
caspases and regulate microbial diversity in the gut. The NOD-, LRR
(leucine‐rich repeat)- and pyrin domain-containing 6 complex (NLRP6) is a
type of in�ammasome co-modulated by microbiota-derived metabolites
that is linked with intestinal homeostasis, intestinal antiviral innate
immunity, and the regulation of epithelial IL-18 secretion and AMP
expression pro�les (Zheng, 2020). To fully grasp the intricacies around this
bidirectional relationship and the pathways that associate the two,
researchers continue to explore this vital frontier.

Discussion
It is clear that the gut-brain axis has an impact on human physiology, so
taking advantage of this non-invasive approach will be the crucial next step
to treating and/or preventing MS. There has been prior evidence
showcasing the relevance of gut microbiota in the treatment of neurological
and motor disorders similar to MS including major depression and
Parkinson’s disease (Bremner, 2020; Haney, 2018; Han, 2018; O'reardon,
2006; Tian, 2020; Winter, 2018; Zhou, 2015; Martin, 2018). Yet, even
though extensive research has been conducted over the past decade, the
speci�c mechanisms of the gut-brain axis in relation to MS have yet to be
found. However, a few notable considerations for these mechanisms include
(1) systemic cytokine activation, (2) neurotransmitter synthesis, and/or (3)
neuronal circuitry alterations (Galland, 2014). One could interpret this as

Berkeley Pharma Tech Journal of Medicine | 81



academia leaning toward investigations on the nervous, immune, and
endocrine systems.

Researchers of the nervous system believe the vagus nerve, the cranial nerve
that controls the signaling between the brain and GI tract, plays a key role in
the interactions of the gut-brain axis (Figure 5).

One study found that the vagus enhances neural plasticity (post-stroke)
with improvements in both cognitive and motor function, both of which
are largely diminished in MS patients (Liu, 2016). The vagus nerve is also
important for neurogenesis through the modulation of brain-derived
neurotrophic factor (O’Leary, 2018). Further research also correlates
neuroelectrical stimulation of the vagus nerve with a decrease in symptoms
of various neurological disorders in mice (Zhou, 2015; Haney, 2018). As it
stands, gut-brain signaling appears to be relatively dependent on vagus nerve
activity, but this may only be true in certain experimental systems (Bercik,
2011).

Impacts on chemical communication in the brain have also illustrated the
value of the gut-brain axis in MS treatment. It has been noted that more
than 90% of the body’s 5-hydroxytryptamine (5-HT), or serotonin, is
produced in the gut (Yano, 2015). 5-HT receptors are critical in the

Berkeley Pharma Tech Journal of Medicine | 82

Figure 5. The vagus nerve is the tenth cranial nerve and extends from the 
brainstem through the neck and the thorax down to the abdomen. It carries 
signals from the digestive system and organs to the brain and vice versa. In 
addition, it modulates inflammation, maintains homeostasis, and regulates 
many body sensations.



mediation of gut-brain axis activity in MS patients (Malinova, 2018). Gut
microbiota have also shown success in the alteration of host serotonin levels
through the mediation of small molecules like SCFAs or secondary bile
acids (2BAs) (Yano, 2015). SCFAs in particular are important in mediating
host-microbe communication via enteroendocrine and enterochroma�n
cells, the latter of which also play a role in tryptophan metabolism (Figure 6)
(Martin, 2018).

Although the gut-brain axis shows great potential for MS therapy, research
on the functions of speci�c bacterial species on the gut-brain axis is limited.
There is signi�cant evidence to suggest that few genera such as Bacteroides
and Firmicutes are a�ected by mental and physiological stress, but their
speci�c e�ect on MS pathology is unclear (Tian, 2020; Choileáin, 2020).
Studying the e�ects of general probiotics versus speci�c bacterial species on
MS symptoms is necessary to determine the direction of future research on
MS therapy via the gut-brain axis. Furthermore, future research directed
toward the integration of current MS therapies and their e�ect on the
gut-brain axis is needed. For example, in regards to neuromodulation
technology, the development of closed-loop adaptive systems which use
predictive models of neural circuitopathies to alter neurostimulation
parameters without clinical supervision is a promising avenue of research
(Drew, 2019; Edwards, 2017; Lozano, 2019). Another promising

Berkeley Pharma Tech Journal of Medicine | 83

Figure 6. Stimulation of the vagus nerve has shown efficacy in 
modulating 5-HT receptors, SCFAs, and 2° BAs in the gut microbiome.



development is the creation of minimally invasive, wireless 
neuromodulation technology to alter biological parameters in real-time 
(Tanabe, 2017; Iodice, 2017).

In recent years, there has been an increase in clinical trials exploring the 
connection between the vagus nerve and neurological de�cits. For example, 
a current clinical trial is exploring how stimulating the transcutaneous vagus 
nerve could improve cognitive function (University of Ostrava, 2019). The 
clinical trial is using non-invasive stimulation provided by a transcutaneous 
electrical nerve stimulation device for four hours a day at 25Hz, 250 μs pulse 
width placed on the tragus. This novel area of preventive medicine could 
provide an interesting perspective on MS therapies. If the technological 
device results in clinically signi�cant applications, it could improve executive 
neurological function and potentially help prevent demyelination.

Conclusion
There has been minimal research regarding many areas of concern such as 
the e�ects on the blood-brain barrier by B cells, the speci�c mechanisms of 
lymphocytes and cytokines on the gut-brain axis, and the association 
between MS and the microbiome. It is unclear whether or not the gut 
microbiome will become a viable therapy speci�cally for neurodegenerative 
disorders, but the association between human physiology and microbiota 
cannot be ignored. With a greater understanding of symbiotic 
human-microbial interactions, there is no doubt that future research will be 
useful in building a greater comprehension that may result in clinically 
signi�cant therapies.

Berkeley Pharma Tech Journal of Medicine | 84



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