Modulation of Gut Microbiota by Probiotics
Pearl Shah, Janani Gurumurthy, Stephen Abishek Raj, Shashank Bagaria, Marcus Mata
Abstract
The gut microbiome refers to the internal micro-environment that constitutes the entirety of our
gastrointestinal tract. It is a complex system consisting of thousands of microbial species, all interacting with
each other, and the human body. These interactions play a role in controlling various physiological processes
within an individual. The role of the gut flora in maintaining human health is extensive, but like any living
system- it too needs to be modulated. Probiotics refer to external species of microorganisms that are ingested
for the purpose of assisting the natural gut flora. This paper is a general review detailing the function of
probiotics in regulating the human gut microbiome. We have discussed the several criteria to be met when it
comes to commercial manufacturing of probiotics. While probiotics have been speculated to have mostly a
range of positive effects, there are certain negative influences that have been taken into consideration. This
paper also explores the possibility of specific tailoring of probiotic consumption and activity to an individual,
since the gut microbiome shows incredible interpersonal variability. Our work concludes with a brief insight
into the future of gut microbiome studies, and the continued relevance of this topic pertaining to human health
and medical advancements.
Keywords: gut microbiome, probiotics, intestinal, specificity of probiotics, metabolites, commercial
manufacturing
INTRODUCTION
The human body harbours a variety of
microorganisms. Those populating the
gastrointestinal tract, from the esophagus to
the large intestine- are termed the “gut
microbiome”. It was originally described as an
“ecological community of commensal,
symbiotic, and pathogenic organisms that
share our body space but are usually
disregarded as determinants of human health”,
by Joshua Lederberg, who was the first person
to explore this topic in the scientific
community (10).
However, research in this field has progressed
vastly since Lederberg’s time, and the
correlation between the gut microbiome and
human health is definite. It has been
established that the presence of these microbes
is responsible for many different physiological
functions and processes, ranging from
assisting digestion to immune regulation (6).
This internal microenvironment hosting
trillions
of
microbes
shows
great
inter-individual
variability,
and
the
composition of the gut flora varies based on
several factors, including age, diet, and
pharmaceutical ingestion (3).
The role of an individual’s diet is among the
most impactful factors, displayed in a study
that compared the compositional differences
in the microbiome between an animal-based
and plant-based diet. This is a fact that has
been speculated since the 1960s (3) (10).
Hence, it is clear that external influences on
the gut microbiome are paramount to its
composition and functioning.
Extrapolating from this, probiotics now come
into the picture, as externally sourced
regulators of the gut flora. According to the
World Health Organization, probiotics are
defined as “living microorganisms that are
administered in adequate amounts to confer
health benefits on the host” (10). Considering
these speculated health benefits, they are
extensively marketed as dietary supplements
in the form of drinks, tablets, or even powders.
Deconstructing the role of probiotics in gut
microbiome regulation, covering both positive
and negative impacts, a perspective on their
relevance in general human health can be
determined.
Gut microbiome
The gut microbiome in a human refers to the
entire collection of microorganisms that are
found on and inside the human body. These
microorganism communities are essential for
human
physiology,
immune
system
Figure 1: General Probiotics
development, digestion, and detoxification
reactions. These microbes perform a variety of
functions, including encoding for proteins
involved in human health-related functions
such as enzymes required for the hydrolysis of
otherwise indigestible dietary compounds and
vitamin synthesis. The microbiome could be
found in several regions of the digestive tract,
but the gut contains the majority of the adult
human microbiota. The cell density of the
microbiome in the guts exceeds 10^11 cells/g,
which is equivalent to 1–2 kg of body
weight(1).
More than 5 million different genes are
thought to be represented by the human gut
microbiome. It is also now known that over
1,000 different species (2), all of which belong
to a small number of phyla, colonize the
human gut where Firmicutes, Bacteroidetes,
and Actinobacteria are the most abundant. (2)
The microbiome inside a human gut is
highly dynamic and can be influenced by a
variety of factors such as age, diet (3),
hormonal cycles (4), travel (5), and illness.
It is also interesting to note that humans are
born sterile, and colonies begin colonization
shortly after birth. The type of delivery and
feeding practices have the greatest influence
on an infant's gut microbiome (6).
Several studies have also found high
intra-individual
variability
in
the
composition of the infant microbiota,
particularly during the first year of life,
composition, a core gut microbiome shared
by all healthy adults, has been identified,
when the baby reaches the age of three. (7)
Despite the high inter-individual variability
in gut microbiota composition, a core gut
microbiome shared by all healthy adults has
been identified, suggesting that it plays a
role in health status maintenance for cases
such as polysaccharide digestion, immune
system development, defence against
infections, vitamin synthesis, fat storage,
angiogenesis regulation, and behaviour
development. (8)
Changes in the human gut microbiome may
play a role in the development of
inflammatory bowel diseases (IBD), such as
Crohn's disease and ulcerative colitis. (9)
Table 1: Composition of microbiota through the Intestinal Tract
Actinobacteri
a
Bacteroidet
es
Firmicutes
Proteobacteria
Verruco
microbia
References
Mouth
Actinomyces
Prevotella
Gemella
Veillonella
Streptococcus
Pseudomonas
Neisseria
-
Rinninella, E., Raoul, P.,
Cintoni, M., Franceschi,
F., Miggiano, G. A.,
Gasbarrini, A., & Mele,
M. C. (2019, January
10)
Oesophag
us
Rothia
Prevotella
Streptococcus
Veillonella
-
-
Rodríguez, J. M.,
Murphy, K., Stanton, C.,
Ross, R. P., Kober, O. I.,
Juge, N., . . . Collado,
M. C. (2015, February
02)
Stomach
-
-
Streptococcus
Bacillus
Veillonella
Lactobacillus
Enterobacteria
Pseudomonas
Helicobacter
-
Ruan, W., Engevik,
M.A., Spinler, J.K. et al.
Small
intestine
Bifidobacteri
um
Prevotella
Bacteroides
Lactobacillus
Veillonella
Clostridium
Enterococcus
Escherichia
coli
-
Rinninella, E., Raoul, P.,
Cintoni, M., Franceschi,
F., Miggiano, G. A.,
Gasbarrini, A., & Mele,
M. C. (2019, January
10)
Large
Intestine
Bifidobacteri
um
Prevotella
Lactobacillus,
Streptococcus
Ruminococcus
Clostridium
Enterobacteria
Escherichia
coliSalmonella
Akkerma
nsia
Sanders, M. E. (2016,
June 02)
Table 1: There is no fixed optimal gut microbiome composition, as it varies through individuals,
depending on factors like age, environment, region of the GI tract, disease presence and antibiotic
consumption. Considering these points, this table is only representative of a very generalized composition
based around an average healthy adult, and assuming minimal external interference.
Influence of Probiotics on the Gut
Microbiome
Probiotics are a type of food or drink that
contains beneficial bacteria and/or yeasts that
may naturally live in your body (14). Through
probiotics, we can either inoculate good
bacteria to live in our gut microbiome or boost
the population of microbes that already exist.
Probiotics come in all shapes and sizes from
pills, fermented foods, and drinks. There are
even specially packaged flavoured milks that
provide
adequate
nutrients
for
the
establishment and encouragement of growth
of whichever bacteria they (14) are
specifically targeted to produce. They can be
beneficial in avoiding certain diseases and for
recovering the gut microbiome after damaging
antibiotic treatment
Table 2: Forms in which Probiotics are ingested
Probiotics
Form
References
Bifidobacteria
Bifidobacterium infantis
Saccharomyces boulardii lyo
Lactobacillus rhamnosus gg
Lactobacillus acidophilus
Lactobacillus bulgaricus
Tablets
Palsdottir, H. (2018, August 28).
Lactic acid bacteria
Bifidobacteria
L. acidophilus
B. animalis
Yogurt
Digestive Health: 10 Probiotic Foods That Help
Digestion. (2017, October 25).
A. oryzae
Miso
Sifferlin, A. (2018, April 12)
Lactic-Acid bacteria
Kombucha tea
Palsdottir, H. (2018, August 28)
Lactobacillus kimchii
Kimchi
CE;, W. (n.d.)
As mentioned before the microbiome can
affect the body in both positive and negative
ways. However, by balancing the composition
of the microbiome using probiotics, we can
reap benefits according to our own desires.
Probiotics, by introducing good bacteria can
end up eliminating harmful bacteria that
would otherwise cause disease or dysentery.
According to one study, (16) the introduction
of probiotics in a Thai population ended up
reducing the population's susceptibility to
infections from Staphylococcus aureus. In a
similar way (17) it was found that probiotics
can reduce the risk of food poisoning or
diarrhoea by preventing the bacteria that cause
those conditions from taking a foothold in the
first place. Hence it can be said to be creating
its own positive feedback loop- probiotics if
taken regularly can reduce and weaken the
populations of “bad” bacteria in the gut, and
this allows the majority of
the microbiome to be composed of “good”
bacteria. This can further stimulate the
immune system or even provide competition
over nutrients to prevent harmful pathogenic
bacteria from being able to infiltrate the
microbiome at all, leading to the useful
bacteria thriving from lack of competition and
higher availability of nutrients. While this
does sound beneficial it should be noted that
in an excess quantity, even “good” bacteria
can turn against us and harm the body.
Probiotics can also be taken in reactive ways,
most notably in the case of an imbalance in
the gut microbiome- or dysbiosis. During
conditions of imbalance where pathogenic
bacteria are already thriving in a colonized gut
microbiome, the introduction of good bacteria
can serve to not just minimize but also
neutralize the effects of the bad bacteria. The
introduction of certain types of beneficial
bacteria can be a possible treatment for
genetic disorders that cause metabolic
deficiencies. This is achieved by the bacteria
itself carrying out the digestion or providing
the body with the means to digest the
substrate. For example, a mild lactose
intolerance could be overcome by introducing
beneficial bacteria that could secrete lactase
thus allowing nutrient digestion and
absorption.
Due to this, probiotics are recommended to be
taken only in moderate amounts. There must
be a balance in the quantity and diversity of
microbes part of the gut flora. Having that
balance has been found to have benefits
related to increased athletic performance and
weight loss. Hence a healthy gut microbiome
is considered proactively by athletes and
patients suffering from obesity
Table 3: Types of Probiotics
Probiotic Species
Effect
Bifidobacterium.
bnimalis
Aids in digestion and defends the body
from food borne bacteria
Where it is found
Reference
In certain brands of probiotic yoghurt
Duggal, N. (2017,
April 15), Hansen, K.
(2018, September 04)
Lives naturally in the digestive and
vaginal tract
Hecht, M. (2017,
December 29)
It is also thought to strengthen the
immune system
Bifidobacterium.
breve
Fights infectious bacteria and yeast
Allowing people to better digest food by
fermenting sugars and breaking down
fibre
Bifidobacterium.
lactis
Used in fermentation of milk
Derived from raw milk
Team, H. (2020, June
23)
Bifidobacterium.
longum
Digestion of carbohydrates as well as
providing antioxidant effects
Lives naturally in the gastrointestinal
tract
Hansen, K. (2018,
September 04)
Bifidobacterium.
infantis
Can relieve symptoms of irritable bowel
syndrome, as well as reduce gas and
bloating.
Found naturally in the mouth and
digestive tract however as you age it is
likely to reduce, as such it can also be
found in pills and capsules as well as
infant formula.
Duggal, N. (2017,
April 15)
To a degree it shows anti-inflammatory
effects
Hansen, K. (2018,
September 04)
Lactobacillus .
Acidophilus
Aids in digestion in the gut and serves as
a secondary defence for the vagina
Found naturally in the small intestine and
vagina but can also be obtained from
yoghurt and probiotics such as miso
Team, H. (2020, June
23)
Lactobacillus .
reuteri
Aids the digestive system and fights off
oral bacteria
Found in the intestine and mouth
Hansen, K. (2018,
September 04)
Escherichia coli
Treatment of Irritable bowel syndrome
and constipation
Most abundant type of bacteria in the
intestines (normally)
Hansen, K. (2018,
September 04)
Lactococcus lactis
Has antimicrobial properties and can
even be used in the treatment of
antibiotic induced diarrhoea
It is commonly added to dairy products
such as milk and even cheese
Team, H. (2020, June
23)
Saccharomyces
boulardii
Reduces the duration of diarrhoeas and
also has been useful for treatment of IBS
and ulcerative colitis
Also known as baker's yeast it is seen in
many fermented products
Duggal, N. (2017,
April 15), Hansen, K.
(2018, September 04)
Effect of different probiotics on Gut
Microbiome
Probiotics are beneficial microbes, which alter
the balance of gut microbiota by an increase in
SCFA production as well as the general
increase in counts of health-positive and
promoting bacteria such as Lactobacilli and
Bifidobacteria species. (19) A glycophile
Bacteroides thetaiotaomicron has been used to
observe the interactions of probiotics with
microbial residents of the gut. The glycophile
possesses a diverse palate of glycoside
hydrolases
which
use
undigested
carbohydrates to produce energy and an array
of probiotic species. Bifidobacterium longum
was found to increase B. thetaiotaomicron’s
catabolic activity, including the hydrolysis of
mannose along with xylose containing
glycans. Lactococcus casei, another microbe,
has also been shown to overexpress genes that
encode hexosaminidases and arabinosidases in
B. thetaiotaomicron.
Another
Bifidobacterium
species,
Bifidobacterium animalis was shown to
dominantly upregulate genes associated with
B. thetaiotaomicron in replication processes
such as transcription, with no change in use of
carbohydrates. (20) Results from this study
discovered species-specific changes in
hydrolyzing abilities of B. thetaiotaomicron
caused by different probiotics at hand. A
single does (10^9 CFU) of Lactobacillus
plantarum WCFS1 has caused a similar
overexpression of genes involved in
carbohydrate transport and the respective
metabolism in germ-free mice who were fed a
high fat and sugar diet was accompanied by
the production of end products of metabolism,
such as alcohol and fumarate (21).
Figure 2: Benefits of Probiotics
The probiotic colonisation and its impact on
gut microbiota greatly differs depending on the
species and strain. Multiple probiotic strains
such as Bifidobacterium animalis subspecies
lactis, two strains of Lactobacillus delbrueckii
subspecies bulgaricus, Lactococcus lactis
subspecies cremoris, and Streptococcus
thermophilus are components of fermented
milk, and were shown to enrich only B.
animalis in monozygotic twins. The
introduction of fermented milk was found to
overexpress
locus
involved
in
xylooligosaccharide catabolism and enzymes
catalysing
propionate
carbohydrates.
Propionate is produced endogenously through
fermentation of undigested carbohydrates. It is
shown to have hypophagic activity along with
direct influences in the gastrointestinal tract.
(21) The host response to probiotics was
revealed by performing NMR (Nuclear
magnetic resonance) global metabolite
profiling of biofluids and tissue extracts. The
colonisation of germ-free mouse models with
live Lactobacillus paracasei strain NCC2461
resulted in regional dependent changes being
observed in intestinal tissue metabolic profiles.
Metabolic processes that were altered include
lipid synthesis, nutrient absorption and
intestinal digestion. A decrease in oxidative
stress was observed and it was evidenced by
reduced levels of oxidative glutathione, and it’s
precursors in the small intestine, specifically
jejunum and ileum. However, no changes in the
large intestinal colon tissue metabolites were
observed, suggesting small intestinal regions
are optimal and preferable as colonisation sites.
The effect of L.paracasei and Lactobacillus
rhamnosus supplementation and humanisation
by infant microbiota in mice is another study to
be taken into consideration on how different
species can affect the gut microbiome.
Administering probiotics causes a decrease in
the acetate: propionate ratio, but also increases
gluconeogenesis, and amino acid catabolism.
This increase is followed by bile acid
modulation, and recirculation in the hepatic
region. However, between the 2 species
administered,
Lactobacillus
paracasei
displayed more complex interactions between
the metabolite and microbiome, creating links
between bile acids and some microbial species.
L. rhamnosus however, did not show these
effects. From this example, we can conclude
that the role of gut microbes in certain
metabolic activities such as the one for bile
acid, varies based on species. (21)
It was observed that in healthy subjects, the
consumption
of
synbiotic
fructo-oligosaccharides with Lactobacillus
helveticus Bar13 and B. longum Bar33 caused
changes in the concentrations of carbon
disulfide, SCFAs, methyl acetate and
ketones.(21).
Furthermore, a
synbiotic
supplementation of Lactobacillus acidophilus,
B. longum, and fructo-oligosaccharides was
found to increase amino acid absorption and
prevent the accumulation amines and ammonia,
which are the toxic byproducts of amino acid
fermentation, along with
an increase in
fermentation metabolites such as acetate,
butyrate, and lactate. The administration of
galacto-oligosaccharides and L. rhamnosus to
axenic mice colonised with human infant
microbiota had little effect on SCFA
production while increasing amino acid
excretion. There were also lower levels of
plasma lipoproteins, hepatic triacylglycerols,
and kidney lipids. When compared to the
prebiotic alone, the synbiotic treatment
increased bile salt deconjugation and showed
changes
in
transmethylation pathways
(homocysteine–betaine) in the liver and
pancreas.(21)
From the various studies, it can be seen that the
effective range of probiotics in the diet is not
constrained only to the gut region, but
continues into extraintestinal tissues such as the
liver and kidneys. (22) Regarding their effects,
in summary, probiotics; affect lipid and bile
acid metabolism, influence nutrient usage
patterns, activates hydrolases in other gut
elements, allows for efficient energy
derivation, and adept nutrient absorption
throughout the gastrointestinal tract. However,
the studies referenced here have mainly been
conducted on gnotobiotic mice, which have
vastly different intestinal physiology in
comparison to regular mice and humans. Some
of these differences include a lower vascularity,
digestive enzyme activity and wall thickness.
However, the usage of metagenomics can be
utilized
in
better
understanding
of
host-microbiome interactions even under these
controlled conditions. (21)
Components of Probiotic Function
The mechanism of probiotic regulation of the
gut epithelium can be approached from two
perspectives- (i) Influence of surface structures
and compounds of regulatory microbes. (ii)
Effects of gut microbiome metabolite
production. It has been found that the different
bacterial structural surface components play a
role in affecting the gut microbiome.
However, only certain fragments of the
probiotics bacteria, such the flagella, pili,
surface layer proteins (SLPs), capsules and
lipopolysaccharides are essential to regulate
microbial pattern signaling- MAMPs, or
microbial associated molecular patterns.
(28)(23)These MAMPs bind to receptors that
regulate different signaling pathways, such as a
protease-dependent, cytokine producing path
that reduces inflammation and increases
intestinal function. (23) The bacterial wall
components can interact with the immune cells,
and this can manifest either as a positive
regulatory effect, or negative consequence in
the form of endotoxemia.(24)For any probiotic
bacteria to act effectively, whether it is through
surface components or metabolite production
the most important function is its ability to
adhere onto the intestinal epithelium.(28)
The cell wall component that plays a role in
this, is Surface Layer Proteins- or SLPs. They
are cell envelope structures mainly found in
Archaea bacteria. It is also known as “S-layer”,
and is the outermost covering. Hence it is also
responsible for cell adhesion to the intestinal
surface. This adhesive property arises due to
hydrophobicity and charge distribution.
It has an immunoregulatory effect, due to
aggregation with pathogenic organisms at
possible adhesive sites on the intestinal
epithelium.(23) It has also been observed that
probiotics
produce
various
metabolic
compounds that are crucial in mediating host
physiology and reactions. For example,
short-chain fatty acids (SCFAs) like butyrate
and propionate (an integral part of colonic
homeostasis), regulate intestinal inflammation
and immunity, and are produced by bacterial
and yeast present in the gut.(24)(25)
Tryptophan catabolites play a role in immune
responses by binding with the AhR mucosal
receptor.(25) Organisms like Lactobacillus and
Bifidobacterium have been found to produce B
group vitamins, and other probiotics have even
exhibited
anti-oxidative
effects(26).
Bacteriocins,
ribosomally
synthesized
antimicrobial peptides produced by gut
microbes like Enterococcus and Lactobacillus
also exhibit antibacterial activity, and can
inhibit pathogenic activity(24) .
Hence probiotics can even inhibit the growth
of various pathogens in the body and thus
prevent infections. Probiotics can also affect
hormone and body chemicals, like insulin. For
example, a study conducted on hyperlipidemic
patients in which they were administered
probiotics for eight weeks showed that
Lactobacillus rhamnosus GG, one of the most
widely used strains in probiotics, along with
Bifidobacterium animalis subsp.lactis and
Lactobacillus acidophilus may have played a
role in causing a decrease in cholesterol levels
and Lactobacillus rhamnosus GG also caused a
decrease in fasting insulin levels.
Figure 3: Digestive path of Probiotics
Drug absorption can be affected by the
metabolite production, as the gut microbiome
produces active compounds that the body
itself cannot synthesize.(27) The metabolites
produced by the gut microbiome can have a
toxic effect, as seen in the generation of
B-glucuronidases
by species such as Escherichia Coli, which
leads to toxic irinotecan excretion and
digestive troubles. (24). From this, we can
understand that there is a complex system of
metabolite and cellular surface interactions
between the host organism and probiotic, that
mediates its activity and functions.
Negative Effects of Probiotic Usage
The consumption of probiotics has been
known to cause bloating/gas in the digestive
tract, and this is attributed to the body
adjusting to the influx of new bacteria. These
symptoms usually fade after repeated usage
over a variable period of time, and the
individual’s body naturally accommodates
them. Some probiotic foods like sauerkraut
and yoghurt which are rich in amines(such as
amino acids, the most common ones being
histamine, tryptamine and phenylethylamine)
have been known to cause headaches(30)as
they excite the nervous system and cause
changes in blood flow in people who are
sensitive to the presence of these amines, with
one of these being histamine. Histamine is
produced by the immune system of the body
in response to Immunoglobulin E(antibody
produced when the body detects the presence
of a pathogen or allergen)(29). The function of
this chemical is to dilate blood vessels, which
increases blood flow to the affected area and
causes inflammation. Some people are
intolerant to histamine, which means that the
histamine produced by these probiotics is not
broken down in their body and instead
absorbed into the bloodstream. This causes the
body to experience symptoms usually seen in
an allergic reaction, such as rashes, red and
watery eyes, itching and breathing troubles.
Not only can some probiotics cause allergic
reactions, they can sometimes contain
allergens as well, which trigger the same
aforementioned reaction. This can be avoided
by not consuming probiotics with these
sensitive ingredients that cause these allergic
reactions . Aside from allergy-related side
effects, probiotic microorganisms can also
(although
seldom)
secrete
harmful
substances(31). Links have been found
between the consumption of probiotics and
SIBO(Small Intestine Bacterial Overgrowth),
which is a condition in which bacteria which
normally grow in the large intestine begin
growing in the small intestine, causing
bloating, gas and diarrhoea.
Table 4: Negative Effects of Probiotics
Sympto
m
Reason
Risk factor
Reference
Gas/
Bloating
Usually occurs due to the body
first adapting to the probiotic.
It will usually occur when starting a new probiotic,
however it will subside after about a week.
“Probiotics: Risks and
Benefits.”
WebMD,
WebMD
Headach
es
Some probiotic-rich foods such
as kimchi and sauerkraut are
rich in amines which excite the
nervous system as well as alter
normal blood flow which can
lead to headaches.
Certain people can be extra sensitive to the amines in
their food, so it is important to understand and learn
for themselves how to manage and keep the amount
of amines they consume below the threshold.
Julson,
Erica.
“5
Possible Side Effects of
Probiotics.” Healthline,
Healthline Media, 17
Dec. 2017
Allergy
symptom
s
It is possible that the probiotic
may contain allergens and can
produce histamine in the gut
directly and cause swelling and
allergy symptoms or reactions.
Normally people have an enzyme known as diamine
oxidase which degrades histamine produced in the
gut, however some people can have lower levels of
the enzyme which leads to the histamine causing a
reaction from the body.
“Probiotics: Possible
Side Effects and How
to Take Them Safely.”
Medical News Today,
MediLexicon
International
Increased
risk
of
infection
In the case the person’s immune
system is unable to directly deal
with or manage the gut
microbiome, it is possible for
the probiotic to challenge and
then cause harm to the body.
Compromised/weakened immune systems due to
diseases or surgery can lead to the probiotic
becoming an opportunistic infection. While this is
still manageable with antibiotics, it should be avoided
by susceptible people.
“Probiotics: What You
Need
to
Know.”
National Center for
Complementary
and
Integrative Health, U.S.
Department of Health
and Human Services
Increased
weight
gain and
obesity
If the wrong probiotic is
introduced into a person, it can
lead to them directly craving
and seeking out unhealthy
foods.
By building a balanced microbiome in one’s gut
either through a balanced diet or several probiotics,
one can reduce the risk of an incorrect probiotic
throwing the microbiome off balance.
Palsdottir,
Hrefna.
“How Probiotics Can
Help You Lose Belly
Fat.”
Healthline,
Healthline Media, 20
Nov. 2020
Productio
n
of
harmful
substance
s
In some cases, it has been seen
that the probiotic ends up
secreting harmful substances
into the body and causing other
side effects such as poisoning.
This can be managed by ensuring the probiotic you
are taking is of appropriate quality and by making
sure it is safe by first consulting with a health
physician.
“Probiotics: What You
Need
to
Know.”
National Center for
Complementary
and
Integrative Health, U.S.
Department of Health
and Human Services
Small
intestinal
bacterial
overgrow
th
(SIBO)
Can occur due to the bacteria
from
the large intestine
infecting the small intestine, it
can cause symptoms similar to
IBS and even brain fogginess
and
short-term
memory
problems
One study showed that in the case, patents had SIBO
and probiotics, the patients who stopped taking
probiotics managed to recover from the disease
“Probiotics: Possible
Side Effects and How
to Take Them Safely.”
Medical News Today,
MediLexicon
International
Figure 4: Negative symptoms of Probiotic Usage
Manufacturing Probiotics on an
Industrial Scale
Several criteria must be met in order to deliver
the probiotic benefits to consumers
successfully. An intricate production process
for manufacturing must be undertaken, which
ensures both high yield and stability, along
with meeting requirements pertaining to
absence of specific allergens and the culture
media ingredients which preclude them (34).
Another important aspect is quality control.
Reproducibility is important to ensure
constant high quality and performance, thus
quality control throughout the entire
production process is documented.
Figure 5: Commercial forms in which Probiotics are sold
Currently, probiotics have been incorporated
as dietary supplements which are expected to
have up to 2 years of shelf life given the
ambient temperature and humidity. High
quality probiotics can be produced to suit
customer requirements with the right choice of
production process, product formulation and
strain selection. A few important points to
remember about probiotics are that they are
living
microorganisms,
need to be
administered in sufficient amounts, and need
to have a health benefit. The most commonly
commercially manufactured microorganisms
to satisfy customer demand in dairy and
dietary supplements include Lactobacillus and
Bifidobacteria.(34)
These,
from
a
manufacturing standpoint have the desired
commercial qualities such as high yield and
high concentrated stable cell count along with
a long shelf-life stability. The first stage of
probiotic manufacture in the industrial process
is strain selection (32) . It is a vital step which
affects the entire process. The strain selection
majorly depends on what specific probiotic
supplement you are aiming to create and it’s
potential health claims. For example, whether
a supplement to support digestion, boost the
health of your immune system, support a
healthy response to occasional stress and so
on. Each strain has its own specificity and
supports different particular benefits. Some
strains improve lactose digestion, whereas
some
support health
immunity. To
manufacture the best quality probiotic
supplements which are healthy, raw materials
acquired must be excellent. The strains
selected should be able to effectively survive
within the gut.
Table 5: Commercially available probiotics
Drug
Generic name
References
Florastor
Saccharomyces boulardii lyo
List of Probiotics. (n.d.)
Phillips Colon Health
Bifidobacterium infantis /
Lactobacillus acidophilus
List of Probiotics. (n.d.)
Intestinex
Lactobacillus acidophilus
List of Probiotics. (n.d.)
Culturelle Digestive Health
Lactobacillus rhamnosus gg
List of Probiotics. (n.d.)
Novaflor
Lactobacillus acidophilus
List of Probiotics. (n.d.)
BD Lactinex
Lactobacillus acidophilus /
Lactobacillus bulgaricus
List of Probiotics. (n.d.)
VSL#3
Streptococcus thermophilus
List of Probiotics. (n.d.)
The genus for some of the commonly used
probiotics include:
Lactobacillus : It refers to a group of lactic
acid producing friendly bacteria which make
up to 400 probiotic species in the human body
and provide many benefits, such as inducing
growth factors, promoting healthy levels of
Candida albicans, a fungal organism in the
human gut. Lactobacillus also have
immunomodulating effects such as promoting
a healthy immune function and support
balance of various lactic acid producing
bacteria.
Bifidobacterium : They, like Lactobacillus,
also produce lactic acid and colonize the
human colon. These are important mainly in
the intestine and help create a microbial
barrier to undesirable bacteria. Some species
of Bifidobacteria bind to the intestinal mucosa
and prevent the attachment of undesirable
bacteria (35) Other common genera include
Bacillus and Streptococcus. Streptococcus
thermophilus is used in the dairy industry for
fermentation of various cheese varieties as
well as yogurt.
Table 6: Natural and Artificial Probiotics
Property
Natural probiotics
Engineered Probiotics
References
Strains
used
Lactobacillus rhamnosus CRL1505,
Bifidobacterium lactis DN-173 010,
Lactobacillus casei Shirota,
Escherichia coli Nissle 1917, etc
Lactobacillus plantarum NC8,
Lactococcus lactis NZ9000,
Lactobacillus gasseri ATCC 33323,
etc
Shi, Lye Huey,
et al.
Principle
Strains of bacteria that when
infected can correct dysbiosis of the
gut and improve immune system
A modified bacteria can break down a
harmful metabolite and act as a form
of treatment
Bober, Josef
R, et al. Fijan,
Sabina
Possible
areas of
applicatio
n
Can be used in treating constipation,
reducing gastric discomfort and
improving immunity.
Has shown results in alleviating
various conditions such as
hypertension, Phenylketonuria,
allergies, Diabetes(Type 1 and 2) and
H. pylori infection
Chua, Koon
Jiew, et al.
The second step is media formulation
(35)(32). The selection of naturally bile and
acid resistant strains is vital along with an
effective formula and the raw materials. The
strains must be tested for intestinal
survivability as the conditions of the gut are
highly acidic, especially in the stomach.
The unique combination of nutrients and
process parameters gets established which
have been checked for optimized growth.
In the third stage (32), fermentation, raw
materials used as ingredients to make
probiotics are sourced from across the globe.
Probiotics are manufactured in specific
batches per order to maintain freshness and
quality. The cultivation period of bacteria
cannot be rushed and the growth of culture
can take up to 6 weeks (35). All the raw
materials must be ensured in the right amounts
and their availability must be checked to make
sure no delay takes place. All the nutrients and
equipment are sterilized to eliminate any
accidental and unwanted contamination during
fermentation. In a huge tank, the strain is
added to the media and multiplies in the
nutritious and warm bath until it reaches the
desired CFU count (colony forming units)
(32). The by-products of bacterial nutrient
metabolism are also formed.
Table 7: Probiotic Manufacturing Criteria
Criteria
Strain
Compatibility, tolerance, high endurance while in digestive tract, flavour
that strains impart, health benefits
References
Bober, Josef R, et al.
pH
Optimum pH for different species of bacteria and strains of said species
must be maintained
Chua, Koon Jiew, et al.
Molecular Oxygen
Different strains have different oxygen sensitivities for survival, and some
even produce toxic substances in the presence or absence of it
Shi, Lye Huey, et al.
Ingredients
Temperature
Packaging
Interaction between probiotics and ingredients such as additives(salts,
sugars, sweeteners and colouring agents) and growth factors must be
observed in order to determine their nature
Optimum ranges of fermentation and storage temperature are different for
different strains and are very important parameters to ensure viability
Packaging mode and conditions alter the permeability of oxygen(which
are influenced by temperature and humidity) of the product which has an
effect on the viability of the probiotics. Price of packaging must also be
taken into consideration because they indirectly influence the volume of
the product.
Chua, Koon Jiew, et al.
Fijan, Sabina
Shi, Lye Huey, et al
Fijan, Sabina.
Figure 6: A diagrammatic representation of the probiotic manufacturing process
After fermentation, the separation of probiotic
strains from metabolites (32) takes place. The
stability of probiotics is another critical aspect
that requires close attention, and probiotic
products begin to lose their stability and
freshness the moment they are packaged (32).
Various methods are used to maintain the
supplement stability and long term storage,
and this influences the strain’s viability as
well.
Methods such as refrigeration (subjected to
extremely low temperatures) as well as
avoiding humid or hot environments maintains
the stability of probiotic bacteria. After freeze
drying or spray drying, the probiotic is then
changed into a dry powder (35).
In the final stage, blending and bottling, the
dry powder contains a single strain. To make a
multi-strain formula, other prebiotic powders
Probiotic Specificity and Individual
Tailoring
As mentioned previously, probiotics can have
many negative side effects if misused.
However, by specifically tailoring certain
probiotics we can reap the benefits of the
probiotic we seek without disrupting the
natural balance and variety of
the
microbiome. We can carry this out by using
certain prebiotics that serve as the nutrition
and growth factors for very specific
probiotics. In one study (36) with turkeys as
the host, scientists found that the performance
of the turkeys was altered on a gene level to
be generally higher when using specific
microorganisms. Furthermore, in the same
are blended together to form an evenly
distributed mixture. (34)
Along with probiotics, essential components
can also be mixed, such as prebiotics,
flavouring ingredients and binders to produce
alternate forms of dosage. The blend is then
transformed into its final dosage form, such as
capsules, tablets and powder (35). Probiotics
have optimum conditions which differ from
strain to strain, but are highly sensitive to
environmental factors such as humidity or
light, and hence should be carefully packaged
and prepared. Probiotics are challenging to
work with, and during the production process
require quality testing and a high amount of
overstock to ensure that each strain meets the
claim mentioned on the supplement label.
study it was discussed how rather than using
harsh antibiotics that could damage the
microbiome or cause antibiotic-resistant
microorganisms,
you
could
instead
supplement the diet with tailored probiotics,
and it would result in the same effect ; the
reduction of harmful microorganisms and
allowing the turkeys to return to health. The
overall balance of the microbiome of the
turkeys was easily maintained using
microbiotic supplements to produce beneficial
results in a sustainable and non-cruel way.
This study showed promise with respect to
microorganisms being tailored
to allow
positive results in the host organism
Using this knowledge comes the next
question- “How do we tailor the
microorganisms for specific hosts or people?”
We may already be close to reaching an
understanding, as a recent study from
Chalmers University of Technology, Swedenproposes an extremely accurate mathematical
model that could be used to predict how the
microbiome could change in response to
probiotic introduction into the diet (37). The
software- “CODY” (38) was shown to be able
to analyse and determine the composition of
the microbiome and also predict high level
changes that may occur due to changes in diet
or the addition of probiotics or antibiotics. The
most important thing to consider is how
specific diseases can be managed by the aid of
a probiotic diet.
As described in table 8 , and research papers
published by the University of Texas- (39),
probiotics can be specially tailored to assist in
the treatment of a variety of diseases and
disorders. According to the paper, many
different functional bowel disorders such as
IBS could be treated using combinations of
Saccharomyces cerevisiae or Bifidobacterium
infantis. Through these findings it is hard not
to get excited about the amazing potential that
the microbiome has in treating a wide variety
of currently incurable and difficult to manage
diseases.
Table 8: Probiotics and their target effect
PROBIOTIC
EFFECTS
References
Bifidobacterium lactis
Helps with constipation
(National Center for
Complementary and Integrative
Health, 2019b)
Bifidobacterium
longum
Can help with chronic constipation
(National Center for
Complementary and Integrative
Health, 2019b)
Saccharomyces
boulardii
Prevents Clostridium difficile-associated
infections (CDI) and Traveler’s Diarrhea
Valdés-Varela, Lorena et al.
Lactobacillus
acidophilus 145
Prevents diverticular disease
Lamiki, Pepu et al.
Bifidobacterium spp.
420
Prevents diverticular disease
Lamiki, Pepu et al.
Lactobacillus casei
Treats antibiotic-associated and
infectious diarrhea in children and adults
(National Center for
Complementary and Integrative
Health, 2019b)
Lactobacillus reuteri
DSM 17938
Treats Infant Colic
(National Center for
Complementary and Integrative
Health, 2019b)
Probiotic mixtures of
Bifidobacterium,
Streptococcus, and
Bifidobacterium, and
Streptococcus spp
Treatment of Necrotizing Enterocolitis
Seghesio, Eleonora et al.
Bifidobacterium breve
99
Treatment of upper and lower respiratory
tract infections in children
Araujo, Georgia Véras de et al.
Propionibacterium
freudenreichii ssp
Treatment of upper and lower respiratory
tract infections in children
Araujo, Georgia Véras de et al.
L. rhamnosus + L.
reuteri
Treatment of Atopic Dermatitis
Rather, Irfan A et al.
Lactobacillus paracasei Prevention of Dental Caries (Tooth
subsp. paracasei NTU
Decay)
101
Lin, Tzu-Hsing et al.
L. paracasei GMNL-33
Lin, Tzu-Hsing et al.
Prevention of Dental Caries (Tooth
Decay)
Figure 7: Individual probiotic personalization
Future Prospects and Conclusion
The various uses of probiotics have been
discussed in the course of this paper, but
mostly through a current frame of reference
regarding their properties.
When it comes to any research topic, the
future of the studies must be considered as
well. Some future angles into gut
microbiome studies delves into therapeutic
usage of probiotics. This has been explored
in the case of neurodegenerative disorders
like Parkinson’s Diseases.
Regarding neurodegenerative disorders, the
correlation between gut flora status and
brain functioning is theorized because of the
gut-brain-axis. This axis is the connection
between the central nervous system and
enteric nervous system, meaning that any
changes happening in the enteric region will
be directly affecting the CNS. The etiology
of most neurodegenerative disorders are
unclear and variable, but it is clear that
lifestyle factors as a major underlying cause.
This includes an individual’s dietary
choices. Diet has already been established as
having a major influence on the gut
microbiome, so the relation between gut and
brain health is very plausible. There is also
now a growing amount of evidence showing
that the probiotics administered to restore
gut flora imbalances has had a positive
impact on the CNS and handling
neurodegenerative diseases. Probiotics like
Lactobacillus and Bifidobacterium have
been found to help reduce oxidative stress
and neuroinflammation. A novel probiotic
named SLAB51 has shown the capability to
protect neural pathways and prevent the
disease progression of Parkinsons [40].
This topic has already been covered, but
personalized probiotics are indeed becoming
the future of probiotic usage. This applies
even to research into therapeutic usage of
probiotics, since the dysbiosis of gut
microbiomes
shows
inter-individual
variability, and the appropriate probiotics
must be administered to counteract the
negative symptoms.
need more clinical trials before it can be
practiced systematically. Currently however,
its potential lies mostly in general day to day
upkeep , nutritional balance and augmenting
various treatment methods. From whichever
perspective this topic is undertaken, we can
conclude with confidence that probiotics and
the microbiome are definitely playing a role
in the future of human healthcare.
Another particularly intriguing and recently
relevant field is the link between probiotics
and COVID-19 treatment. Dysbiosis of the
gut microbiome is heavily linked to the
pathogenesis of many diseases, including
acute respiratory disorders. This is because
the gut microbiome, as stated through the
course of the paper- plays a large role in the
body’s immune responses. The increased
vulnerability of the elderly and very young
children to COVID-19 and most pathogens
may indeed be causally related to decreased
gut microbiome diversity. During the initial
onset of COVID-19, many health
organizations
recommended
ingesting
probiotics to reinforce immunity. [41]
However, unlike the therapeutic usage of
probiotics described for neurodegenerative
disorders and other diseases- probiotics are
not being used as a treatment itself here but
only as a supplement that could strengthen
the body’s own defences and immune
response.
Acknowledgement
These are just a few examples of future
prospects of probiotic and gut microbiome
studies. But with the increasing scope of this
field, research involving probiotics can only
increase. Therapeutic treatments involving
probiotics are still under scrutiny, and will
We would like to express our deep gratitude
to our Professor, Dr. Mythili S and Ms.
Shivani, for all the guidance given through
the course of this subject. We are extremely
grateful for the opportunity to write this
paper on the gut microbiome and it has been
an extremely enriching experience.
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