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NORMAL MICROBIOTA AS
BARRIERS AND STIMULATORS OF IMMUNE RESPONSE

INTRODUCTION:

Immunity is
the capability of the host body to prevent the entry of microorganisms and resisting
them from causing diseases. The host immune system involves many cells,
chemicals and barriers to evade, kill and to nullify the effects of the
invading microbes. The immune system involves two types of systems they are the

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·       Innate immune system and

·       Adaptive immune system.

The innate
immune system involves surface barriers, cellular barriers, complement systems
to tackle the incoming antigens and restrict them from entering the system. It
does not recognise the antigen but initiates a generalised immune response and
eliminates them. Hence no memory response is there in innate immunity

the adaptive
immunity involves the lymphocytes T cells, B cells and antibodies produced by
them to kill the immunogens. Adaptive immunity is specific to a particular invading
microbe. Hence, it also has memory.

                the barriers involved in the
innate immunity are the first line of defence because they prevent the entry of
the pathogens. The barriers may be physical, chemical and biological barriers.

Physical
barriers involve skin, cuticle etc that inhibit the antigens from entering.

Chemical
barriers include the antimicrobial peptides like beta-defensin, enzymes like
lysozyme in saliva, tears and breast milk that can lyse the incoming microbe by
breaking the 1,3-glycosidic linkage.

The
biological barriers include commensal flora that are in symbiotic relationship
with the host body. They all together protect the host from invasion of the
pathogens. In this assignment we will see in detail about the normal microbiota
and their role in host immune function.

NORMAL MICROBIOTA:

Humans are
colonized by a variety of microorganisms. These microbes can either cause
diseases or they can have any beneficial effects or they may remain neutral
without causing any complications. These microorganisms that reside within the
human bodily tissues, fluids and which does not cause any diseases to the host
are called as the normal microbiota.

The microbes
that colonise humans can either be

·       Commensals – a relationship in which
both the species live together and only one is benefited but the other species
is not harmed. i.e. they can coexist without harming humans

·       Mutualistic – a relationship where
both the organisms live together and both are benefited.

The total
cells in the human body is approximately 1013 cells and around 1014
 bacteria are present within the
human body. These microbes can be either bacteria, viruses mainly
bacteriophages or archaea.

VARIOUS REGIONS OF THE BODY AND THE
MICROBES INHABITING NORMAL MICROBIOME:

SKIN – staphylococcus epidermidis and other bacteria belonging to the
phylum proteobacteria, Actinobacteria, Firmicutes, Bacteroidetes, Cyanobacteria
etc.

ORAL CAVITY AND UPPER
RESPIRATORY TRACT – Streptococcus mutans, Staphylococcus aureus, Streptococcus pneumoniae and
bacteria belonging to the genera Neisseria, Villanelle, lactobacillus etc

LOWER RESPIRATORY TRACT – this region does not have resident
microflora due to the constant movement of air and also due to the presence of
ciliated epithelium.

GASTROINTESTINAL TRACT – Helicobacter
sp., lactobacillus sp., Peptostreptococcus, Enterococcus faecalis, certain
protozoans like Entamoeba hartmanni,
trichomonas hominis, lodamoeba sp. Etc.

URINOGENITAL TRACT- 
this region of the body is colonised mainly by the gram-negative
facultative cocci and bacilli bacteria. Lactobacillus
acidophilus, streptococci and E. coli
may also be present.

 

 

 

 

 

 

 

NORMAL MICROBIOTA AS BARRIERS:

Whenever a
damage occurs in the skin all opportunistic pathogens in the atmosphere gets a
chance to enter into the body. After gaining access into the body, the pathogen
will try to adhere on the host cells. During this period all the innate immune
cells like the macrophages, neutrophils will try to phagocytose those antigens.
The normal microbiota present in the gastrointestinal, urinogenital and the
respiratory tract will also try to eliminate these foreign microbes. They
involve the following mechanisms

·       Some gram-positive bacteria with the
peptide glycan layer stimulates the alternative complement pathway. This
pathway is also induced by the exotoxins produced by certain bacteria. They
induce the C3 complement which ultimately induces the innate immune mechanism
and initiates a generalised immune response. The macrophages and neutrophils
are activated and they kill the antigens.

·       Some normal microflora secretes the
exotoxins Lipopolysaccharides (LPS). They in turn stimulate the macrophages to secrete
the cytokines TNF-alpha, IL-1, IL-6.  These
cytokines activate other neutrophils to phagocytose.

·       The commensals also stimulate the
B-cells to produce the immunoglobulin IgA. IgA can neutralise the toxins
produced by the pathogens and they also promote the development of the
regulatory T-cells TH17 and FOXP3+. They can also coat the antigens and prevent
their attachment. This is called immune exclusion.

 

Figure from: O’Hara et al, EMBO reports, 2006

 

·       Apart from these responses these
microbes also compete for food in the areas they are located

·       They also alter the pH of the
environment in which they live making it difficult for the invaded pathogens to
survive.

·       The exotoxins secreted by the normal
microbiota may directly kill the pathogen or they may induce certain host
immune response and kill them.

Thus, the
normal microbiota along with the epithelial cells act as the first line of
defence and prevents pathogenic invasion.

 

NORMAL MICROBIOTA AS STIMULATORS OF
IMMUNE RESPONSE:

Now we have
an idea about how the normal microbiota helps the host in initiating an immune
response and killing the pathogen. But how do the normal microbes live within
the host without being attacked by the host immune cells? And how the toxins
secreted by the specifically kill the foreign pathogens without affecting them
and the host? Are few questions that are needed to be answered.

·       There are a large number of commensal
bacteria living within our system and many immune cells around them
scrutinizing for the presence of antigens. But the host immune cells and the
commensal organisms have evolved to maintain a homeostasis between them.
particularly in the intestine where these commensal organisms are found
abundant the immune system is activated only by the stimulation of toll-like
receptors. The toll-like receptors are a class
of proteins that are expressed on the macrophages, dendritic cells, NK cells, T
cells and B cells.  When these receptors
get activated they lead to the innate immune responses like phagocytosis, activation
of complement pathways and development of antigen specific adaptive immunity.

Example the polysaccharide
A produced by the symbiont Bacteroides
fragilis binds to the TLR-2 present on the CD4 T cells. This polysaccharide
A initiates an anti-inflammatory response which supresses the pro-inflammatory
response caused due to the T-helper cell Th17. This promotes tolerance and the
commensal bacteria can establish colonies within the gut.

·       The commensal bacteria produce toxins
in a very minute quantity that doesn’t have any effect over the host cells. But,
it stimulates the host immune cells to create immune response and evade other
pathogens.

·       The normal microbiota also help in
the development of the gut associated lymphoid tissue(GALT), payer’s patch and
other lymphoid follicles. The mucosal plasma cells are stimulated by the
dendritic cells and they produce IgA .researches speculate that this is
mediated by MY-D88 in the lamina propria and in the follicles of the dendritic
cells. But these MY-D88 can be activated only by the gut microbes.

 

IMPORTANCE OF NORMAL MICROBIOTA:

·       Recent studies suggest that the T
regulatory cells are also regulated by these commensals. Generally, the Treg
cells are abundant in the small intestine than in any other lymphoid organs. but
in case of gnotobiotic animals its number was substantially reduced.  Thus, those organisms were less immuno-tolerant.
According to Atarashi et al., 2011 when
these organisms were inoculated with clostridial strain they found the level of
Treg cells to be increasing. This also led to the production of IL and
anti-inflammatory cytokines. The level of interleukins was also increased in
other organs like liver, skin and lungs.

·       Respiratory diseases are one of the
major cause for death around the world. Though the epithelial cells and the alveolar
macrophages provide the first line of defence, the presence of normal
microbiota is also essential.  According to
Clarke T.B. et al., 2014 when microbe
free mice was infected with klebsiella pneumonia,
failed to produce IL6 and TNF-alpha and the rate of mortality was high. But when the microbiota was increased
through prebiotics the chances of getting susceptible to disease decreased.

·       The inflammatory bowels disease(IBD)
is the inflammation of the colon and small intestine. This disease may be
caused due to the loss of integrity of the intestinal epithelium or it can be
inherited from parents. But, the major cause for IBD is the absence of normal
microbiota in the intestine. It has been noted that the patients suffering from
IBD were treated with antibiotics in their past. This must have killed the
normal microbes and hence it led to the ulceration and inflammation.

·       when
mice are grown free of microbes they fail to develop the mucosal t-cells,
antimicrobial proteins and they also cannot produce mucus. These gnotobiotic
organisms are also found to lack tolerance and suffer from hypersensitive
conditions. thus commensals are important.

 

PHARMABIOTICS:

After knowing about the importance of the normal
microbiota in the human body it has been established that the microbiome is
susceptible to manipulation. These manipulations can be done by chemotherapeutics,
dietary or by inoculating microbes. This will significantly alter the health
and life style of humans. The research done by Jeffrey
Gordon of Washington University in St. Louis, showed that when the intestinal
bacterium from a lean-mice was injected into the intestine of a fat mice the
mice lost weight. This proves that the human microbiota also helps in
maintaining the homeostasis. After knowing these importance certain terms and
ideologies were established

·       PROBIOTICS
– the probiotics are live microorganisms that when administer can confer health
benefit to the individual.

·       PREBIOTICS
– these are food ingredients that alter the growth and activity of normal
microbiome. They induce the growth of bifidobacterial and lactic acid bacteria.
Probiotics and prebiotics are known to reduce the chances of colorectal cancer,
bowel acidity and also inflammatory bowels disease.

 

Categories: Development

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