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Summary – Willem de Vos

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One of the most
microbial rich niches is located in the human body. The Gram-negative anaerobe Akkemansia muciniphila, which belongs to
the Planctomycetes-Verrucomicrobia-Chlamydiae superphylum, is found in the alimentary
canal of more than 90% of the evaluated cases. A. muciniphila is well adapted to the human gut environment and
uses glycosolated proteins of the epithelial mucus layer as its C and N source.
A study which is conducted earlier suggests that the health of the gastrointestinal tract is correlated with the
abundance of A. muciniphila. For example, when
the density of A. muciniphila is low
this is associated to diabetes type 1, Crohn’s disease (CD) and in Ulcerative colitis
(UC). Furthermore, the recovery of the mucus layer in the human colon and
decreasing endotoxemia are accociated with
A. muciniphila.



State of the art


There is not much
known about the interactions between A.
muciniphila and the host, nor how it handles the different environmental
circumstances. Previous studies do suggest that there is a positive consequence
for the health of the gastrointestinal
tract when A. muciniphila is present, but
further investigation is needed for future application. The interaction of the
bacteria and its hosts starts with colonizing in which
they can adhere by binding to the mucus layer of the intestines epithelium or via
the cells underneath, the enterocytes.

It is unclear to which components A. muciniphila binds neither has been studies whether it is
able survive in an oxygen rich setting. This study will answer which mechanisms A. muciniphila uses to
adhere to the mucus layer or the epithelium cells of the gastrointestinal


Recent findings


Although the human
colon mainly consists out of an anaerobic microbe community, doesn’t mean that
all microbes are intolerant to oxygen. The results suggest that A. muciniphila is able to cope in oxic
and anoxic environments. As A.
muciniphila is aerotolerant, contrasting incubation conditions were compared in an adhesion
experiment. The binding efficiency with epithelial cells  HT29 and Caco-2 do not differ between aerobic
and anaerobic atmosphere. Thus, A.
muciniphila does not have to be treated as a true anaerobe, but is able to
cope with oxygen.


Also, it turned
out that the only significant binding of A.
muciniphila, compared to BSA, occurred with laminin. The bindingprocess of A. muciniphila with other extracellular matrix (ECM) proteins, was not significant. As
the adhesion between A. muciniphila and
the intestinal mucus is less than 1%, it can be stated that there is no adhesion
at all. Several bacteria are known for binding to the colonic mucus and
therefor it was unexpected that A.
muciniphila did not attach to the colonic mucus. An explanation for this is
that these species do not utilize and degrade the mucus, like A. muciniphila does. Although the
adhesion of A. muciniphila and L. rhamnosus on colonic mucus was not
comparable, A. muciniphila adhered to
both enterocrytes equally well as L.
rhamnosus. This might indicate that the enterocytes are true binding sites
for A. muciniphila.


A. muciniphila and B. fragilis were both cocultivated for 24 hours and indicated an expansion
in transepithelial electrical
resistance (TER). Compared to the Caco-2 cultures, without bacteria the TER of
Caco-2 cocultures of Escherichia coli declined
significantly. This shows that at this timepoint E. coli cells increased and that there is no cell interruption for
the OD600 values of A.
muciniphila and B. fragilis,
which indicates a stagnation of growth. The positive impact of cell monolayer
integrity for the first 24 hours was the most succesful with B. fragilis, followed by A. muciniphila.
After 48 hours the transepithelial
electrical resistance of
Caco-2 cocultures of A. muciniphila became
equal to the cocultures of B.
fragilis. During the 48 hour incubation the cell density of B. fragilis and
A. muciniphila did not diversify, neither seems that the bacteria are
severly affected. Under the same circumstances, E. coli affected TER
development negatively. During the second 24 hours the coculture increased,
suggesting that the transepithelial
electrical resistance in
E. coli cocultures will further decline.


Earlier studies
have associated obesity and diabetes to decreased gut health and inflammation,
which result in lipopolysaccharide (LPS) induced endotoxemia. When LPS is
released, enterocytes start producing the chemokine interleukin-8 (IL-8) which
leads to inflammation. Needless inflammation can cause disorder in the
intestinal epithelium and can disturb the homeastasis of the intestinal mucus. The
production of IL-8 in HT-29 cells was lower in A.
muciniphila when compared to
the IL-8 production of E. coli. Thus, there will be no strong
inflammation when A. muciniphila is present in the gastrointestinal tract. Because in the
presence of A. muciniphila alsmost no inflammatory reaction was induced, it
was checked wether it does or does not produce LPS and whether it is different
compared to E. coli. This study indicates that LPS is produced by A.
muciniphila but no HT-29 cells were activated to produce interleukin-8. Therefor it is
likely that the produced LPS by A. muciniphila is different compared to that of E. coli.




The results show
that A. muciniphila does not bind to the intestinal mucus but prefers
to bind to the epithelial cells Caco-2 and HT-29 and the ECM laminin. It remains unknown how this
organism is able to live in this continually adjusting habitat and should be
further investigated to answer this question. A possible justification why A. muciniphila is not able to effectively
bind to the intestinal mucus is because A.
muciniphila might release a certain stimulus which attacks the mucus.

It is likely that
different microbes are competing among each other for bindingsites as both
pathogens and A. muciniphila want to
bind on damaged parts of the intestines. It is therefor likely that A. muciniphila is able to strengthen the
barrier of the intestinal track. Future research could study the helpful role of
A. muciniphila in connection with its
host in for example obesity and diabetes.




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