Future perspectives
In the decades after their discovery, macrophages have been suggested as
promising targets in almost all areas of biomedical research.
Developments in the field of macrophage research in the past decade have
led to a better understanding of the maturation and differentiation
dynamics of this cell type. Accumulating evidence suggests that, apart
from their well-known role in phagocytosis and foreign-antigen
recognition, macrophages are endowed with high functional plasticity
allowing them to acquire pro- or anti-inflammatory and tissue-reparative
phenotypes during the course of inflammation, dependent on the signals
they receive from the surrounding cells or from the pathogen itself.
Given that the injury specific signals derived from the local
microenvironment are integrated to generate specific macrophage
polarization patterns, it is hypothesized by us that different
compositions of microbiota dysbiosis generate unique macrophage
polarization patterns at defined time points during inflammation or
infection, to serve the needs of the infected/inflamed intestinal niche.
A better understanding of these processes would allow the selective
targeting of the macrophage pool for better host defences and
accelerated intestinal epithelial barrier repair. Despite there being
studies showing a relation between microbiota and macrophage phenotype,
their released specific mediators that are involved in tissue repair are
not well studied. Probiotics and fecal microbiota transplantation have
been investigated in clinical trials for the treatment of gut leakage
associated diseases including type 1 diabetes, multiple sclerosis, and
rheumatoid arthritis [88]. Therefore, there is an urgent need to
conduct experimental studies that focus more on those specific
macrophage subsets with distinct functions and their relation to
different compositions of microbiota to investigate their specific
targets and released mediators, which would help explain those events
instrumental in mediating pro- and anti-inflammatory mechanisms. This
would help us to understand the microbiota induced macrophage-derived
mediators and their interactions in an inflammatory microenvironment.
Understanding these mechanisms would enable innovative therapeutic
approaches like in-situ repolarization towards a regulatory or
tissue-reparative phenotype, and ex-vivo generation of regulatory
macrophages as a cell-based therapy to target host defense, termination
of inflammation and tissue repair, to reduce intestinal epithelial
barrier damage.
In addition, other possibilities of modulating microbiota and their
metabolites, and so in turn the functional phenotype of the intestinal
macrophages, must be considered. In one study, microbes likeLacticaseibacillus casei Strain Shirota were shown to modulate
intestinal epithelial cell barrier integrity in vitro, via macrophages
through their bacterial sensing ability and cytokine production
[89]. Interestingly, the microbial metabolite butyrate was observed
to be a potential regulator of epithelial barrier integrity in both in
vivo and in vitro studies, by driving macrophages to an M2 phenotype,
and was proposed as a candidate therapeutic target for UC [77, 78].
However, in future, the evidence for employing microbiota-derived
metabolites to target macrophage plasticity, regulating the release of
pro-repair mediators including EVs, method to generate the
reprogrammed/reengineered macrophages and association of pro-repair
macrophages and microbiota must be explored in detail.
Furthermore, the underlying pathological mechanisms of gut leakage
associated diseases remain mostly unknown. Moreover, the precise part of
the intestine (proximal or distal) where epithelial barrier dysfunction
initially occurs has yet to be determined. Furthermore, there need to be
established gut leakage animal models to enable further investigations
and proof-of-concept for developing promising therapies. Finally, the
role of non-bacterial microbiota like the virome, mycobiome, etc. must
also be carefully considered in future investigations.