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.