The frequency of Cesarean sections (CS) have increased in affluent areas as women are choosing to have them for voluntary, non-medical reasons [1,2].
Source: https://www.cfhi-fcass.ca/SearchResultsNews/2011/05/06/ab4a74cd-ffbc-427b-9995-7f7434a87a67.aspx
Previous studies have demonstrated that individuals delivered via CS have an increased risk of developing chronic inflammatory diseases, such as allergies and inflammatory bowel disease (IBS) [3,4]. It has been suggested that these individuals have altered gut microbiome (GM) compositions as result of lessened exposure to maternal vaginal and intestinal bacteria during birth [5,6]. The microbiome is composed of a diverse range of bacteria, viruses, and other microbes that reside in the gut. Thus, these researchers aimed to investigate how the observed changes in CS-born individuals' immune systems occurred. Some studies have shown that CS-born mice have smaller proportions of Tregs and decreased IL-10 gene expression. A Treg is a type of white blood cell, a T cell, that regulates other immune cells and suppresses immune response to foreign entities. IL-10 is an anti-inflammatory cytokine, or substance that is released by cells to allow them to communicate with other cells. They hoped to determine if the compromised immunity in CS-born mice is dependent upon differences in gut microbiome composition.
They first hoped to establish GM composition differences between CS and vaginal delivered (VD) mice at both 5 and 8 weeks old. At 5 weeks old, the CS-born mice had a greater abundance of Prevotella genus and Ruminococcaceae family members. VD mice had a greater abundance of Candidatus savagella and of Bacteroides genus members. Only the abundance difference of Prevotella genus members was sustained until 8 weeks old.
Next, using flow cytometry, the authors determined proportions of Tregs and iNKT cells in the mediastinal lymph nodes (MLN) and spleens of germ-free (laking any microbiota) or conventional mice born via CS or VD. iNKT cells are immunoregulatory and able to respond quickly to danger signals and inflammatory cytokines. They then produce their own cytokines to communicate to other cells, including NK cells, T cells, macrophages, etc.
To investigate the effect of CS delivery on intestinal immunity, the authors analyzed the expression of genes known to be associated with gut immunity. Immune cells from ileum tissue, a part of the small intestine, were also analyzed. They found that genes related to Tregs, Th1, Th17, cytotoxic T cells, and macrophages had decreased expression. Genes related to Th2, iNKT cells, gut barrier, and innate lymphoid cells had increased expression. Interestingly, there were no changes in colonic gene expression.
Then, in hopes of determining if these differences in MB composition between CS-born and VD mice could be transferred to germ-free mice, they transferred GM from conventional to 5 week old germ-free mice through fecal transfer. They saw differences in Prevotella genus members, Anaeroplasma, Mogibacteriaceae, and Erysipelotrichaceae in the mice transfected with CS-born MB and VD mice. Furthermore, they saw a reduction in Tregs and an increase in iNKTs in the germ-free mice transfected from CS-born mice, as was also seen in the conventional CS-born mice.
Finally, the authors attempted to restore GM composition by adding the prebiotic xylooligosaccharide (XOS) to the diet of CS-born and VD mice to see if CS-induced effects were reversed. Prebiotics are plant fibers that stimulate the growth of gut bacteria [7]. The original differential abundance of Prevotella genus members was not seen in XOS-fed 5 week old mice. Instead, they found a greater abundance of Bacteroides genus members in CS-born then VD mice. Without XOS, VD mice had a greater abundance of Bacteroides genus members than CS-born mice. Additionally, XOS restored iNKT cell proportion but did not restore Treg proportion. The genes implicated in CS delivery, including Cd8a and Prf1, were found to be no longer downregulated, shown below.
In conclusion, the decrease of Tregs and IL10 indicate that there may be a GM composition-mediated effect of CS delivery on regulatory immunity. Interestingly, because the XOS did not restore Treg levels, there may be crucial bacteria other than Prevotella that is involved in the differences in GM compositions and immune cell proportions between CS-born and VD mice.
iNKT cell regulation by GM was supported by this study in that the iNKT levels were able to be restored through both VD-GM transfer and XOS diet. Large amounts of iNKT cells can increase susceptibility to allergy and intestinal inflammation, symptoms seen in CS-born individuals [8-10]. Future directions of this research may include determining if the effects of CS-delivery are involved with differences in iNKT abundance.
However, on a larger scale, this study is not able to suggest that GM therapies for CS-born individuals will reduce known CS-associated heath effects. The main take-away from this research is that prebiotics may have some effect on restoring negative effects of CS-delivery on GM composition. Moreover, microbiome-focused therapies have a diverse range of applications.
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