For many years, scientists have studied the link between gut microbiota and diseases such as dementia, autism, Parkinson’s, diabetes, obesity or colitis, proving that each disease has a specific gut microbiota profile. Studies have also focused on the gut-brain axis, in which bacterial lipopolysaccharides (LPS) translocate to the brain through circulating blood, while gut microbiota also generates metabolites that affect brain function and the immune system. However, we are yet to identify the specific mechanisms, molecules, and genes that cause a disease: a finding that would allow us to develop appropriate therapies.

A new publication from Alan T. Tang of the University of Pennsylvania focuses on explaining the relationship between gut microbiota and cerebral cavernous malformation (CCM), which is a neurological disease that leads to hemorrhagic stroke and seizure. The disease mainly occurs due to genetic variation with heterozygous loss-of-function mutations in the KRIT1, CCM2 and PDCD10 genes, which encode components of an adaptor protein complex. Studies have shown that the individuals who present a PDCD10 gene mutation are more likely to suffer brain hemorrhage and stroke than those showing a mutation of the two other genes in the complex.

Recent studies have shown that the lipopolysaccharide (LPS), presented by gram-negative bacteria in the gut microbiota, activate Toll-like receptor 4 (TLR4) in the brain. Dr. Mark L. Kahn’s team studied the mechanism by which the LPS reaches TLR4 in the brain vasculature and how the PDCD10 gene mutation affects this translocation.

In order to do so, they created a mouse model with brain endothelial cell-specific deletion of PDCD10 and compared CCM lesions with mouse model in which KRIT1 or CCM2 were deleted. Scientists did not observe changes in the severity of symptoms. These first results thus led them to investigate an unidentified role for PDCD10 in cell types other than brain epithelial cells or the gut microbiome.

To identify PDCD10’s role, they first compared the gut microbiota composition of 75 genotyped CCM patients from the United States with that of 29 healthy volunteers. They observed an increase in the proportion of gram-negative Bacteroides and a reduction in gram-positive Lachnospiraceae in CCM patients. Interestingly enough, there was no variation in the gut microbiota community between the three different gene mutations, thus further highlighting PDCD10’s unidentified role.

In a third objective, Tang decided to investigate the impact of disrupted gut microbiota and epithelium cells damage induced by dextran sulfate sodium (DSS). In mice that develop CCM due to endothlial cell specific deletion of Krit1, only 50% survived DSS treatment, and survivors showed a twofold increase in CCM volume compared to vehicle treated littermate controls. Thus, chemical disruption of the gut epithelial barrier exacerbated CCM disease.   In consequence, they next focused on the role of gut epithelial cells in CCM. Comparing CCM formation in mice with loss of intestinal epithelial cell Pdcd10, Ccm2 or Krit1 they observed significant differences.

Indeed, only PDCD10 deletion led to an increase in colonic epithelium lesions, characterized by reduction of mucus layer, crypt dilation and abscesses and presence of Ly6G positive neutrophils. In addition, loss of epithelial PDCD10 resulted in increased TLR4 agonist activity in serum. Prior studies from the same group showed that the amount of circulating gut derived (TLR4-agonist) LPS determines CCM formation.

Altogether, these results show that the gut barrier of the PDCD10-deleted animals allows for greater LPS translocation from the lumen to circulating blood.

To further address the role of the intestinal mucus layer in CCM formation they next used mice with loss of Mucin-2 (MUC2).  MUC2 genes encode for mucus secretion by the goblet cells, which can physically separate bacteria from epithelium cells. Loss of MUC-2 increased CCM burden similar to epithelial PDCD10 deletion. Following these results, the team of scientists decided to undertake 16S rRNA sequencing of fecal DNA from mice with PDCD10 or MUC2 deletion in their gut epithelium. Mucus also serves as a food source for luminal bacteria and herewith affects microbiome composition. Both of these deletions led to the same gut microbiota composition, again suggesting that a major effect of PDCD10 loss is disruption of colonic mucosal barrier through mucus secretion.

Researchers wanted to prove their hypotheses with non-invasive treatment. As it is known that emulsifiers found in processed foods promote colitis by degrading the mucosal barrier, they treated a PDCD10-deleted mouse with a low quantity of P80 (emulsifier) and noted a low but significant increase in mucosal barrier lesions.

The main goal of this research was to identify the mechanism by which PDCD10 deletion in individuals is responsible for increased bacterial translocation and CMM symptoms. However, at the end of the article, Tang proposes a new therapy model using dexamethasone, which targets gut barrier function and the TLR4 signaling pathway. As this glucocorticoid can increase the MUC2 gene in intestinal epithelium cells, it would have a dual effect on brain endothelial cell signaling and intestinal epithelium cells.

In conclusion, this study identifies a new mechanism by which PDCD10 is linked to bacterial translocation, LPS secretion, TRL4 activation, and CCM symptoms. Further studies about the gut microbiota will need to evaluate both the gut microbiota community and intestinal barrier integrity.

Reference:

Tang AT, Sullivan KR, Hong CC, et al. Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Sci Transl Med. 2019; 11(520). doi: 10.1126/scitranslmed.

Manon Oliero
Manon Oliero
Manon Oliero is starting her PhD about gut microbiota, nutrition and cancer at the CRCHUM of Montreal. Before, she specialized in the gut microbiota and nutrition field by obtaining a master’s degree in Paris in microbiology and a food and health engineer degree in Beauvais. She first meets the scientific communication world in Barcelona after her work on gut microbiota and diet at the VHIR. She is really concern about health of the population and believe that with a better diet and lifestyle we can all make ourselves healthier.