Strains of Klebsiella spp. from the salivary microbiota may colonize the gut and induce chronic intestinal inflammation

Recent research has started focusing on the role of the oral microbiota in host health and exacerbation of some systemic diseases. Although increased levels of certain oral-derived microbes have been found in the gut microbiota of patients with inflammatory bowel disease, human immunodeficiency virus infection, liver cirrhosis, and colon cancer, little is known regarding whether oral pathobionts -resident bacteria that have the potential to cause disease- could have a causal role in exacerbating intestinal disease.

A recent study, led by Dr. Kenya Honda from the Department of Microbiology and Immunology at Keio University School of Medicine in Tokyo (Japan), has found that gut colonization of certain saliva bacteria isolated from patients with Crohn’s disease can exacerbate intestinal inflammation in mice.

By obtaining saliva samples from two patients with Crohn’s disease and transplanting them into germ-free mice by gavage, the researchers found that the faecal microbiota compositions differed significantly between recipient mice depending on the accumulation of intestinal T helper 1 (Th1) cells -a subset of T lymphocytes with a strong pro-inflammatory profile.

The faecal microbiota compositions differed markedly between recipient germ-free mice, depending on the accumulation of interferon-gamma (IFN-g) CD4+ T cells (T helper 1 -Th1- cells) in the intestinal lamina propria. Although the saliva samples of both patients contained similar microbial communities, the resulting faecal microbiota compositions differed markedly between two groups of colonized germ-free mice, and most of the bacterial species in their faecal microbiota were minor components of the salivary microbiota. These data suggest that certain oral bacteria can colonize the gut, and a subset of them can induce the accumulation of intestinal Th1 cells.

Klebsiella pneumoniae strain 2H7 (Kp-2H7) was the predominant component of the gut microbiota of the colonized germ-free mice and was identified to be the major inducer of Th1 cell-mediated inflammatory immune responses. When it was orally administered alone, it significantly induced Th1 cells specifically in the colon and to a lesser extent in the small intestine – while a mixture of seven other strains of K. pneumoniae failed to induce Th1 cells. Interestingly, intestinal colonization of Kp-2H7 induced preferentially inflammatory Th1 cell generation in the colon, while it did not affect anti-inflammatory pathways and regulatory T cell generation.

Kp-2H7 was resistant to multiple antibiotics, including ampicillin and tylosin. Although antibiotic-naïve specific pathogen-free mice were resistant to intestinal colonization by Kp-2H7, ampicillin or tylosin treatment allowed Kp-2H7 to persist in the intestine, and this was accompanied by increased colonic Th1 cells. Besides this, Kp-2H7 colonization did not induce any inflammatory changes in the intestines of wild-type hosts despite inducing Th1 cells. However, monocolonization of Kp-2H7 in a model of colitis-prone interleukin-10-deficient mice -which spontaneously develop intestinal inflammation with a highly polarized Th1 response- caused severe inflammation in the proximal colon. These results support the previously known fact that both microbial and host genetic factors are involved in the pathogenesis of inflammatory bowel disease.

On the whole, these results demonstrate that intestinal colonization and pathogenic inflammation induced by oral Kp-2H7 occur only under certain circumstances such as antibiotic-induced microbiota perturbation. In this context, Kp-2H7 acts as a gut pathobiont that does not induce inflammation in the oral mucosa but can cause severe colonic inflammation in a genetically susceptible host.

In order to investigate the mechanisms for the Th1-mediated inflammation by Kp-2H7, the researchers used several mouse models deficient in certain innate and adaptive immune responses. It was found that Klebsiella antigen-specific Th1 responses were induced by dendritic cells via Toll-like receptor 4 (TLR4) signalling, which indicates that intestinal dendritic cells may act as antigen-presenting cells to sense the signals from pathobionts and then produce cytokines to initiate T cell responses. Besides this, epithelial cells activated by TLR4 signalling produced interleukin-18 that further amplified the Th1 response.

Other Klebsiella strains rather than Kp-2H7 -Ka-11E12 from the saliva sample of a patient with active ulcerative colitis and Kp-40B3 from a saliva sample of a healthy individual- also induced Th1-mediated inflammatory responses in the intestine.

Regarding the clinical relevance of this study, the researchers found that the aggregated relative abundance of Klebsiella species was significantly higher in patients with Crohns disease and primary sclerosing cholangitis when compared with healthy controls. In addition, several genes that have been previously reported to be increased in the faecal microbiomes of patients with inflammatory bowel diseases -genes that include hemolysin-coregulated protein and enzymes involved in fructose-, galactitol-, mannose-, and long-chain fatty acid-related uptake and metabolic pathways- were enriched in most faecal samples of the patients with inflammatory disease who carried Klebsiella species.

In conclusion, the oral microbiota may be a source of potential pathobionts that can aggravate intestinal inflammation in genetically susceptible hosts under antibiotic-induced dysbiosis. Further studies in humans are needed in order to explore therapeutic approaches to manage chronic intestinal inflammatory diseases by targeting oral-derived bacteria.

 

References:

Atarashi K, Suda W, Luo C, et al. Ectopic colonization of oral bacteria in the intestine drives Th1 cell induction and inflammation. Science. 2017; 358(6361):359-65.

Cao X. Intestinal inflammation induced by oral bacteria. Science. 2017; 358(6361):308-9.

Andreu Prados
Andreu Prados
Andreu Prados holds a Bachelor of Science Degree in Pharmacy & Human Nutrition and Dietetics. Science writer specialised in gut microbiota and probiotics, working also as lecturer and consultant in nutrition and healthcare. Follow Andreu on Twitter @andreuprados