The dormant blood microbiome in chronic, inflammatory diseases

Abstract

Blood in healthy organisms is seen as a 'sterile' environment: it lacks proliferating microbes. Dormant or not-immediately-culturable forms are not absent, however, as intracellular dormancy is well established. We highlight here that a great many pathogens can survive in blood and inside erythrocytes. 'Non-culturability', reflected by discrepancies between plate counts and total counts, is commonplace in environmental microbiology. It is overcome by improved culturing methods, and we asked how common this would be in blood. A number of recent, sequence-based and ultramicroscopic studies have uncovered an authentic blood microbiome in a number of non-communicable diseases. The chief origin of these microbes is the gut microbiome (especially when it shifts composition to a pathogenic state, known as 'dysbiosis'). Another source is microbes translocated from the oral cavity. 'Dysbiosis' is also used to describe translocation of cells into blood or other tissues. To avoid ambiguity, we here use the term 'atopobiosis' for microbes that appear in places other than their normal location. Atopobiosis may contribute to the dynamics of a variety of inflammatory diseases. Overall, it seems that many more chronic, non-communicable, inflammatory diseases may have a microbial component than are presently considered, and may be treatable using bactericidal antibiotics or vaccines.

Keywords: Alzheimer disease; Parkinson's disease; atopobiosis; culturability; dormancy; dysbiosis; ‘sterile’ blood microbiome.

Graphical Abstract Figure.

Atopobiosis of microbes (the term describing microbes that appear in places other than where they should be), as well as the products of their metabolism, seems to correlate with, and may contribute to, the dynamics of a variety of inflammatory diseases.

Figure 1.

An overview figure summarizing the contents of this manuscript.

Figure 2.

A diagrammatic representation of the major macroscopic physiological states of microbes and their interrelationships.

Figure 3.

Schematic representation of dysbiosis, bacterial translocation and atopobiosis. (A) When intestinal microbiota are associated with dysbiosis, (B) the gut barrier (1 and 2) becomes compromised; this leads to (C), a route of entry via the gut epithelia causing (D) bacterial translocation. Bacterial translocation is also associated with a compromised systemic immune system barrier (3). Therefore, intestinal microbiota dysbiosis (A) followed by bacterial translocation (D) results in (E) atopobiosis. (F) The results of bacterial translocation are seen in various conditions (see Table 4).

Figure 4.

Micrographs taken from previously published manuscripts. (A–C) Bacterial presence in PD, originally shown in Fig. 8A, C and G in Pretorius et al. (2014a). (D) Bacterial presence in AD, originally shown in Fig. 2 in Lipinski and Pretorius (2013).

Figure 5.

RBCs with microbiota from patients with diagnosed AD (additional micrographs from sample used in Lipinski and Pretorius 2013). These micrographs are representative of bacteria found in smears of 14 of the 30 AD individuals. (A and B) coccus-shaped bacteria associated with white blood cell; (B) coccus-shaped bacteria associated with an erythrocyte and white blood cell; (C) two white blood cells associated with coccus-shaped bacteria; (D) a string of cocci-blue arrow shows possibly dividing coccoid bacteria; (E) an erythrocyte associated with coccus-shaped bacteria; (F) a high machine magnification of a coccus-shaped bacteria associated with a dense matted fibrin deposit. Scale bar: 1 μm.

Figure 6.

RBCs with microbiota from patients with diagnosed PD (additional micrographs from sample used in Pretorius et al. 2014a). These micrographs are representative of bacteria found in smears of 21 of the 30 PD individuals. (A) A collection of coccus- and bacillus-shaped bacteria; (B) coccus- and bacillus-shaped bacteria associated with erythrocyte; (C) bacillus-shaped bacteria in close proximity with erythrocyte. Erythrocyte forms extensions towards bacteria; (D and E) bacillus-shaped bacteria associated with elongated erythrocytes; (F) coccus- and bacillus-shaped bacteria close to erythrocyte that extends pseudopodia towards the bacteria. Coccus-shaped bacteria shown with pink arrows; bacillus-shaped bacteria shown with white arrows. Dividing coccus-shaped bacteria shown with blue arrow. Scale bar: 1 μm.

Figure 7.

TEM confirming the presence of bacteria inside erythrocytes of (A and B) AD, (C and D) PD. (Additional micrographs from sample used in Lipinski and Pretorius (2013) and Pretorius et al. (2014a). Arrows in each micrograph show the presence of cellular inclusions, without visible membranes. Inclusions are not typically noted in erythrocytes. We suggest that these inclusions are bacteria, possibly as L-forms. Scale bar = 1 μm (A, C, D); 200 nm (D).

Figure 8.

Relationships between a dormant blood microbiome and chronic disease dyamics.