Abnormal Blood Bacteriome, Gut Dysbiosis, and Progression to Severe Dengue Disease

Abstract

Despite a well-known association between gut barrier defect (leaky gut) and several diseases, data on translocation of pathogen molecules, including bacterial DNA (blood bacteriome), lipopolysaccharide (LPS), and serum (1→3)-β-D-glucan (BG), from the gut to the blood circulation (gut translocation) in dengue are still less studied. Perhaps, dengue infection might induce gut translocation of several pathogenic molecules that affect the disease severity. At the enrollment, there were 31 dengue cases in febrile and critical phases at 4.1 ± 0.3 days and 6.4 ± 1.1 days of illness, respectively, with the leaky gut as indicated by positive lactulose-to-mannitol excretion ratio. With blood bacteriome, the patients with critical phase (more severe dengue; n = 23) demonstrated more predominant abundance in Bacteroidetes and Escherichia spp. with the lower Bifidobacteria when compared with the healthy control (n = 5). Meanwhile, most of the blood bacteriome results in dengue with febrile stage (n = 8) were comparable to the control, except for the lower Bifidobacteria in dengue cases. Additionally, endotoxemia at the enrollment was demonstrated in five (62.5%) and 19 (82.6%) patients with febrile and critical phases, respectively, while serum BG was detectable in two (25%) and 20 (87%) patients with febrile and critical phases, respectively. There were higher peripheral blood non-classical monocytes and natural killer cells (NK cells) at the enrollment in patients with febrile phage than in the cases with critical stage. Then, non-classical monocytes (CD14-CD16+) and NK cells (CD56+CD16-) increased at 4 and 7 days of illness in the cases with critical and febrile stages, respectively, the elevation of LPS and/or BG in serum on day 7 was also associated with the increase in monocytes, NK cells, and cytotoxic T cells. In summary, enhanced Proteobacteria (pathogenic bacteria from blood bacteriomes) along with increased endotoxemia and serum BG (leaky gut syndrome) might be collaborated with the impaired microbial control (lower non-classical monocytes and NK cells) in the critical cases and causing more severe disease of dengue infection.

The Regulatory Roles of Ezh2 in Response to Lipopolysaccharide (LPS) in Macrophages and Mice with Conditional Ezh2 Deletion with LysM-Cre System

“…The presence of lipopolysaccharide (LPS), a microbial molecule from Gram-negative bacteria, in blood has been clinically demonstrated as endotoxemia in several conditions, including sepsis [ 55 , 56 , 57 ], partly through gut barrier damage [ 1 , 22 , 24 , 58 ]. The activation of macrophages by LPS is possibly important in sepsis because macrophages are the innate immune cells responsible for the recognition of foreign molecules [ 51 , 59 ].…”

“…During sepsis, the translocation of LPS, which is a major molecule of Gram-negative bacteria (the most abundant gut organism), from the intestine into the blood circulation, referred to as “leaky gut”, is a common cause of endotoxemia [ 21 , 22 , 23 ]. Meanwhile, an adaptation to the prolonged LPS stimulations in sepsis may initiate LPS tolerance [ 24 , 25 ].…”

Candida Administration in 5/6 Nephrectomized Mice Enhanced Fibrosis in Internal Organs: An Impact of Lipopolysaccharide and (1→3)-β-D-Glucan from Leaky Gut

“…Additionally, our results support the importance of gut fungi in uremic conditions, especially in patients with severe uremia, before performing kidney replacement therapies (dialysis and renal transplantation). In patients with CKD with positive residual renal function (still producing urine), the determination of leaky gut using an oral administration of non-absorbable carbohydrate before detection in the urine [15,75] might be an interesting biomarker that demonstrates a possibly persistent chronic inflammation from uremia-induced leaky gut. The interventions for the attenuation of leaky gut, such as probiotics and other renal replacement therapies, act through the reduction in uremic toxins (gut-derived and non-gut-derived toxins).…”

“…Although the presence of Candida spp. in the gut does not directly cause disease, gut fungi alter the gut microbiota and provide a higher BG in gut content [13], which possibly worsens systemic inflammation following a gut barrier malfunction (gut leakage) through the systemic immune responses against BG [14][15][16][17][18][19][20]. Indeed, the possible fungal mechanisms that interfere with the growth of specific bacteria (mostly the lower virulence) in the gut are mentioned, including some bactericidal molecules (yeast killer toxins, Candida exotoxin, and endogenous alcohol) [21][22][23][24], and the competition for certain nutrients [25].…”

Lacticaseibacillus rhamnosus dfa1 Attenuate Cecal Ligation-Induced Systemic Inflammation through the Interference in Gut Dysbiosis, Leaky Gut, and Enterocytic Cell Energy

“…For the intra-intestinal factors, increased gut pathogens, some diets, antibiotics, and the local inflammation (infection or non-infection) [ 7 , 8 , 9 , 10 ] induce gut dysbiosis, in part, through the enhanced intestinal immune cells that might have a different impact on different groups of gut organisms causing selective growth in some groups of bacteria (dysbiosis) [ 11 , 12 , 13 , 14 ]. For systemic alterations, the selected growth of some organisms over other groups might be due to increased uremic toxin in the gut (the intestine is used as an alternative route for the toxin excretion during renal insufficiency), reduced blood perfusion in sepsis, immune responses defects, deposition of circulating immune complex [ 15 , 16 , 17 , 18 , 19 , 20 ], and systemic viral infection (COVID-19 and dengue) [ 21 , 22 ]. While gut dysbiosis from both factors damages the gut barrier (a single cell layer separating the host’s circulation and the microbial molecules in the gut contents), gut eubiosis (the balanced microbiota in the healthy regular condition) improves gut integrity [ 7 , 23 ], partly through the increased short-chain fatty acids (SCFAs; the growth factors for gut epithelium) that are altered from the ingested complex carbohydrates by the hosts [ 24 ].…”