Critical roles of sepsis-reshaped fecal virota in attenuating sepsis severity

Abstract

Because studies on all fecal organisms (bacteria, fungi, and viruses) in sepsis are rare and bacteriophages during sepsis might have adapted against gut bacteria with possible pathogenicity, cecal ligation and puncture (CLP; a sepsis mouse model) was evaluated. In fecal bacteriome, sepsis increased Bacteroides and Proteobacteria but decreased Firmicutes, while fecal virome demonstrated increased Podoviridae when compared with sham feces. There was no difference in the fungal microbiome (predominant Ascomycota in both sham and CLP mice) and the abundance of all organisms between sepsis and control groups. Interestingly, the transfers of feces from CLP mice worsened sepsis severity when compared with sham fecal transplantation, as evaluated by mortality, renal injury (serum creatinine and histology), liver damage (liver enzyme and histology), spleen apoptosis, serum cytokines, endotoxemia, and bacteremia. In contrast, the transfers of fecal viral particles from sepsis mice, but not from sham mice, attenuated inflammation in CLP sepsis possibly through the decrease in several fecal pathogenic bacteria (such as Proteobacteria, Gammaproteobacteria, and Prevotellaceae) as evaluated by fecal microbiome analysis. Perhaps the isolation of favorable bacteriophages in sepsis feces and increased abundance ex vivo before oral treatment in a high concentration are beneficial.

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

“…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 ].…”

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

“…Then, Lacticaseibacillus rhamnosus dfa1 (Chulalongkorn University, Bangkok, Thailand) that isolated from the Thai healthy volunteers from a previous project [ 29 ] at 1 × 10 8 CFU in 0.3 mL phosphate-buffered solution (PBS), or PBS alone, were daily orally administered for 4 days prior to cecal ligation or sham operation. The cecal ligation protocol was modified from previous publications [ 87 , 88 , 89 , 90 , 91 , 92 ]. Briefly, the whole length of the cecum was ligated by silk 2-0 before closing the abdominal wall layer by layer, whereas sham surgery was only the identification of the cecum before suturing the abdominal wall with nylon 6–0.…”

The leaky gut and the gut microbiome in sepsis – targets in research and treatment

“…Despite the lack of information regarding the gut mycobiota in patients with sepsis, septic mice demonstrate subtle changes in gut fungi (the abundance of fungal 18sRNA by PCR in sepsis is different from the control group), including a reduction of only Myrothecium spp. fungi that can produce some molecules against several harmful factors (some organisms and toxic substances) [ 15 ]. The differences in sepsis conditions between humans and mice [ 140 , 141 ] raise the possibility that gut fungi in patients with sepsis might be enhanced by several factors that differ from those in mice, such as the duration of sepsis (human patients survive longer than mice), antibiotic use (more potent in human conditions), intensive care unit (ICU) environment (nosocomial infections are likelier in patients in ICUs than in mice in controlled animal facilities) and naturally higher Candida levels in human faeces and underlying diseases (such as altered gut fungi in Type 2 diabetes) [ 142–144 ].…”

“…by stress) into lytic phages and killing the bacteria [ 150 ], any alteration in the bacterial microbiome during sepsis might automatically induce changes in virota (virome). Indeed, the faecal virota from septic mice demonstrates an alteration in the abundance of several groups of bacteriophages, including Myoviridae (in sham mice) and Podoviridae (in septic mice), which are components of several phage cocktails used in other studies [ 15 ]. The observation that viral particles isolated from faeces of a septic mouse can attenuate sepsis in another mouse [ 15 ] raises the possibility that bacterial stress during sepsis activates lytic phages that might be able to control some sepsis-induced pathogenic bacteria.…”

“…The importance of PAMPs in sepsis implicates the gastrointestinal tract as an endogenous reservoir of several groups of organisms, including prokaryotes, i.e., bacteria and archaea, eukaryotes, i.e., fungi, and viruses, mostly bacteriophages, which are jointly referred to as ‘gut microbiota’. These organisms are separated from the host by only a single layer of enterocytes containing tight junction molecules [ 14 , 15 ]. During sepsis, enterocytes experience hyperpermeability caused by several factors, including intestinal hypoperfusion, enterocyte apoptosis, a systemic cytokine storm, and gut dysbiosis, which could promote the translocation of microbial molecules from the gut into systemic circulation.…”