Daily Sepsis Research Analysis

The pathophysiology of sepsis is characterized by a systemic inflammatory response to infection; however, the cytokine blockade that targets a specific early inflammatory mediator, such as tumor necrosis factor, has shown disappointing results in clinical trials. During sepsis, excessive endotoxins are internalized into the cytoplasm of immune cells, resulting in dysregulated pyroptotic cell death, which induces the leakage of late mediator alarmins such as HMGB1 and PTX3. As late mediators of lethal sepsis, overwhelming amounts of alarmins bind to high-affinity TLR4/MD2 and low-affinity RAGE receptors, thereby amplifying inflammation during early-stage sepsis. In this study, we developed a novel alarmin/receptor-targeting system using a TLR4/MD2/RAGE-blocking peptide (TMR peptide) derived from the HMGB1/PTX3-receptors interacting motifs. The TMR peptide successfully attenuated HMGB1/PTX3- and LPS-mediated inflammatory cytokine production by impairing its interactions with TLR4 and RAGE. Moreover, we developed TMR peptide-conjugated liposomes (TMR-Lipo) to improve the peptide pharmacokinetics. In combination therapy, moderately antibiotic-loaded TMR-Lipo demonstrated a significant therapeutic effect in a mouse model of cecal ligation- and puncture-induced sepsis. The identification of these peptides will pave the way for the development of novel pharmacological tools for sepsis therapy.

AIM: Sepsis is a potentially fatal condition characterized by organ failure resulting from an abnormal host response to infection, often leading to liver and kidney damage. Timely recognition and intervention of these dysfunctions have the potential to significantly reduce sepsis mortality rates. Recent studies have emphasized the critical role of serum exosomes and their miRNA content in mediating sepsis-induced organ dysfunction. The objective of this study is to elucidate the mechanism underlying the impact of miR-122-5p on sepsis-associated liver and kidney injury using inhibitors for miR-122-5p as well as GW4869, an inhibitor targeting exosome release. MATERIALS AND METHODS: Exosomes were isolated from serum samples of septic rats, sepsis patients, and control groups, while liver and kidney tissues were collected for subsequent analysis. The levels of miR-122-5p, inflammation indices, and organ damage were assessed using PCR, ELISA, and pathological identification techniques. Immunohistochemistry and Western blotting methods were employed to investigate the activation of inflammatory pathways. Furthermore, big data analysis was utilized to screen potential targets of miR-122-5p in vivo. KEY FINDINGS: Serum exosomal levels of miR-122-5p were significantly elevated in septic patients as well as in LPS-induced septic rats. Inhibition of miR-122-5p reduced serum pro-inflammatory factors and ameliorated liver and kidney damage in septic rats. Mechanistically, miR-122-5p upregulated TAK1, downregulated SIRT1, and facilitated NF-κB activation. CONCLUSION: Serum exosomal miR-122-5p promotes inflammation and induces liver/kidney injury in LPS-induced septic rats by modulating the TAK1/SIRT1/NF-κB pathway, highlighting potential therapeutic targets for sepsis management.

BACKGROUND: Patients admitted to the intensive care unit (ICU) often have gut colonization with pathogenic bacteria and such colonization is associated with increased risk for death and infection. We conducted a trial to determine whether a prebiotic would improve the gut microbiome to decrease gut pathogen colonization and decrease downstream risk for infection among newly admitted medical ICU patients with sepsis. METHODS: This was a randomized, double-blind, placebo-controlled trial of adults who were admitted to the medical ICU for sepsis and were receiving broad-spectrum antibiotics. Participants were randomized 1:1:1 to placebo, inulin 16 g/day, or inulin 32 g/day which were given for seven days. The trial primary outcome was a surrogate measure for gut colonization resistance, namely the within-individual change from ICU admission to Day 3 in the relative abundance of short chain fatty acid (SCFA)-producing bacteria based on rectal swabs. Additional outcomes sought to evaluate the impact of inulin on the gut microbiome and downstream clinical effects. RESULTS: Ninety participants were analyzed including 30 in each study group. There was no difference between study groups in the within-individual change in the relative abundance of SCFA-producing bacteria from ICU admission to ICU Day 3 (placebo: 0.0% change, IQR - 8·0% to + 7·4% vs. combined inulin: 0·0% change, IQR - 10·1% to + 4·8%; p = 0·91). At end-of-treatment on ICU Day 7, inulin did not affect SCFA-producer levels, microbiome diversity, or rates of gut colonization with pathogenic bacteria. After 30 days of clinical follow-up, inulin did not affect rates of death or clinical, culture-proven infection. Patients who died or developed culture-proven infections had lower relative abundance of SCFA-producing bacteria at ICU admission compared to those who did not (p = 0·03). CONCLUSIONS: Prebiotic fiber had minimal impact on the gut microbiome in the ICU and did not improve clinical outcomes. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03865706.