Novel tripeptide RKH derived fromAkkermansia muciniphilaprotects against lethal sepsis

Abstract

ObjectiveThe pathogenesis of sepsis is complex, and the sepsis-induced systemic proinflammatory phase is one of the key drivers of organ failure and consequent mortality.Akkermansia muciniphila(AKK) is recognised as a functional probiotic strain that exerts beneficial effects on the progression of many diseases; however, whether AKK participates in sepsis pathogenesis is still unclear. Here, we evaluated the potential contribution of AKK to lethal sepsis development.DesignRelative abundance of gut microbial AKK in septic patients was evaluated. Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) injection were employed to establish sepsis in mice. Non-targeted and targeted metabolomics analysis were used for metabolites analysis.ResultsWe first found that the relative abundance of gut microbial AKK in septic patients was significantly reduced compared with that in non-septic controls. Live AKK supplementation, as well as supplementation with its culture supernatant, remarkably reduced sepsis-induced mortality in sepsis models. Metabolomics analysis and germ-free mouse validation experiments revealed that live AKK was able to generate a novel tripeptide Arg-Lys-His (RKH). RKH exerted protective effects against sepsis-induced death and organ damage. Furthermore, RKH markedly reduced sepsis-induced inflammatory cell activation and proinflammatory factor overproduction. A mechanistic study revealed that RKH could directly bind to Toll-like receptor 4 (TLR4) and block TLR4 signal transduction in immune cells. Finally, we validated the preventive effects of RKH against sepsis-induced systemic inflammation and organ damage in a piglet model.ConclusionWe revealed that a novel tripeptide, RKH, derived from live AKK, may act as a novel endogenous antagonist for TLR4. RKH may serve as a novel potential therapeutic approach to combat lethal sepsis after successfully translating its efficacy into clinical practice.

Toll‐like receptors in health and disease

“…RKH binds to TLR4 directly and inhibits TLR4 activation in immune cells, preventing organ damage and death brought on by sepsis. It considerably lowers sepsis‐induced inflammatory cell activation and overproduction of proinflammatory factors, and it protects against sepsis‐induced death and organ damage 159 . In LPS‐treated rats, ferrostatin‐1 ameliorates sepsis‐induced cardiac dysfunction and dramatically lowers TLR4, NF‐κB, and IκBα levels 160 …”

Global research trends on sepsis and septic shock during 2003–2022: A data-driven bibliometric analysis

“…Regarding metabolites of gut microbes, the latest studies have shown that Akkermansia can produce a new tripeptide Arg-Lys-His, which directly binds to TLR4 to inhibit in ammatory signalling pathways in immune cells, showing signi cant anti-in ammatory activity [102]. Another study on the metabolites of the gut symbiotic Candida albicans revealed that phenylpyruvate, which directly binds to TLR4, increases the production of dependent reactive oxygen species, enhances the phagocytic capacity of macrophages, thereby inhibiting sepsis-related organ function damage [103].…”

Akkermansia muciniphila in infectious disease: A new target for this next-generation probiotic?

“…14 Furthermore, a tripeptide derived from Akkermansia (Arg-Lys-His; RKH) can prevent lethal sepsis in a variety of model systems. 15 Akkermansia has also been shown to specifically modulate the adaptive immune response influencing T cell and antibody responses in the host; factors that potentially influence cell-mediated responses to pathogens and pathobionts. 16 Indeed, the systemic immune-modulatory effects of orally administered live or pasteurised A. muciniphila have been linked to reduced pulmonary viral load in a mouse model of influenza infection.…”

“…18 The tripeptide RKH is produced by Akkermansia and has been shown to reduce TLR4 signalling pathways resulting in moderation of potentially lethal sepsis. 15 Finally, A. muciniphila is known to activate the enteric nervous system and impact signalling to the hypothalamus, 21 although the implications of this interaction for immune homoeostasis are currently unclear. Figure was generated using Biorender.…”

“…A. muciniphila produces the β-carboline alkaloid harmaline which protects against phlebovirus infection in the lungs through a proposed mechanism that involves up-regulation of bile acid synthesis in the liver and modulation of immune signalling via the TGR5 bile acid receptor 18. The tripeptide RKH is produced by Akkermansia and has been shown to reduce TLR4 signalling pathways resulting in moderation of potentially lethal sepsis 15. Finally, A. muciniphila is known to activate the enteric nervous system and impact signalling to the hypothalamus,21 although the implications of this interaction for immune homoeostasis are currently unclear.…”