Cultivated human intestinal fungusCandida metapsilosisM2006B attenuates colitis by secreting acyclic sesquiterpenoids as FXR agonists

Abstract

ObjectiveDysbiosis of the intestinal fungal community has been observed in inflammatory bowel disease (IBD); however, its potential role in IBD development and prevention remains unclear. Here, we explored the biological effects and molecular mechanisms of intestinal fungi isolated from human faeces on colitis in mice.DesignIntestinal fungal strains with differential abundance in IBD were cultivated in human faeces and their effects on various mouse models of experimental colitis were evaluated. In addition, the bioactive metabolites secreted by the target fungus were accurately identified and their pharmacological effects and potential molecular targets were investigated in vitro and in vivo.ResultsThe abundance of Candida spp was significantly higher in patients with IBD. After large-scale human intestinal fungal cultivation and functional analysis, Candida metapsilosis M2006B significantly attenuated various models of experimental colitis in wild-type, antibiotic-treated, germ-free, and IL10-/- mice by activating farnesoid X receptor (FXR). Among the seven acyclic sesquiterpenoids (F1–F7) identified as major secondary metabolites of M2006B, F4 and F5 attenuated colitis in mice by acting as novel FXR agonists. The therapeutic effects of M2006B and its metabolites on colitis via specific FXR activation were confirmed in Fxr-/- mice.ConclusionThis study revealed that C. metapsilosis M2006B significantly attenuated colitis in mice and identified two acyclic sesquiterpenoids (F4 and F5) as major active metabolites of M2006B. Notably, these metabolites were able to effectively treat experimental colitis by selectively activating FXR. Together, this study demonstrates that M2006B could be a beneficial intestinal fungus for treating and preventing IBD.

Fungal gut microbiota dysbiosis in systemic lupus erythematosus

“…Over the past 10 years, sequencing technology has continued to advance ( Hoggard et al, 2018 ) a large number of fungi in the intestine that are protective or harmful to human health are gradually discovered and verified. Fungal microbiota dysbiosis was considered to be associated with many diseases, including cancers ( Conche and Greten, 2018 ; Wang et al, 2018 ; Coker et al, 2019 ; Dohlman et al, 2022 ; Lin et al, 2022 ; Narunsky-Haziza et al, 2022 ), autoimmune diseases ( Lemoinne et al, 2020 ; Shah et al, 2021 ; Huo et al, 2022 ; Iliev, 2022 ), metabolic disorders ( Sun et al, 2021 ), and chronic disease ( Hu et al, 2022 ). The colonization and growth of opportunistic fungal pathogens in the intestine can induce host immune dysregulation ( Limon et al, 2019 ; Jain et al, 2021 ; Zhang et al, 2022 ).…”

Recent advances in gut microbiota-associated natural products: structures, bioactivities, and mechanisms

“…The novel farnesoid X receptor (FXR) agonists, acyclic sesquiterpenoids F1–F7 ( 14–20 ) isolated from Candida metapsilosis M2006B, significantly attenuate colitis. 17 Characterization of the products of gut terpenoid BGCs should be deeply investigated. As shown above, secondary metabolites derived from the BGCs of gut microbes show great potential as leading compounds against pathogens.…”

“…The use of articial intelligence, and computational prediction algorithms, together with metabolomics can enhance our ability to identify gut-microbiome-derived mediators and the proteins involved. 17,83 Recently, a computing platform named MetaWIBELE was introduced to identify and assess the biological activity of numerous unresolved microbial protein families related to inammatory bowel diseases in the human microbiome; 84 (3) culturomics can be used to identify specic gut microbes that contribute to observed differences in the metabolome and metaproteome. It is necessary to culture enriched gut microbes by treatment with NPs and further demonstrate the effects of theses microbes in parallel with those of NPs.…”

Gut mycobiome: A “black box” of gut microbiome–host interactions

“…M2006B alleviates colitis through the secretion of acyclic sesquiterpenoids and activation of FXR. (Huo et al, 2022) Patients with Crohn's disease. Increase: granular hyphal morphologies of Candida albicans.…”