Berberine and its structural analogs have differing effects on functional profiles of individual gut microbiomes

Abstract

The understanding of the effects of compounds on the gut microbiome is limited. In particular, it is unclear whether structurally similar compounds would have similar or distinct effects on the gut microbiome. Here, we selected berberine (BBR), an isoquinoline quaternary alkaloid, and 16 structural analogs and evaluated their effects on seven individual gut microbiomes cultured in vitro. The responses of the individual microbiomes were evaluated by metaproteomic profiles and by assessing butyrate production. We show that both interindividual differences and compound treatments significantly contributed to the variance of metaproteomic profiles. BBR and eight analogs led to changes in proteins involved in microbial defense and stress responses and enrichment of proteins from Verrucomicrobia, Proteobacteria, and Bacteroidetes phyla. It also led to a decrease in proteins from the Firmicutes phylum and its Clostridiales order which correlated to decrease proteins involved in the butyrate production pathway and butyrate concentration. Three of the compounds, sanguinarine, chelerythrine, and ethoxysanguinarine, activated bacterial protective mechanisms, enriched Proteobacteria, increased opacity proteins, and markedly reduced butyrate production. Dihydroberberine had a similar function to BBR in enriching the Akkermansia genus. In addition, it showed less overall adverse impacts on the functionality of the gut microbiome, including a better maintenance of the butyrate level. Our study shows that ex vivo microbiome assay can assess differential regulating effects of compounds with subtle differences and reveals that compound analogs can have distinct effects on the microbiome.

Revealing Protein-Level Functional Redundancy in the Human Gut Microbiome using Ultra-deep Metaproteomics

“…This was in agreement with our previous findings that seven of these compounds (except flucytosine) resulted in global alterations in individual microbiome functionality (Li et al, 2020b). Similar findings were observed in the Berberine dataset, in which compounds that were previously found to alter microbiome functionalities (Li et al, 2020a) resulted in significant alterations in dij distributions (Supplementary Figure S10 and Supplementary Table S6).…”

“…In the Berberine dataset, the dij values between Akkermansia and a few other genera were increased by eight of the tested compounds (Supplementary Figure S12). We previously observed responses of Akkermansia to six of these compounds by differential protein analysis (Li et al, 2020a). However, response of Akkermansia in the presence of 6-ethoxysanguinarine (EOSANGR) and sanguinarine (SANGR) was not discovered before.…”

“…In addition, samples are analyzed with different analytical protocols, different parameters and using different models of LC-MS/MS platforms, etc. Here, we compared the topological properties of PCNs in four of our previously published datasets, briefly referred to as SISPROT (Zhang et al, 2017), RapidAIM (Li et al, 2020b), Berberine (Li et al, 2020a) and IBD (Zhang et al, 2018a) datasets, respectively. These four datasets vary considerably in the metaproteomic approaches used and in the types of environmental factors (xenobiotics, biogeography, diseases status etc.)…”

Effect of berberine on hyperglycaemia and gut microbiota composition in type 2 diabetic Goto-Kakizaki rats

“…Similar results[ 41 ] were observed in studies by Zhao et al [ 40 ] and Tian et al [ 42 ]. Berberine led to changes in proteins involved in microbial defense and stress responses and enrichment of proteins from the Verrucomicrobiota phylum[ 43 ]. For instance, Desulfovibrionaceae was enriched in patients with T2DM.…”

MetaProClust-MS1: A tool for clustering metaproteomes using rapid MS1 profiling

“…Recently, Li et al (2020c) intro-duced RapidAIM, an in vitro assay used to assess the microbiome’s response to drugs using high-throughput metaproteomics and metagenomics. Thus far, RapidAIM has been used to identify drugs that cause sig-nificant alterations to the gut microbiome (Li et al, 2020c), determine how structural analogs affect the gut microbiome (Li et al, 2020b), and explore the ways individual microbiome profiles vary in response to resistant starches (Li et al, 2020a).…”