Berberine inhibits intestinal carcinogenesis by suppressing intestinal pro-inflammatory genes and oncogenic factors through modulating gut microbiota

Abstract

Background The role of Berberine (BBR) in colorectal cancer (CRC) and gut microbiota has begun to appreciate. However, there was no direct evidence confirm that the gut microbiota regulated by BBR could inhibit CRC. This report investigated the effect of stool from BBR treated subjects and its effect on CRC. Methods A mouse model for CRC was developed using azoxymethane (AOM) and dextran sulfate sodium (DSS). Intestinal tissue from affected mice were used to determine the efficacy of BBR against CRC. Stool samples were collected for the 16s rRNA gene sequencing and fecal microbiota transplantation (FMT). Finally, the mechanism of gut microbiota from BBR treated mice on CRC was explored using immunohistochemistry, RNA-Sequencing, quantitative RT-PCR, and western blot analyses. Results BBR significantly reduced intestinal tumor development. The richness of gut microbiota were notably decreased by BBR. Specifically, the relative abundance of beneficial bacteria (Roseburia, Eubacterium, Ruminococcaceae, and Firmicutes_unclassified) was increased while the level of bacteria (Odoribacter, Muribaculum, Mucispirillum, and Parasutterella) was decreased by BBR treatment. FMT experiment determined that the mice fed with stool from BBR treated AOM/DSS mice demonstrated a relatively lower abundance of macroscopic polyps and a significantly lower expression of β-catenin, and PCNA in intestinal tissue than mice fed with stool from AOM/DSS mice. Mechanistically, intestinal tissue obtained from mice fed with stool from BBR treated AOM/DSS mice demonstrated a decreased expression of inflammatory cytokines including interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α), C-C motif chemokine 1 (Ccl1), Ccl6, and C-X-C motif ligand (Cxcl9). In addition, the NF-κB expression was greatly suppressed in mice fed with stool from BBR treated AOM/DSS mice. Real-time PCR arrays revealed a down-regulation of genes involved in cell proliferation, angiogenesis, invasiveness, and metastasis in mice fed with stool from BBR treated AOM/DSS mice. Conclusions Stool obtained from BBR treated AOM/DSS mice was able to increase colon length while simultaneously decreasing the density of macroscopic polyps, cell proliferation, inflammatory modulators and the expression of NF-κB. Therefore, it was concluded that suppression of pro-inflammatory genes and carcinogens factors by modulating gut microbiota was an important pathway for BBR to inhibit tumor growth in conventional mice.

Enhancing tumor-specific recognition of programmable synthetic bacterial consortium for precision therapy of colorectal cancer

“…In the AOM/DSS model, LEfSe results between groups solicit specific microbial taxa. Consistent with previous studies, AOM/DSS treatment was associated with increased abundance of Bacteroides 95 – 97 , Muribaculum 96 , 97 , and Parabacteroides 97 , while Lachnospiraceae _NK4A136_group 96 and Rnikenella 97 showed decreased abundance. Of these taxa, the presence of Bacteroides is known to be positively correlated with intestinal inflammation and the occurrence of colorectal cancer 98 , 99 .…”

Gut microbes of the cecum versus the colon drive more severe lethality and multi-organ damage

“…Furthermore, inflammation-associated Lachnoclostridium and Desulfovibrio [45] also increased in the cecum compared to the colon group. In the present study, we knew Helicobacter could stimulate CD4 + T cells to Th1 differentiation through IL-12 production and enable these cells to secrete cytokines such as IL-1, IL-6, TNF-α and IFN-γ [46]; Mucispirillum and Lachnospiraceae_FCS020_group can promote intestinal inflammatory response [47,48];…”

“…Furthermore, inflammation-associated Lachnoclostridium and Desulfovibrio [45] also increased in the cecum compared to the colon group. In the present study, we knew Helicobacter could stimulate CD4 + T cells to Th1 differentiation through IL-12 production and enable these cells to secrete cytokines such as IL-1, IL-6, TNF-α and IFN-γ [46]; Mucispirillum and Lachnospiraceae_FCS020_group can promote intestinal inflammatory response [47, 48]; Desulfovibrionaceae were known for their sulfate-reducing capacities, as a result of this producing toxic hydrogen sulfide [49]. Therefore, these potentially pathogenic bacteria would explain their high IC-associated pathogenic potential for mouse survival and more severe multi-organ injury.…”

Deficiency of SR‐B1 reduced the tumor load of colitis‐induced or APCmin/+‐induced colorectal cancer

“…So Lachnoclostridium was used as an early diagnostic biomarker of CRC. The Muribaculum genus was significantly enriched in AOM/DSS induced CRC and T cell‐induced colitis mice 38,39 . Furthermore, Desulfovibrio , one of the sulfidogenic bacteria, participated in the progress of CRC 40–42 .…”