Journal: Frontiers in Cell and Developmental Biology

Article Title: Dietary Patterns and Associated Microbiome Changes that Promote Oncogenesis

doi: 10.3389/fcell.2021.725821

Figure Lengend Snippet: Microbial signatures of the gut microbiome, in respect to Western dietary (WD) pattern and plant-based (PD) dietary pattern (N/I non-identified).

Article Snippet: The Arivale study analysed 3,409 individuals enrolled in a wellness program with extensive characterization of metabolic markers, lifestyle, diet, and stool microbiome 16S amplicon sequencing.

Techniques: Western Blot, Bacteria, Activity Assay

Journal: Frontiers in Cell and Developmental Biology

Article Title: Dietary Patterns and Associated Microbiome Changes that Promote Oncogenesis

doi: 10.3389/fcell.2021.725821

Figure Lengend Snippet: Effect of plant-diet on the gut microbiome and intestinal homeostasis. A diet rich in plant-based foods results in high abundance of short-chain fatty acid (SCFA) producing bacteria in the gut lumen. High production of SCFAs by gut microbiome is strongly associated with pathogen suppression, mucus production, improved barrier function and immune tolerance (see Molecular Mechanisms of the Role of Plant-Based Diet in Cancer Protection ). SCFAs induce a set of anti-inflammatory events via interaction with GPR41, GPR43, GPR109A receptors and MCT and SLC5A8 transporters that are expressed on the surface of intestinal epithelial cells and immune cells. 1) SCFAs bind GPR109A on the epithelial cell which leads to increase in TGF- β production, enhancing the differentiation of Treg cells, which leads to increase of immune tolerance in the gut. 2) SCFAs also bind to GPR43 inhibiting HDAC and NF- κB, resulting in decreased inflammation. 3) SCFAs bind to GPR41, inhibiting HDAC and MAPK signaling pathway, resulting in inhibition of proliferation. 4) SCFAs cross the epithelial cell barrier and reach lamina propria, where they induce cascade of anti-inflammatory reactions, regulating immune homeostasis in the lower bowel. In the lamina propria, SCFAs bind to macrophage (MQ cell) inhibiting HDAC, facilitating polarization of macrophages to M2-anti-inflammatory type, and increasing production of antimicrobial peptides (AMPs). 5) SCFAs bind to dendritic (DC) cell enhancing retinoic acid production, further facilitating production immunoglobulin A (IgA) and differentiation of Tregs. 6) SCFAs induce production of TGF- β and retinoic acid, causing B cells to stimulate production of IgA and facilitate plasma B cell differentiation. 7) SCFAs bind to GPR on T cells, initiating the production of IL-10, which increases Tregs pool, and inhibits expansion of T helper (Th) 17.

Article Snippet: The Arivale study analysed 3,409 individuals enrolled in a wellness program with extensive characterization of metabolic markers, lifestyle, diet, and stool microbiome 16S amplicon sequencing.

Techniques: Bacteria, Inhibition, Clinical Proteomics, Cell Differentiation

Journal: Frontiers in Cell and Developmental Biology

Article Title: Dietary Patterns and Associated Microbiome Changes that Promote Oncogenesis

doi: 10.3389/fcell.2021.725821

Figure Lengend Snippet: Effect of Western diet on the gut microbiome and local pro-carcinogenic pathways. Adherence to Western diet results in the high abundance of Fusobacterium nucleatum , Enterotoxigenic Bacteroides fragilis (ETBF), pks + Escherichia coli and Peptostreptococcus anaerobius . Overpopulation of these bacteria in the gut microbiome leads to the increased cell proliferation, elevated grade of inflammation and accumulation of DNA damage, eventually resulting in an environment favorable to initiation or progression of colorectal cancer. (A) F. nucleatum secretes FadA toxin, which binds the E-cadherin complex on the wall of intestinal epithelial cells. Upon interaction with FadA, E-cadherin undergoes phosphorylation, which lead to cleavage and subsequent translocation of the β-Catenin component of the complex to the nucleus. β-Catenin binds with TCF/LEF transcription complex, triggering the expression of CCND1 and MYC, that govern cell proliferation. (B) LPS is a polysaccharide on the cell wall of F. nucleatum , that binds the TLR4 receptor which are expressed on the intestinal epithelial cell membrane. LPS-TLR4 complex activates MYD88 adaptor that results in inhibition of a Ras GTPase—RASA1. The inhibition of RASA1 leads to unwanted cell proliferation. LPS-TLR4-MYD88 complex also induces the production of microRNA miR 21, that in turn activates NF-κB transcription factor and leads to the production of pro-inflammatory agents including KRT-7AS long non-coding RNA. (C) Upon binding of microbial protein Fap2 with cell membrane receptor, surface expressed polysaccharide Gal-Gal-NAc modulates the activation of NF-κB transcription factor that leads to the increase in intestinal inflammation through the production of TNF-α, IL-6, and IL-8. Increased intestinal permeability also, known as “Leaky gut” phenomena, allows the bi-directional passage of bacteria and their metabolites, as well as immune inflammatory agents. Through the leaky gut, Fap2 is able to reach lamina propria and diminish the activity of Natural killer (NK) cells and T cells. (D) F. nucleatum interacts with intestinal epithelial cells to stimulate the production of long non-coding RNA (lncRNA) ENO1-IT1 via SP1 transcription factor. Production of ENO1-IT1 increases concurrently the expression of ENO1. This cascade of reactions leads to the increased level of carcinogenesis and inflammation. (E) ETBF produces BFT toxin, that interacts with epithelial cells to trigger intestinal inflammation via activation of STAT3 signaling pathway. BFT activates RAS/MAPK pathways to further initiate AP1 and start the production of IL-8 resulting in intestinal inflammation. BFT stimulates the translocation of β-Catenin to the nucleus initiating expression of C-Myc and production of reactive oxygen species (ROS), leading to DNA damage. (F) BFT also induce the production of spermine oxidase (SMO) and SMO-dependent ROS production, resulting in DNA damage. (G) Colibactin is secreted by of pks + E. coli . Interaction of colibactin with epithelial cells results in accumulation of DNA adducts and further DNA damage. (H) P. anaerobius surface protein PCWBR2 binds to α 2 /β 1 integrin on the epithelial cells to initiate cell proliferation via activation of PI3K/Akt signaling pathway and NF-κB transcription factor. This interaction also leads to expansion of neutrophils, macrophages and myeloid derived suppressor cells driving chronic inflammation and tumor progression.

Article Snippet: The Arivale study analysed 3,409 individuals enrolled in a wellness program with extensive characterization of metabolic markers, lifestyle, diet, and stool microbiome 16S amplicon sequencing.

Techniques: Western Blot, Bacteria, Phospho-proteomics, Translocation Assay, Expressing, Membrane, Inhibition, Binding Assay, Activation Assay, Permeability, Activity Assay, Derivative Assay

Journal: Frontiers in Cell and Developmental Biology

Article Title: Dietary Patterns and Associated Microbiome Changes that Promote Oncogenesis

doi: 10.3389/fcell.2021.725821

Figure Lengend Snippet: Effect of Western diet on the gut microbiome and extraintestinal pro-carcinogenic pathways. Adherence to Western diet promote the establishment of chronic dysbiosis in the gut, leading to translocation of pathogenic bacteria and toxic bacterial metabolites entering systemic circulation and reaching extraintestinal organs. Main drivers of the pro-carcinogenic and pro-inflammatory processes are LPS, lipoteichoic acid, numerous exotoxins, PAMPs, and deoxycholic acid. When bacterial metabolites reach liver, pancreas, and breast, they bind to receptors, such as TLR4 to activate signaling pathways that drives inflammation and proliferation.

Article Snippet: The Arivale study analysed 3,409 individuals enrolled in a wellness program with extensive characterization of metabolic markers, lifestyle, diet, and stool microbiome 16S amplicon sequencing.

Techniques: Western Blot, Translocation Assay, Bacteria, Protein-Protein interactions

Journal: Frontiers in Cell and Developmental Biology

Article Title: Dietary Patterns and Associated Microbiome Changes that Promote Oncogenesis

doi: 10.3389/fcell.2021.725821

Figure Lengend Snippet: Effect of alcohol overconsumption on the gut microbiome and intestinal homeostasis. Over consumption of alcohol positively correlates with the severity of manifested dysbiosis in the lower bowel and occurrence liver diseases. Dysbiosis resulted from alcohol overconsumption, leads to the increase in abundance of pathogenic bacteria, increase in viral diversity, production of LPS, secondary bile acids and activation of farnesoid X receptor (FXR). Alcohol overconsumption also downregulates production of SCFAs, results in decreased alpha and fungal diversity and decrease reabsorption of primary bile acids (PAMPs = pathogen associated molecular patterns).

Article Snippet: The Arivale study analysed 3,409 individuals enrolled in a wellness program with extensive characterization of metabolic markers, lifestyle, diet, and stool microbiome 16S amplicon sequencing.

Techniques: Bacteria, Activation Assay