Microbiota and host form a complex 'super-organism' in which symbiotic relationships confer benefits to the host in many key aspects of life. However, defects in the regulatory circuits of the host that control bacterial sensing and homeostasis, or alterations of the microbiome, through environmental changes (infection, diet or lifestyle), may disturb this symbiotic relationship and promote disease. Increasing evidence indicates a key role for the bacterial microbiota in carcinogenesis. In this Opinion article, we discuss links between the bacterial microbiota and cancer, with a particular focus on immune responses, dysbiosis, genotoxicity, metabolism and strategies to target the microbiome for cancer prevention.

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The microbiome and cancer

The biological properties of dietary polyphenols are greatly dependent on their bioavailability that, in turn, is largely influenced by their degree of polymerization. The gut microbiota play a key role in modulating the production, bioavailability and, thus, the biological activities of phenolic metabolites, particularly after the intake of food containing high-molecular-weight polyphenols. In addition, evidence is emerging on the activity of dietary polyphenols on the modulation of the colonic microbial population composition or activity. However, although the great range of health-promoting activities of dietary polyphenols has been widely investigated, their effect on the modulation of the gut ecology and the two-way relationship "polyphenols ↔ microbiota" are still poorly understood. Only a few studies have examined the impact of dietary polyphenols on the human gut microbiota, and most were focused on single polyphenol molecules and selected bacterial populations. This review focuses on the reciprocal interactions between the gut microbiota and polyphenols, the mechanisms of action and the consequences of these interactions on human health.

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Benefits of polyphenols on gut microbiota and implications in human health.

Although the importance of human genetic polymorphisms in therapeutic outcomes is well established, the role of our 'second genome' (the microbiome) has been largely overlooked. In this Review, we highlight recent studies that have shed light on the mechanisms that link the human gut microbiome to the efficacy and toxicity of xenobiotics, including drugs, dietary compounds and environmental toxins. Continued progress in this area could enable more precise tools for predicting patient responses and for the development of a new generation of therapeutics based on, or targeted at, the gut microbiome. Indeed, the admirable goal of precision medicine may require us to first understand the microbial pharmacists within.

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The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism

While numerous changes in human lifestyle constitute modern life, our diet has been gaining attention as a potential contributor to the increase in immune-mediated diseases. The Western diet is characterized by an over consumption and reduced variety of refined sugars, salt, and saturated fat. Herein our objective is to detail the mechanisms for the Western diet’s impact on immune function. The manuscript reviews the impacts and mechanisms of harm for our over-indulgence in sugar, salt, and fat, as well as the data outlining the impacts of artificial sweeteners, gluten, and genetically modified foods; attention is given to revealing where the literature on the immune impacts of macronutrients is limited to either animal or in vitro models versus where human trials exist. Detailed attention is given to the dietary impact on the gut microbiome and the mechanisms by which our poor dietary choices are encoded into our gut, our genes, and are passed to our offspring. While today’s modern diet may provide beneficial protection from micro- and macronutrient deficiencies, our over abundance of calories and the macronutrients that compose our diet may all lead to increased inflammation, reduced control of infection, increased rates of cancer, and increased risk for allergic and auto-inflammatory disease.

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Fast food fever: reviewing the impacts of the Western diet on immunity

Antimicrobials have been used extensively as growth promoters (AGPs) in agricultural animal production. However, the specific mechanism of action for AGPs has not yet been determined. The work presented here was to determine and characterize the microbiome of pigs receiving one AGP, tylosin, compared with untreated pigs. We hypothesized that AGPs exerted their growth promoting effect by altering gut microbial population composition. We determined the fecal microbiome of pigs receiving tylosin compared with untreated pigs using pyrosequencing of 16S rRNA gene libraries. The data showed microbial population shifts representing both microbial succession and changes in response to the use of tylosin. Quantitative and qualitative analyses of sequences showed that tylosin caused microbial population shifts in both abundant and less abundant species. Our results established a baseline upon which mechanisms of AGPs in regulation of health and growth of animals can be investigated. Furthermore, the data will aid in the identification of alternative strategies to improve animal health and consequently production.

https://www.pnas.org/content/pnas/109/38/15485.full.pdf

Microbial shifts in the swine distal gut in response to the treatment with antimicrobial growth promoter, tylosin

High dietary lignan exposure is implicated in a reduced breast cancer risk in women. The bacterial transformation of plant lignans to enterolignans is thought to be essential for this effect. To provide evidence for this assumption, gnotobiotic rats were colonized with the lignan-converting bacteria Clostridium saccharogumia, Eggerthella lenta, Blautia producta and Lactonifactor longoviformis (LCC rats). Germ-free rats were used as the control. All animals were fed a lignan-rich flaxseed diet and breast cancer was induced with 7,12-dimethylbenz(a)anthracene. The lignan secoisolariciresinol diglucoside was converted into the enterolignans enterodiol and enterolactone in the LCC but not in the germ-free rats. This transformation did not influence cancer incidence at the end of the 13 weeks experimental period but significantly decreased tumor numbers per tumor-bearing rat, tumor size, tumor cell proliferation and increased tumor cell apoptosis in LCC rats. No differences between LCC and control rats were observed in the expression of the genes encoding the estrogen receptors (ERs) α, ERβ and G-coupled protein 30. The same was true for IGF-1 and EGFR involved in tumor growth. The activity of selected enzymes involved in the degradation of oxidants in plasma and liver was significantly increased in the LCC rats. However, plasma and liver concentrations of reduced glutathione and malondialdehyde, considered as oxidative stress markers, did not differ between the groups. In conclusion, our results show that the bacterial conversion of plant lignans to enterolignans beneficially influences their anticancer effects.

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Lignan transformation by gut bacteria lowers tumor burden in a gnotobiotic rat model of breast cancer

Agrobacterium rhizogenes is gaining intensity in research to develop and produce a large number of commercially important secondary metabolites, such as lignans. Worldwide, lignans are receiving great attention because of their putative beneficial effects on human health. In this study, we investigated the potential of callus and A. rhizogenes, hairy roots, of flax Linum usitatissimum in accumulating lignans, namely, secoisolariciresinol diglucoside (SDG), secoisolariciresinol (SECO) and matairesinol (MAT). Callus cultures were established on Gamborg B5 medium supplemented with 2,4-dichlorophenoxyacetic acid (2,4-D) alone or in combination with 6-benzyladenine or gibberellic acid (GA3). These callus cultures were transformed with A. rhizogenes, which were initiated on 1.0 mg l−1 2,4-D + 0.5 mg l−1 GA3 or 1.0 mg l−1 GA3 media. Both hairy root culture 1 and hairy root culture 2 accumulated SDG, SECO and MAT with a total lignan concentration of 1.227 and 1.057 µmol g−1, respectively. However, non-transformed cultures did not accumulate MAT but accumulated SECO. Determination of total phenolic content by high-performance liquid chromatography revealed higher phenolic acid content in hairy root cultures compared with that in non-transformed cultures. Antioxidant activity, as measured by 2,2-diphenyl-1-picryl-hydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid-free radical scavenging assays, was significantly higher in hairy root cultures than in non-transformed cultures. Furthermore, the extract of hairy root culture showed inhibition of proliferation of human breast cancer cell line (MCF-7).

Lignan accumulation in callus and Agrobacterium rhizogenes-mediated hairy root cultures of flax (Linum usitatissimum)

Background and Objectives: The present study aimed to evaluate the effect of fish oil and Artichoke (Cynara scolymus l.) against diethylnitrosamine (DEN) induced hepa- tocellular carcinoma in rats. Materials and Methods: Animals were divid- ed into 8 groups. Group 1, control rats. Group 2: rats injected with single dose of DEN (100 mg/kg body weight). Groups 3-8 supplemented with dif- ferent concentrations of either fish oil or arti- choke for 25 days before DEN injection. Results: DEN treatment revealed a significant decrease in tissue xanthine oxidase (XO), glu- tathione, glutathione-s-transferase (GST), and a marked increase in malondialdehyde (MDA) and nitric oxide (NO) levels. Vascular endothelial growth factor (VEGF), alpha-fetoprotein (AFP), and ferritin levels showed a significant increase. A significant increase in serum aspartate amino transferase (AST), alanine amino transferase (ALT), gamma glutamyl transferase (GGT), alka- line phosphatase (ALP), and total bilirubin levels were found. A significant decrease in tissue total proteins and serum albumin was observed. The administration of DEN affected the liver cell through occurrence of hepatic cellular degeneration and necrosis.Treatment with fish oil (5%,10%) or ar- tichoke heads or leaves (0.5, 1 g) for 25 days led to significant amelioration of DEN-induced changes in the biochemical parameters. An almost normal his- tological architecture of the liver, in treated groups, was showed as compared to the controls. Conclusions: The results pointed that 10% fish oil and 1 g% leaves of artichoke succeeded to protect from hepatocellular carcinoma to a certain degree. In addition, they may be consid- ered as protective foods against angiogenesis.

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The protective effects of fish oil and artichoke on hepatocellular carcinoma in rats

Background/aim Cape gooseberry is golden-colored spherical fruit commercially produced in Egypt. It is primarily used in folk medicine for treating some diseases. To identify the aroma compounds in Cape gooseberry and to evaluate its antioxidant activities as well as its anticancer (for colon and breast cancers) effects in human cell lines. Materials and methods The volatile compounds were identified using gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). Polyphenols (phenolics and flavonoids) were also determined. Antioxidant activity was determined by three different methods: 2,2΄-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azinobis(3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS), and ferric reducing antioxidant power (FRAP) assays. Anticancer (for colon or breast cancer) activity was determined in cancer cell lines using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Results A total of 34 components of the essential oil were identified by GC and GC-MS. The volatile compounds were grouped in classes of substances, including 11 terpene compounds (six monoterpenoids and five sesquiterpene), 11 esters, five alcohols, two phenolic compounds, two aldehydes, two ketones, and one lactone. Terpenes (monoterpenes and sesquiterpenes) were the most abundant volatile constituents, accounting for the largest portion of the total volatiles (36.09%). The next most abundant compounds were esters, comprising 17.17% of the total volatile components identified. Phenolic compounds were the next most abundant compounds, comprising 16.04% of the total volatiles. Alcohols and aldehydes represented 6.37 and 1.88% of the total volatile compounds, respectively. Ketones and lactones are less abundant in the profile of volatile compounds in Cape gooseberry. Ethanol extract had higher phenolic and flavonoid contents than did hexane extract. As ethanol extract of Cape gooseberry achieved higher antioxidant activity than did hexane extract, it tested as an anticancer (for colon or breast cancer) agent. Cape gooseberry extract was more potent in inhibiting colon cell lines (IC 50 : 142 μg/ml) compared with breast cell line (IC 50 : 371 μg/ml). Conclusion Egyptian Cape gooseberry fruits may be suggested as a potential source of natural antioxidants and anticancer agents.

Volatile compounds, antioxidants, and anticancer activities of Cape gooseberry fruit (Physalis peruviana L.): An in-vitro study

Background/Aim Anethum graveolens L. (dill) (Apiaceae) is one of the most popular culinary herbs in the world. Dill has been cultivated since ancient times, and the use of this plant for medicinal and consumption purposes has been recorded dating back to the Greek and Egyptian civilizations. Dill is widely used to give flavor to food. The aim of this work was to assess the chemical composition of the volatile compounds in dill as well as their hepatoprotective and nephroprotective activity against free radicals generated by paracetamol. Materials and methods The chemical composition of the volatile compounds of dill was assessed by gas chromatography and gas chromatography-mass spectrometry. Four groups of rats were used (the normal control group, the A. graveolens-supplemented group, the paracetamol-intoxicated group, and the A. graveolens-protected group) for studying the effect of plant infusion on panadol (paracetamol)-induced free radicals and hepatotoxicity. Plasma total antioxidant capacity, plasma catalase, cellular glutathione peroxidase, plasma total protein, albumin, alanine amino transferase, aspartate amino transferase, alkaline phosphate, γ-glutamyl transferase, total bilirubin, and direct bilirubin levels were determined. In addition, kidney functions (plasma urea and creatinine) and histopathological and histochemical changes in the liver were investigated. Results The phytochemical results identified volatile components 7-α-hydroxy manool (24.43%), l-carvone (14.28%), limonene (13.9%), epi-α-bisabolol (6.81%), α-terpinene (5.44%), and α-phellandrene (4.63%) as the main constituents. p-Cymene (2.13%), sabinene (1.98), and α-pinene (1.43%) were determined as the minor constituents. The biochemical results showed that a mega dose of paracetamol induced the production of free radicals, which caused damage to hepatocytes and nephrocytes in rats. The aqueous extract of dill revealed high antioxidant properties and acted as an extracellular neutralizer of free radicals. Histopathological and histochemical observations showed severe damage in the liver. Supplementation with dill in paracetamol-intoxicated rats attenuated the damage to the liver. Conclusion The present study revealed that A. graveolens has antihepatotoxic properties that could minimize the deleterious effects generated by hepatotoxin paracetamol, and therefore it can be used as a potent antihepatotoxic agent.

Kadry Z. Ghanem

Papers

Lignan transformation by gut bacteria lowers tumor burden in a gnotobiotic rat model of breast cancer

Lignan accumulation in callus and Agrobacterium rhizogenes-mediated hairy root cultures of flax (Linum usitatissimum)

The protective effects of fish oil and artichoke on hepatocellular carcinoma in rats

Volatile compounds, antioxidants, and anticancer activities of Cape gooseberry fruit (Physalis peruviana L.): An in-vitro study

Volatile compounds and antioxidant activity of the aromatic herb Anethum graveolens