Gut Microbiota and Cancer: From Pathogenesis to Therapy

In the paper

“Multiple studies using different mice deficient for inflammasomes components (including NLRP3, NLRP1, NLRP6, NLRC4 and Caspase-1) found that the inflammasomes protect mice from colitis-associated CRC [120,121,122,123,124].”

What the sources say

• Partly supported

  The section on colitis-associated tumorigenesis (page unavailable) reports increased tumor formation in Nlrp3-deficient mice and similar findings for caspase-1-deficient mice. The section on intestinal epithelial homeostasis also reports protection by NLRC4. The copy does not report colitis-associated colorectal cancer findings from NLRP1- or NLRP6-deficient mice; its reference to NLRP1 concerns expression in human tissues. (LLM, conf=0.87)

  cites [120] Zaki, 2011, The NLRP3 inflammasome: Contributions to intestinal homeostasis, Trends Immunol. sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract reports that NLRP3, PYCARD, and caspase-1 protect mice against colitis-associated cancer. It also reports no significant difference for NLRC4-deficient mice, while the Experimental animals section lists no NLRP1- or NLRP6-deficient mice. This source therefore supports the claim for some, but not all, of the listed components. (LLM, conf=0.90)

  cites [121] Allen, 2010, The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer, J. Exp. Med. sourceExperimental — accuracy not yet measured
• Not checked yetcites [122] Hu, 2010, Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4, Proc. Natl. Acad. Sci. USA source
• Not checked yetcites [123] Yeretssian, 2010, Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases, Immunity source
• Partly supported

  The Results section reports significantly greater AOM/DSS-induced tumor burdens in Nlrp3-, ASC-, and Casp1-deficient mice than in wild-type mice, supporting a protective role for those inflammasome components. This paper does not establish the same finding for NLRP1, NLRP6, or NLRC4; the sentence cites several studies collectively, but does not specify which citation supports those additional components. Page numbers are unavailable in our copy. (LLM, conf=0.87)

  cites [124] Zaki, 2010, IL-18 production downstream of the NLRP3 inflammasome confers protection against colorectal tumor formation, J. Immunol. sourceExperimental — accuracy not yet measured

In the paper

“The probiotics, including Lactobacilli, are studied as supportive treatment for chemotherapy-associated gastrointestinal toxicity, thanks to their ability to restore gut microbial balance, as further described in Section 5 [86].”

What the sources say

• ?Could not verify

  The Conclusion (page unavailable) discusses supportive strategies for chemotherapy-related GI toxicity, and the GLUCAGON-LIKE PEPTIDE-1 AND -2 section discusses GLP-based approaches. Neither addresses probiotics or Lactobacilli restoring gut microbial balance; searches for those terms and intestinal flora found no supporting passage in our copy. (LLM, conf=0.76)

  cites [86] Lee, 2014, Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer: The role of inflammation, World J. Gastroenterol. sourceExperimental — accuracy not yet measured

In the paper

“The explanation is that commensal microbiome members within the gut of the mice might produce TLR agonists, thus promoting the rise of an oxidative stress milieu and tumor cell death.”

What the sources say

• Partly supported

  The paper’s discussion of oxaliplatin experiments (section labeled Abstract; page unavailable) suggests that gut commensals may prime tumor-associated cells through TLR-related microbial product sensing. It also links commensal-dependent reactive oxygen species production to chemotherapy-induced tumor damage. The proposed TLR-agonist mechanism was investigated rather than directly demonstrated, and the oxidative damage and tumor-cell death described depend on platinum chemotherapy—not on microbial products alone. (LLM, conf=0.85)

  cites [165] Iida, 2013, Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment, Science sourceExperimental — accuracy not yet measured

In the paper

“In fact, the gut microbiome can either be tumor-suppressive or oncogenic [22,23].”

What the sources say

• Not checked yetcites [22] Fulbright, L.E., Ellermann, M., and Arthur, J.C. (2017). The microbiome and the hallmarks of cancer. PLoS Pathog., 13. source
• Not checked yetcites [23] Gagnaire, 2017, Collateral damage: Insights into bacterial mechanisms that predispose host cells to cancer, Nat. Rev. Microbiol. source

In the paper

“A number of these hormones can be sensed by the gut bacteria, as in the case of leptin and ghrelin, which, in turn, finely tune the gut microbiota composition in rodents [29,30].”

What the sources say

• Not checked yetcites [29] Ravussin, 2012, Responses of gut microbiota to diet composition and weight loss in lean and obese mice, Obesity source
• Not checked yetcites [30] Queipo-Ortuño, M.I., Seoane, L.M., Murri, M., Pardo, M., Gomez-Zumaquero, J.M., Cardona, F., Casanueva, F., and Tinahones, F.J. (2013). Gut microbiota composition in male rat models under different nutritional status and physical activity and its association with serum leptin and ghrelin levels. PLoS ONE, 8. source

In the paper

“Metabolomics and metagenomics studies highlighted the dual role of the gastro-intestinal microbiome in cancer prevention, tumorigenesis and anti-cancer therapy [21].”

What the sources say

• Not checked yetcites [21] Knight, 2017, The Microbiome and Human Biology, Annu. Rev. Genom. Hum. Genet. source

In the paper

“In particular, it is known that host’s hormones and neuro-hormones are able to modify the gut microbiome composition, as during stress response [27].”

What the sources say

• Not checked yetcites [27] Sandrini, 2015, Microbial endocrinology: Host-bacteria communication within the gut microbiome, J. Endocrinol. source

In the paper

“Among the human symbiotic microbial populations, the gut microbiota is the most extensively studied and it deeply influences host’s homeostasis [7].”

What the sources say

• Not checked yetcites [7] Feng, 2018, Gut Microbiota: An Integral Moderator in Health and Disease, Front. Microbiol. source

In the paper

“Progresses in metagenomics studies, together with the advancements in transcriptomics and metabolomics, allowed to describe the impact of individual bacterial species on host’s health [15,16].”

What the sources say

• Not checked yetcites [15] Sefik, 2017, Mining the Human Gut Microbiota for Immunomodulatory Organisms, Cell source
• Not checked yetcites [16] Haber, 2017, A single-cell survey of the small intestinal epithelium, Nature source

In the paper

“The link has been found both with local gastro-intestinal cancers, as well as with other distal tumors [20].”

What the sources say

• Not checked yetcites [20] Goodman, 2018, The microbiome and cancer, J. Pathol. source

In the paper

“In the recent years, numerous evidences pointed towards the central role of commensal bacteria colonizing body surfaces as key determinants of health or pathologic conditions, including cancer [6].”

What the sources say

• Not checked yetcites [6] Zhang, 2015, Impacts of gut bacteria on human health and diseases, Int. J. Mol. Sci. source

In the paper

“Importantly, gastro-intestinal dysbiosis has been linked with both local and distant tumors [52].”

What the sources say

• Not checked yetcites [52] Sheflin, 2014, Cancer-promoting effects of microbial dysbiosis, Curr. Oncol. Rep. source

In the paper

“Although only Helicobacter pylori is included among class I carcinogens by the World Health Organization (WHO) [57], several studies performed in cell culture and animal models, assessed the ability of additional microbiota populations to affect host’s DNA replication and integrity [58,59,60].”

What the sources say

• Not checked yetcites [57] Moss, 2017, The Clinical Evidence Linking, Cell. Mol. Gastroenterol. Hepatol. source

In the paper

“For example, Helicobacter pylori or Bacteroides fragilis are both able to activate the host’s spermine oxidase, which, in turn, generates hydrogen peroxide and reactive oxygen species (ROS)-induced accumulation of DNA damage [77,78].”

What the sources say

• Not checked yetcites [77] Goodwin, 2011, Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis, Proc. Natl. Acad. Sci. USA source
• Not checked yetcites [78] Chaturvedi, 2011, Spermine oxidase mediates the gastric cancer risk associated with Helicobacter pylori CagA, Gastroenterology source

In the paper

“Importantly, SCFAs have a role in controlling the glucose and the lipidic metabolism, by affecting the intestine hormone peptide secretion, including Peptide YY (PYY) and Glucagon-like peptide 1 (GLP-1) [37].”

What the sources say

• Not checked yetcites [37] Clarke, 2014, Minireview: Gut microbiota: The neglected endocrine organ, Mol. Endocrinol. source

In the paper

“In fact, it has been widely studied the link between bacterial secretion of the β-glucuronidase enzymes and the increased bioavailability of the host’s estrogen hormones (both originating from hepatic catabolism and phytoestrogens).”

What the sources say

• Not checked yetcites [81] Plottel, 2011, Microbiome and malignancy, Cell Host Microbe source

In the paper

“One good example is ferricrome metabolite secreted from Lactobacillus casei, able to trigger apoptosis in tumor cells via JNK pathway direct activation [44].”

What the sources say

• Not checked yetcites [44] Konishi, 2016, Probiotic-derived ferrichrome inhibits colon cancer progression via JNK-mediated apoptosis, Nat. Commun. source

In the paper

“Regarding cancer, within a dysbiotic gut, certain bacterial pathogens can negatively affect either the host’s metabolism or the host’s gut and immune system functionalities, thereby triggering tumor growth [51].”

What the sources say

• Not checked yetcites [51] Rea, 2018, Microbiota effects on cancer: From risks to therapies, Oncotarget source

In the paper

“In the same way, the product of the cytotoxin associated gene A (CagA) from Helicobacter pylori, induces the proteasome-mediated degradation of p53 in gastric epithelial cells, by interfering with the host’s AKT pathway, thus promoting the rise of gastric cancer [66].”

What the sources say

• Not checked yetcites [66] Buti, 2011, Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host, Proc. Natl. Acad. Sci. USA source

In the paper

“Gut dysbiosis and the consequent development of pathogenic populations within the gut microbiota, may contribute to a wide variety of pathologies, even in sites distant from the gut, ranging from bowel inflammation, to neurodegenerative diseases (including Parkinson’s disease) and cancer [43,49,50].”

What the sources say

• Not checked yetcites [43] Warzecha, 2016, Synergic Interaction of Rifaximin and Mutaflor (Escherichia coli Nissle 1917) in the Treatment of Acetic Acid-Induced Colitis in Rats, Gastroenterol. Res. Pract.
• Not checked yetcites [49] Lane, 2017, The microbiota in inflammatory bowel disease: Current and therapeutic insights, J. Inflamm. Res. source
• Not checked yetcites [50] Caputi, V., and Giron, M.C. (2018). Microbiome-Gut-Brain Axis and Toll-Like Receptors in Parkinson’s Disease. Int. J. Mol. Sci., 19. source

In the paper

“When gut dysbiosis is coupled with an increase in the β-glucuronidase-secreting bacteria, such as Clostridium leptum and Clostridium coccoides, the enzyme deconjugates liver-catabolized and plant-derived estrogens, enabling them to bind and activate the estrogen receptors expressed by target cells [81].”

What the sources say

• Not checked yetcites [81] Plottel, 2011, Microbiome and malignancy, Cell Host Microbe source

In the paper

“For example, gut bacterial butyrate and propionate are able to inhibit host’s tumor cells histone deacetylases with a general anti-cancer effect.”

What the sources say

• Not checked yetcites [38] Jan, 2002, Propionibacteria induce apoptosis of colorectal carcinoma cells via short-chain fatty acids acting on mitochondria, Cell Death Differ. source
• Not checked yetcites [39] Wei, 2016, Butyrate production from high-fiber diet protects against lymphoma tumor, Leuk. Lymphoma source

In the paper

“In fact, during pathogenic infections, when the gut microbiome is affected by dysbiosis, bacterial pathogens can expand and release a large amount of toxins which, in turn, induce host’s DNA breaks, thus contributing to genomic instability, tumor initiation and progression in those predisposed cells [61,62,63].”

What the sources say

• Not checked yetcites [61] Halazonetis, 2004, Constitutively active DNA damage checkpoint pathways as the driving force for the high frequency of p53 mutations in human cancer, DNA Repair source
• Not checked yetcites [62] Yao, Y., and Dai, W. (2014). Genomic Instability and Cancer. J. Carcinog. Mutagen., 5.
• Not checked yetcites [63] Frisan, 2016, Bacterial genotoxins: The long journey to the nucleus of mammalian cells, Biochim. Biophys. Acta source

In the paper

“Additionally, it has been reported that gut resident commensals can produce hormone-like metabolites, such as the short chain fatty acids (SCFAs), as a consequence of the bacterial fermentation of dietary fibers in the large intestine [36].”

What the sources say

• Not checked yetcites [36] Fukui, 2018, Role of Gut Microbiota-Gut Hormone Axis in the Pathophysiology of Functional Gastrointestinal Disorders, J. Neurogastroenterol. Motil. source

In the paper

“Moreover, a number of gut commensals can modify small aminoacids into signaling molecules, as for example histidine to histamine or glutamate to γ-aminobutyric acid (GABA) [35].”

What the sources say

• Not checked yetcites [35] Mohajeri, 2018, The role of the microbiome for human health: From basic science to clinical applications, Eur. J. Nutr. source

In the paper

“Helicobacter pylori produced protein CagA was the first bacterial protein shown to be involved in human cancer [56].”

What the sources say

• Not checked yetcites [56] Hatakeyama, 2017, Structure and function of Helicobacter pylori CagA, the first-identified bacterial protein involved in human cancer, Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. source

In the paper

“Estrogen receptors activation promotes cell proliferation in tissues responding to estrogens, as breast and endometrium [82].”

What the sources say

• Not checked yetcites [82] Sergio, 2003, Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells, Endocr. Relat. Cancer

In the paper

“Several commensal bacteria play a probiotic role thanks to their capability to confer health benefits, either protecting against gut dysbiosis or enhancing host’s immune defense mechanisms [22,24].”

What the sources say

• Not checked yetcites [22] Fulbright, L.E., Ellermann, M., and Arthur, J.C. (2017). The microbiome and the hallmarks of cancer. PLoS Pathog., 13. source
• Not checked yetcites [24] Zitvogel, 2017, Anticancer effects of the microbiome and its products, Nat. Rev. Microbiol. source

In the paper

“The administration of such probiotics, as for example Mutaflor (Escherichia coli Nissle 1917) combined with the intestinal antibiotic rifaximin, demonstrated a clear anti-inflammatory activity, enhancing the anti-inflammatory effect of rifaximin in a rat model of inflammatory bowel disease [43].”

What the sources say

• Not checked yetcites [43] Warzecha, 2016, Synergic Interaction of Rifaximin and Mutaflor (Escherichia coli Nissle 1917) in the Treatment of Acetic Acid-Induced Colitis in Rats, Gastroenterol. Res. Pract.

In the paper

“In the same direction, the Salmonella enterica effector avirulence protein A (AvrA) is able to translocate into host’s cells and activate β-catenin via its intrinsic de-ubiquitinase activity [70].”

What the sources say

• Not checked yetcites [70] Lu, 2014, Enteric bacterial protein AvrA promotes colonic tumorigenesis and activates colonic beta-catenin signaling pathway, Oncogenesis source

In the paper

“Such mechanism is mediated by the bacterial virulence factor Fap2, able to bind and block the NK inhibitory receptor TGIT, thus arresting the NK-mediated tumor cell attack [80].”

What the sources say

• Not checked yetcites [80] Gur, 2015, Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack, Immunity source

In the paper

“Such mechanism is the cause of the anti-tumoral in vitro and in vivo effect of butyrate observed in both colorectal cancer (CRC) and lymphoma [38,39].”

What the sources say

• Not checked yetcites [38] Jan, 2002, Propionibacteria induce apoptosis of colorectal carcinoma cells via short-chain fatty acids acting on mitochondria, Cell Death Differ. source
• Not checked yetcites [39] Wei, 2016, Butyrate production from high-fiber diet protects against lymphoma tumor, Leuk. Lymphoma source

In the paper

“Additionally, changes in the host’s lifestyle, diet and immune system are among the factors which deeply influence the microbiota composition and activity [85].”

What the sources say

• Not checked yetcites [85] Conlon, 2014, The impact of diet and lifestyle on gut microbiota and human health, Nutrients source

In the paper

“In line with that, many preclinical studies performed using germ-free mice models demonstrated how the gut microbiome is able to deeply affect cancer genesis and progression through different mechanisms [33,54,55].”

What the sources say

• Not checked yetcites [33] Bultman, 2014, Emerging roles of the microbiome in cancer, Carcinogenesis source
• Not checked yetcites [54] Arthur, 2012, Intestinal inflammation targets cancer-inducing activity of the microbiota, Science source
• Not checked yetcites [55] Homburg, 2006, Escherichia coli induces DNA double-strand breaks in eukaryotic cells, Science source

In the paper

“Moreover, bacterial derived pyridoxine, a group B vitamin, can stimulate host’s antitumoral immunosurveillance [42].”

What the sources say

• Not checked yetcites [42] Aranda, 2015, Immune-dependent antineoplastic effects of cisplatin plus pyridoxine in non-small-cell lung cancer, Oncogene source

In the paper

“In the same way, the monophosphoryl lipid A (MPL) from Salmonella enterica has been currently used as adjuvant in the vaccine formulation used against anti-cervical carcinoma [41].”

What the sources say

• Not checked yetcites [41] Paavonen, 2009, Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): Final analysis of a double-blind, randomised study in young women, Lancet source

In the paper

“In fact, IL-18 KO or IL-18R KO mice are also highly sensitive to colitis-associated CRC [124,125].”

What the sources say

• Not checked yetcites [124] Zaki, 2010, IL-18 production downstream of the NLRP3 inflammasome confers protection against colorectal tumor formation, J. Immunol. source
• Not checked yetcites [125] Salcedo, 2010, MyD88-mediated signaling prevents development of adenocarcinomas of the colon: Role of interleukin 18, J. Exp. Med. source

In the paper

“Importantly, the gut microbiome may also influence the outcome of the specific inflammasomes activation [119].”

What the sources say

• Not checked yetcites [119] Kantono, 2017, Inflammasomes and Cancer: The Dynamic Role of the Inflammasome in Tumor Development, Front. Immunol. source

In the paper

“They can detect pathogenic and non-pathogenic microorganisms-derived molecules, as well as sterile stressors molecules, via a subset of cytoplasmic pattern recognition receptors (PRRs), called NOD-like Receptors (NLRs) [116].”

What the sources say

• Not checked yetcites [116] Levy, 2015, Inflammasomes and the microbiota–partners in the preservation of mucosal homeostasis, Semin. Immunopathol. source

In the paper

“LGG is a gut resident bacterium known to have several anti-inflammatory effects within the intestinal microenvironment [88,89,90].”

What the sources say

• Not checked yetcites [88] Khailova, 2017, Lactobacillus rhamnosus GG treatment improves intestinal permeability and modulates inflammatory response and homeostasis of spleen and colon in experimental model of Pseudomonas aeruginosa pneumonia, Clin. Nutr. source
• Not checked yetcites [89] Wang, 2017, An LGG-derived protein promotes IgA production through upregulation of APRIL expression in intestinal epithelial cells, Mucosal Immunol. source
• Not checked yetcites [90] Fong, 2016, Immunomodulation of Lactobacillus rhamnosus GG (LGG)-derived soluble factors on antigen-presenting cells of healthy blood donors, Sci. Rep. source

In the paper

“On this line, it has been recently observed how LGG attenuates NLRP6-mediated inflammasomes activation in the intestine [113].”

What the sources say

• Not checked yetcites [113] Yu, 2017, Anti-inflammatory capacity of Lactobacillus rhamnosus GG in monophasic variant Salmonella infected piglets is correlated with impeding NLRP6-mediated host inflammatory responses, Vet. Microbiol. source

In the paper

“Dysregulation of inflammasomes results in a variety of diseases, ranging from autoimmunity to cancer [118].”

What the sources say

• Not checked yetcites [118] Zitvogel, 2012, Inflammasomes in carcinogenesis and anticancer immune responses, Nat. Immunol. source

In the paper

“In those cases, IL-1β is the key player, acting as pro-inflammatory, tumor-promoting trigger [126,127,128,129,130].”

What the sources say

• Not checked yetcites [126] McLoed, 2016, Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer, Cell Rep. source
• Not checked yetcites [127] Okamoto, 2010, Constitutively active inflammasome in human melanoma cells mediating autoinflammation via caspase-1 processing and secretion of interleukin-1beta, J. Biol. Chem. source
• Not checked yetcites [128] Zhong, 2016, Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation, Cell source
• Not checked yetcites [129] Kolb, 2016, Obesity-associated NLRC4 inflammasome activation drives breast cancer progression, Nat. Commun. source
• Not checked yetcites [130] Daley, 2017, NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma, J. Exp. Med. source

In the paper

“Several potential benefits of LGG administration to cancer patients have been foregrounded since long time, by in vitro, in vivo and clinical studies, as recently reviewed by Banna et al. [94].”

What the sources say

• Not checked yetcites [94] Banna, 2017, GG: An Overview to Explore the Rationale of Its Use in Cancer, Front. Pharmacol. source

In the paper

“This could be mediated through the direct modulation of several host’s proliferation pathways, such as mTOR or WNT [107].”

What the sources say

• Not checked yetcites [107] Nouri, 2016, Differentially Modulate mTOR and WNT/β-Catenin Pathways in Different Cancer Cell Lines, Iran J. Cancer Prev.

In the paper

“Importantly, among all the stimuli, inflammasomes are also capable of sensing host-microbiota interactions, thus taking an active role in response to commensal and pathogenic bacteria [116].”

What the sources say

• Not checked yetcites [116] Levy, 2015, Inflammasomes and the microbiota–partners in the preservation of mucosal homeostasis, Semin. Immunopathol. source

In the paper

“In fact, treatment with LGG in a rat dimethyl hydrazine-induced colon cancer model, is able to reduce the tumor mass through the modulation of the commensal gut microbiome and the downregulation of pro-inflammatory molecules produced by both gastrointestinal cells and gut-resident immune cells [110].”

What the sources say

• Not checked yetcites [110] Gamallat, 2016, Lactobacillus rhamnosus induced epithelial cell apoptosis, ameliorates inflammation and prevents colon cancer development in an animal model, Biomed. Pharmacother. source

In the paper

“It has been demonstrated within several in vitro tumor models (including colorectal, ovary, breast, cervical, hepatic and oral squamous) that LGG is able to exert either anti-proliferative effects or anti-metastatic effects [102,103,104,105,106].”

What the sources say

• Not checked yetcites [102] Orlando, 2016, Antiproliferative effects on colon adenocarcinoma cells induced by co-administration of vitamin K1 and Lactobacillus rhamnosus GG, Int. J. Oncol. source
• Not checked yetcites [103] Nouri, 2016, Dual Anti-Metastatic and Anti-Proliferative Activity Assessment of Two Probiotics on HeLa and HT-29 Cell Lines, Cell J.
• Not checked yetcites [104] Zhao, 2017, Protective effect of surface layer proteins isolated from four Lactobacillus strains on hydrogen-peroxide-induced HT-29 cells oxidative stress, Int. J. Biol. Macromol. source
• Not checked yetcites [105] Behzadi, 2017, The inhibitory impacts of Lactobacillus rhamnosus GG-derived extracellular vesicles on the growth of hepatic cancer cells, Microb. Pathog. source
• Not checked yetcites [106] Cheng, 2017, Lactobacillus raises in vitro anticancer effect of geniposide in HSC-3 human oral squamous cell carcinoma cells, Exp. Ther. Med.

In the paper

“LGG administration can also change gene expression in intestinal porcine epithelial cells and intestine myo-fibroblasts towards an anti-inflammatory profile [114,115].”

What the sources say

• Not checked yetcites [114] Taranu, I., Marin, D.E., Braicu, C., Pistol, G.C., Sorescu, I., Pruteanu, L.L., Berindan Neagoe, I., and Vodnar, D.C. (2018). In Vitro Transcriptome Response to a Mixture of Lactobacilli Strains in Intestinal Porcine Epithelial Cell Line. Int. J. Mol. Sci., 19. source
• Not checked yetcites [115] Uribe, 2018, Lactobacillus rhamnosus GG increases COX-2 expression and PGE, Cell. Microbiol. source

In the paper

“In detail, the inflammasomes complex mediates the activation of caspase-1 which, in turn, triggers the secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) as well as pyroptosis, a form of programmed cell death [117].”

What the sources say

• Not checked yetcites [117] Franchi, 2009, The inflammasome: A caspase-1-activation platform that regulates immune responses and disease pathogenesis, Nat. Immunol. source

In the paper

“As a direct consequence, without a healthy gut microbiota there is a decreased microbiota-dependent ROS production, thus a less effective chemotherapeutic response [165].”

What the sources say

• Not checked yetcites [165] Iida, 2013, Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment, Science source

In the paper

“If cisplatin is combined with probiotics, such as Lactobacilli, mice show an improved response to therapy.”

What the sources say

• Not checked yetcites [166] Gui, 2015, Well-balanced commensal microbiota contributes to anti-cancer response in a lung cancer mouse model, Genet. Mol. Res. source

In the paper

“The mechanism behind involves the direct bacterial stimulation of host’s NK cells and macrophages, in turn responsible of a strong antitumoral immune response [157].”

What the sources say

• Not checked yetcites [157] Hoesl, 2005, The probiotic approach: An alternative treatment option in urology, Eur. Urol. source

In the paper

“Another widely used anti-cancer molecule, cyclophosphamide, coupled with oral bacterial administration (Lactobacillus johonsoni and Enterococcus hirae), leads to the conversion of T cells from naïve to pro-inflammatory T helper 17 (TH17), with the final effect of improving cyclophosphamide efficacy in tumor-bearing mice [167,168].”

What the sources say

• Not checked yetcites [167] Viaud, 2013, The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide, Science source
• Not checked yetcites [168] Waldschmitt, 2016, Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects, Immunity source

In the paper

“For example, it has been observed that the intradermal injection of Mycobacterium obuense in melanoma and in pancreatic ductal carcinoma activates antitumoral immune response, acting on host’s antigen presenting cells (APCs) and cytotoxic T cells [159,160].”

What the sources say

• Not checked yetcites [159] Stebbing, 2012, An intra-patient placebo-controlled phase I trial to evaluate the safety and tolerability of intradermal IMM-101 in melanoma, Ann. Oncol. source
• Not checked yetcites [160] Dalgleish, 2016, Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer, Br. J. Cancer source

In the paper

“Commensal bacteria and their bioproducts induce inflammasomes activation and IL-18 production in the gut, which, in turn, prevents intestinal barrier disruption and dysbiosis [121,124,131,132,133].”

What the sources say

• Not checked yetcites [121] Allen, 2010, The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer, J. Exp. Med. source
• Not checked yetcites [124] Zaki, 2010, IL-18 production downstream of the NLRP3 inflammasome confers protection against colorectal tumor formation, J. Immunol. source
• Not checked yetcites [131] Chen, 2011, A functional role for NLRP6 in intestinal inflammation and tumorigenesis, J. Immunol. source
• Not checked yetcites [132] Williams, 2015, The NLRP1 inflammasome attenuates colitis and colitis-associated tumorigenesis, J. Immunol. source
• Not checked yetcites [133] Zaki, 2010, The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis, Immunity source

In the paper

“Dysbiosis has been observed in mice deficient for inflammasomes components, including NLRP6, ASC, caspase-1, and IL-18 [131,132,133,134].”

What the sources say

• Not checked yetcites [131] Chen, 2011, A functional role for NLRP6 in intestinal inflammation and tumorigenesis, J. Immunol. source
• Not checked yetcites [132] Williams, 2015, The NLRP1 inflammasome attenuates colitis and colitis-associated tumorigenesis, J. Immunol. source
• Not checked yetcites [133] Zaki, 2010, The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis, Immunity source
• Not checked yetcites [134] Elinav, 2012, Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity, Nature source

In the paper

“On their side, tumor cells, thanks to their genetic instability, constantly evolve novel strategies to escape from such immunosurveillance and expand within the host [147].”

What the sources say

• Not checked yetcites [147] Thorsson, 2018, The Immune Landscape of Cancer, Immunity source

In the paper

“It has been observed that the bacteria, by inducing a local immune response, helped to reduce the relapse of the tumor [155].”

What the sources say

• Not checked yetcites [155] Zbar, 1970, Tumor immunity produced by the intradermal inoculation of living tumor cells and living Mycobacterium bovis (strain BCG), Science source

In the paper

“Although these results are encouraging, many clinical trials are currently ongoing in order to ameliorate the patients’ clinical outcomes, given bacteria-associated toxicity, mainly correlated to their long half-life [163].”

What the sources say

• Not checked yetcites [163] Kramer, 2018, Bacterial Therapy of Cancer: Promises, Limitations, and Insights for Future Directions, Front. Microbiol. source

In the paper

“With regard to chemotherapy, it has been reported how tumor-bearing mice, either germ free or having their gut microbiota depleted after antibiotics therapy, do not respond to oxaliplatin drug treatment.”

What the sources say

• Not checked yetcites [165] Iida, 2013, Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment, Science source

In the paper

“Moreover, it has been discovered how oral administration of Lactobacillus casei decreased superficial bladder cancer recurrence [156].”

What the sources say

• Not checked yetcites [156] Aso, 1992, Prophylactic effect of a Lactobacillus casei preparation on the recurrence of superficial bladder cancer. BLP Study Group, Urol. Int. source

In the paper

“Given the multiplicity of effects that gut microbiome may play on the host’s immune system, it is not surprising that emerging studies strongly linked the patients’ microbiome composition with the intrinsic efficacy of immune checkpoint inhibitors-based immunotherapy, in the treatments of different solid tumors [170,171,172].”

What the sources say

• Not checked yetcites [170] Routy, 2018, Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors, Science source
• Not checked yetcites [171] Gopalakrishnan, 2018, Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients, Science source
• Not checked yetcites [172] Matson, 2018, The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients, Science source

In the paper

“In parallel, Gopalakrishnan et al. [171] demonstrated through metagenomics analysis of melanoma patients’ fecal samples that the anti-PD1 responders’ microbiome was different in composition compared with that of non-responders.”

What the sources say

• Not checked yetcites [171] Gopalakrishnan, 2018, Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients, Science source

In the paper

“The authors found that this probiotic was able to downregulate pro-inflammatory cytokines in treated patients, although with lacking effects on the post-operative infection rates [99].”

What the sources say

• Not checked yetcites [99] Consoli, 2016, Randomized Clinical Trial: Impact of Oral Administration of Saccharomyces boulardii on Gene Expression of Intestinal Cytokines in Patients Undergoing Colon Resection, JPEN J. Parenter. Enter. Nutr. source

In the paper

“In line with this observation, it has been seen that patients treated with anti-CTLA4 antibody, toxic side effects are mediated by an increased abundance of Firmicutes, such as Faecalisbacterium, and a decreased abundance of Bacterioides [178,179].”

What the sources say

• Not checked yetcites [178] Chaput, 2017, Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab, Ann. Oncol. source
• Not checked yetcites [179] Frankel, 2017, Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients, Neoplasia source

In the paper

“The authors found that this probiotic was able to downregulate pro-inflammatory cytokines in treated patients, although with lacking effects on the post-operative infection rates [99].”

What the sources say

• Not checked yetcites [99] Consoli, 2016, Randomized Clinical Trial: Impact of Oral Administration of Saccharomyces boulardii on Gene Expression of Intestinal Cytokines in Patients Undergoing Colon Resection, JPEN J. Parenter. Enter. Nutr. source

In the paper

“Subsequently, in 2014, a randomized double-blind controlled trial assessed the beneficial administration of the probiotics Bifilact (Lactobacillus acidophilus LAC361 and Bifidobacterium longum BB536) on significantly reducing moderate and severe treatment-induced diarrhea during pelvic radiation [96].”

What the sources say

• Not checked yetcites [96] Demers, 2014, A randomized double-blind controlled trial: Impact of probiotics on diarrhea in patients treated with pelvic radiation, Clin. Nutr. source

In the paper

“Several preclinical studies and clinical trials share the common goal of evaluating the overall efficacy of probiotics in decreasing the risk and the severity of such anti-cancer treatments related-toxicity, mainly diarrhea and mucositis [187,188].”

What the sources say

• Not checked yetcites [187] Alexander, 2017, Gut microbiota modulation of chemotherapy efficacy and toxicity, Nat. Rev. Gastroenterol. Hepatol. source
• Not checked yetcites [188] Sokol, 2018, The microbiota: An underestimated actor in radiation-induced lesions?, Gut source

In the paper

“Vetizou et al. demonstrated that the efficacy of anti-CTLA4 antibodies in reducing sarcoma tumor growth in mice is significantly increased when the gut microbiome is enriched in Bacteroides fragilis and Burkholderia cepacia [175].”

What the sources say

• Not checked yetcites [175] Pitt, 2015, Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota, Science source

In the paper

“In particular, Routy et al. [170] found that melanoma patients treated with antibiotics along with the anti-PD1/anti-PD-L1 immunotherapy had a lower survival rate.”

What the sources say

• Not checked yetcites [170] Routy, 2018, Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors, Science source

In the paper

“In 2016, another double-blind, randomized trial demonstrated that the administration of a combination of prebiotics and probiotics to patients subjected to CRC resection may alleviate irritable bowel syndrome (IBS), often following the operation [98].”

What the sources say

• Not checked yetcites [98] Theodoropoulos, 2016, Synbiotics and gastrointestinal function-related quality of life after elective colorectal cancer resection, Ann. Gastroenterol.

In the paper

“Anti-PD1 responders were enriched in two phyla (Akkermansia and Alistipes).”

What the sources say

• Not checked yetcites [170] Routy, 2018, Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors, Science source

In the paper

“Along the same line, Matson et al. [172] performed a metagenomics characterization of stools samples from melanoma patients treated with immune checkpoint inhibitors, further corroborating the finding that responders showed a different microbiome compared to those not responding to therapy.”

What the sources say

• Not checked yetcites [172] Matson, 2018, The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients, Science source

In the paper

“The same year a randomized clinical trial with CRC patients demonstrated that the perioperative administration of a mixture of prebiotics and probiotics, significantly reduced postoperative infection rates in patients with CRC [101].”

What the sources say

• Not checked yetcites [101] Flesch, 2017, Perioperative synbiotics administration decreases postoperative infections in patients with colorectal cancer: A randomized, double-blind clinical trial, Rev. Col. Bras. Cir. source

In the paper

“Multiple translational studies, published in 2018, further support the pivotal role of the gut microbiome in modulating the response to immune checkpoint blockade [170,171,172].”

What the sources say

• Not checked yetcites [170] Routy, 2018, Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors, Science source
• Not checked yetcites [171] Gopalakrishnan, 2018, Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients, Science source
• Not checked yetcites [172] Matson, 2018, The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients, Science source

In the paper

“In animals, oral gavage of Bacterioides fragilis and Burkholderia cepacia demonstrated an amelioration of such immunotherapy-associated toxic side effects [175].”

What the sources say

• Not checked yetcites [175] Pitt, 2015, Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota, Science source

In the paper

“In 2010, it was assessed for the first time the interaction between probiotic administration, variation of gut microbiota composition, and regulation of intestinal immune-functions in cancer patients undergoing colorectal resection [95].”

What the sources say

• Not checked yetcites [95] Gianotti, 2010, A randomized double-blind trial on perioperative administration of probiotics in colorectal cancer patients, World J. Gastroenterol. source

In the paper

“They identified and functionally proven in vivo the importance of Bifidobacterium longum, Enterococcus faecium and Collinsella aerofaciens in ameliorating anti-PD-L1 efficacy [172].”

What the sources say

• Not checked yetcites [172] Matson, 2018, The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients, Science source

In the paper

“In fact, the heterogenous patients’ microbiome can either be detrimental or beneficial to tumor progression and therapy, depending on its composition and prevailing species.”

In the paper

“On the same line, Sivan et al., found that the efficacy of PD-L1 targeting-antibody in the cure of melanoma in mice is improved in the presence of gut microbiome enriched in Bifidobacterium species [176].”

What the sources say

• Not checked yetcites [176] Sivan, 2015, Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy, Science source

In the paper

“Such treatments may cause diverse and even drastic side effects in patients [180,181,182,183,184,185,186].”

What the sources say

• Not checked yetcites [180] Bajic, 2018, From the Bottom-Up: Chemotherapy and Gut-Brain Axis Dysregulation, Front. Behav. Neurosci. source
• Not checked yetcites [181] Scaife, 2015, Exploiting biological and physical determinants of radiotherapy toxicity to individualize treatment, Br. J. Radiol. source
• Not checked yetcites [182] Griggs, 1998, Reducing the toxicity of anticancer therapy: New strategies, Leuk. Res. source
• Not checked yetcites [183] Samaan, 2018, Gastrointestinal toxicity of immune checkpoint inhibitors: From mechanisms to management, Nat. Rev. Gastroenterol. Hepatol. source
• Not checked yetcites [184] Dong, 2018, Cardiotoxicity of Anticancer Therapeutics, Front. Cardiovasc. Med. source
• Not checked yetcites [185] Shahid, 2018, Cisplatin-induced gastrointestinal toxicity: An update on possible mechanisms and on available gastroprotective strategies, Eur. J. Pharmacol. source
• Not checked yetcites [186] Lawrie, 2018, Interventions to reduce acute and late adverse gastrointestinal effects of pelvic radiotherapy for primary pelvic cancers, Cochrane Database Syst. Rev.

In the paper

“The authors observed in patient’s gut microbiome an increase in the abundance of Clostridiales, Ruminococcaceae and Faecalibacteriae.”

What the sources say

• Not checked yetcites [171] Gopalakrishnan, 2018, Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients, Science source

In the paper

“In line with that observation, this year have witnessed novel breakthrough studies on the association between probiotics and anti-cancer therapy efficacy, as three parallel studies identified specific gut species populating the gastro-intestinal tract of cancer immunotherapy responders, able to improve the efficacy of immunotherapy treatments.”

In the paper

“Moreover, FMT has been used in a Graft Versus Host Disease (GVHD) after allogeneic stem cell transplantation [197].”

What the sources say

• Not checked yetcites [197] Kakihana, 2016, Fecal microbiota transplantation for patients with steroid-resistant acute graft-versus-host disease of the gut, Blood source

In the paper

“Given the observed functions as anti-inflammatory and anti-cancer agent in both cellular and animal models, this probiotic may be suggested to be further characterized as adjuvant in integrated anti-cancer therapies in the future.”

In the paper

“Despite the success of FMT, there is still a lack of control in this procedure because the whole gut microbiota is transferred along with the therapeutic bacteria species.”

In the paper

“Genetics, together with functional studies, highlighted a dual role played by the gut microbiome in cancer.”