User:Clin93/sandbox

SANDBOX for GROUP 7

https://dashboard.wikiedu.org/courses/Rush_University_Medical_Center/RMC_Summer_Research_Fellowship_2017_(Summer_2017)/home

List of possible topics to write/edit

Chosen topics: 1) Inflammation, 2) Human Microbiota

Article Evaluation

Human Microbiota

Inflammation

Bibliography

Human Microbiota: ______________________________________________________________________________________________________________________________
 * expand on research/ environmental section
 * expand on H. Pylori role in microbiome/gastric cancer <-- go under "Disease" or "Cancer" section(s)
 * https://link.springer.com/article/10.1007%2Fs15010-017-1031-2
 * https://www.ncbi.nlm.nih.gov/pubmed/28560291
 * https://www.ncbi.nlm.nih.gov/pubmed/28560288
 * Add disease sections related to our studies (i.e. HIV w/ gut microbiome, Ulcerative Colitis and Crohn's Disease w/ gut microbiome)
 * https://www.nature.com/nrgastro/journal/v9/n10/full/nrgastro.2012.152.html
 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921503/
 * http://www.nature.com/ajgsup/journal/v1/n1/full/ajgsup20124a.html
 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891875/
 * Edit disease section to include generalized role of microbiome in disease
 * https://www.ncbi.nlm.nih.gov/pubmed/27383982
 * http://www.nature.com/nri/journal/v16/n6/abs/nri.2016.42.html
 * Work on fixing issues identified on the talk page

ARTICLE SECTION(s) TO EDIT

Disease
The role of microbiota in disease is tied into the relationship between microbiota and the adaptive immune system. Recent studies suggest that the various species of microbiota can influence the expression, induction, and differentiation of lymphocytes. The adaptive immune response, in turn, effects the environment of the microbiota which influences the composition of the microbiota. This symbiotic relationship is most notably seen with the gut microbiota and the relative prevalances of different bacteria greatly influence an individual's immune response.

Communities of microflora have been shown to change their behavior in diseased individuals.

Cancer
Although cancer is generally a disease of host genetics and environmental factors, microorganisms are implicated in ≈20% of human malignancies. Mucosal microbes can become part of the tumor microenvironment (TME) of aerodigestive tract malignancies. Intratumoral microbes can affect cancer growth and spread. Gut microbiota also detoxify dietary components, reducing inflammation and balancing host cell growth and proliferation. Coley's toxins were one of the earliest forms of cancer bacteriotherapy. Synthetic biology employs designer microbes and microbiota transplants against tumors.

Microbes and the microbiota affect carcinogenesis in three broad ways: (i) altering the balance of tumor cell proliferation and death, (ii) regulating immune system function and (iii) influencing metabolism of host-produced factors, foods and pharmaceuticals.

Modes of action
Ten microbes are designated by the International Agency for Research on Cancer (IARC) as human carcinogens. Most of these microbes colonize large percentages of the human population, although only genetically susceptible individuals develop cancer. Tumors arising at boundary surfaces, such as the skin, oropharynx and respiratory, digestive and urogenital tracts, harbor a microbiota, which complicates cancer-microbe causality. Substantial microbe presence at a tumor site does not establish association or causal links. Instead, microbes may find the tumor's oxygen tension or nutrient profile supportive. Decreased populations of specific microbes may also increase risks.

Human oncoviruses can drive carcinogenesis by integrating oncogenes into host genomes. Human papillomaviruses (HPV) express oncoproteins such as E6 and E7. Viral integration selectively amplifies host genes in pathways with established cancer roles.

Microbes affect genomic stability, resistance to cell death and proliferative signaling. Many bacteria can damage DNA, to kill competitors/survive. These defense factors can lead to mutational events that contribute to carcinogenesis. Examples include colibactin encoded by the pks locus (expressed by B2 group Escherichia coli as well as by other Enterobacteriaceae), Bacteroides fragilis toxin (Bft) produced by enterotoxigenic B. fragilis and cytolethal distending toxin (CDT) produced by several ε- and γ-proteobacteria. Colibactin is of interest in colorectal carcinogenesis, given the detection of pks+ E. coli in human colorectal cancers and the ability of colibactin-expressing E. coli to potentiate intestinal tumorigenesis in mice. Data also support a role for enterotoxigenic B. fragilis in both human and animal models of colon tumors. Both colibactin and CDT can cause double-stranded DNA damage in mammalian cells. In contrast, Bft acts indirectly by eliciting high levels of reactive oxygen species (ROS), which in turn damage host DNA. Chronically high ROS levels can outpace DNA repair mechanisms, leading to DNA damage and mutations.

β-catenin
Several microbes possess proteins that engage host pathways involved in carcinogenesis. The Wnt/β-catenin signaling pathway, which regulates cells' polarity, growth and differentiation, is one example and is altered in many malignancies. Multiple cancer-associated bacteria can influence β-catenin signaling. Oncogenic type 1 strains of Helicobacter pylori express CagA, which is injected directly into the cytoplasm of host cells and modulates β-catenin to drive gastric cancer. This modulation leads to up-regulation of cellular proliferation, survival and migration genes, as well as angiogenesis—all processes central to carcinogenesis. Helicobacter pylori infection's strong association with gastric cancer is often attributed to the induced chronic inflammation, which causes carcinogenic genetic and epigenetic changes in gastric epithelial cells. This induced instability has been associated with an increased secretion of gastrin in affected cells.

Oral microbiota Fusobacterium nucleatum is associated with human colorectal adenomas and adenocarcinomas and amplified intestinal tumorigenesis in mice. F. nucleatum expresses FadA, a bacterial cell surface adhesion component that binds host E-cadherin, activating β-catenin. Enterotoxigenic B. fragilis, which is enriched in some human colorectal cancers, can stimulate E-cadherin cleavage via Btf, leading to β-catenin activation. Salmonella Typhi strains that maintain chronic infections secrete AvrA, which can activate epithelial β-catenin signaling and are associated with hepatobiliary cancers.

Several of these bacteria are normal microbiota constituents. The presence of these cancer-potentiating microbes and their access to E-cadherin in evolving tumors demonstrate that a loss of appropriate boundaries and barrier maintenance between host and microbe is a critical step in the development of some tumors.

Inflammation
Mucosal surface barriers are subject to environmental insult and must rapidly repair to maintain homeostasis. Compromised host or microbiota resiliency also reduce resistance to malignancy. Cancer and inflammatory disorders can then arise. Once barriers are breached, microbes can elicit proinflammatory or immunosuppressive programs.

Inflammation, whether high-grade as in inflammatory disorders or low-grade as in malignancies and obesity, drive a tumor-permissive milieu. Pro-inflammatory factors such as reactive oxygen and nitrogen species, cytokines and chemokines can also drive tumor growth and spread. Tumors can up-regulate and activate pattern recognition receptors (e.g. toll-like receptors), driving feedforward loops of activation of cancer-associated inflammation regulator NF-κΒ. Cancer-associated microbes appear to activate NF-κΒ signaling within the TME. The activation of NF-κΒ by F. nucleatum may be the result of pattern recognition receptor engagement or FadA engagement of E-cadherin. Other pattern recognition receptors, such as nucleotide-binding oligomerization domain–like receptor (NLR) family members NOD-2, NLRP3, NLRP6 and NLRP12, may play a role in mediating colorectal cancer.

Immune system TME engagement is not restricted to the innate immune system. Once the innate immune system is activated, adaptive immune responses ensue, often with tumor progression. The interleukin-23 (IL-23)–IL-17 axis, tumor necrosis factor–α (TNF-α)–TNF receptor signaling, IL-6–IL-6 family member signaling, and STAT3 activation all represent innate and adaptive pathways contributing to tumor progression and growth.

The microbiota adapts to host changes such as inflammation. Adaptation shift microbiota to a vulnerable tissue site. Genotoxin azoxymethane and colon barrier–disrupting agent dextran sodium sulfate independently result in colon tumors in susceptible mouse strains; combining them accelerates tumorigenesis.

Perturbations to a host immune system coupled with inflammatory stimulus may enrich bacterial clades that attach to host surfaces, invade host tissue, or trigger host inflammatory mediators. Fecal microbiota from NOD2- or NLRP6-deficient mice acquire features that enhance the susceptibility of wild-type mice to caCRC. In mice, gut microbiota modulate colon tumorigenesis, independent of genetic deficiencies. Germ-free mice developed more tumors when colonized from donors with caCRC, once followed by treatments that induced caCRC.

Inflammatory Bowel Disease
Inflammatory Bowel Disease (IBD) consists of two different diseases: ulcerative colitis (UC) and Crohn’s disease (CD) and both of these diseases present with disruptions in the gut microbiota (also known as dysbiosis). This dysbiosis presents itself in the form of decreased microbial diversity in the gut. This dysbiosis has been correlated to defects in host genes that changes the innate immune response in individuals.

Human Immunodeficiency Virus (HIV)
The HIV disease progression influences the composition and function of the gut microbiota, with notable differences between HIV-negative, HIV-positive, and post-ART HIV-positive populations. This is largely due to the fact that ~60% of CD4+ T cells are in the gut-associated lymphoid tissue (GALT) in a healthy individual. In the initial acute phase of HIV, this reservoir is depleted and the environment of the gut is altered. Additionally, HIV decreases the integrity of the gut epithelial barrier function by affecting tight junctions. This breakdown allows for translocation across the gut epithelium, which is thought to contribute to increases inflammation seen in HIV patients.

The specific differences between microbiota composition amongst HIV-negative, HIV-positive, and post-therapy HIV-positive patients are seen as differences is microbiota genus population prevalence. Of note, an increase in Prevotella are seen in HIV-postivie individuals when compared to healthy HIV-negative controls. Additionally, the region of the gut may influence the effect of HIV on the microbiome composition. While these differences have been described in multiple studies, the repercussions of these changes have yet to be fully explored.

Vaginal microbiota plays a role in the infectivity of HIV, with an increased risk of infection and transmission when the woman has bacterial vaginosis, a condition characterized by an abnormal balance of vaginal bacteria. The enhanced infectivity is seen with the increase in pro-inflammatory cytokines and CCR5 + CD4+ cells in the vagina. However, a decrease in infectivity is seen with increased levels of vaginal Lactobacillus, which promotes an anti-inflammatory environment.

Research
Diabetic foot ulcers develop their own, distinctive microbiota. Investigations into characterizing and identifying the phyla, genera and species of bacteria or other microorganisms populating these ulcers may help identify one group of microbiota that promotes healing.

Periodontal disease and urinary tract infections (UTIs) are often linked to bacteria (ex. Helicobacter pylori and Chlamydia pneumonia), numerous viral agents  (ex. Cytomegalo-virus, herpes simplex virus type-2, HIV), and parasites (ex. Plasmodium spp. and Toxoplasma gondii). Consequently, these agents can also play a significant role in the development of preeclampsia.