1. tumour proliferation through fungal activation of host's C3 complement cascade (pancreatic cancer)
2. the microbial taxa associated with complex organisms
3. adulthood
3.1. increase in richness
3.2. increase in complexity
3.3. resilience to dietary changes
3.4. increase in proteobacteria
3.5. increase actinobacteria
3.6. influences sex hormones
4. Microbiota
4.1. effects of gut microbiota on adaptive immunity
4.1.1. anticancer therapies have demonstrated strong links between distinct commensals and protective antitumor T-cell response
4.1.2. Gut-derived metabolites can also modulate immune response
4.2. effects of gut microbiota on TME
4.2.1. influence both local and distant neoplasia
4.2.1.1. affect their immune context
4.2.1.2. influx of myeloid and lymphoid cells
4.2.1.3. affect their inflammatory and metabolic patterns
4.3. gut microbiota and colorectal cancer
4.3.1. genotoxicity induced CRC-associated bacteria
4.3.2. microbiota-divern metabolism
4.3.3. influx of immune-stimulating microorganisms
4.3.4. inflammation-driven bacterial niche
4.3.5. 'Oncomicrobes' alter immune-composition creating a permissive tumour microenvironment
4.4. extraintestinal barriers and cancer microbiota
4.4.1. Lung Surface: not sterile
4.4.1.1. oncogenes driven lung cancer models in mice
4.4.1.2. local commensals may be perturbed by carcinogens
4.4.1.3. triggering inflammation
4.4.1.4. contributing to tumour progression
4.4.2. Skin
4.4.2.1. microbiota appears to influence nonmelanoma skin carcinogenesis
4.4.2.2. cervical cancer caused by human papillomavirus infection
4.4.2.2.1. often associated with a deviated cervical microflora
4.5. Intratumor microbiota effects on TME
4.5.1. general effects
4.5.1.1. suppress local antitumor immunity or at time provides immunostimulatory effects
4.5.2. cancer-specific effects
4.5.2.1. mutagenesis through secreted genotoxins (gastrointestinal and urinary tract)
4.5.2.2. mediate inflammation (stomach and lung cancers)
4.5.2.3. chemoresistance through direct microbial metabolism
4.5.2.4. metastasis through up-regulation of tumour matrix metalloproteinases (breast cancer) or reduction of tumour immunosurveillance (lung cancer)
4.6. Metastasis
4.6.1. distant (metabolite) mechanisms
4.6.2. local (dissemination) mechanisms
4.6.3. both modify immune environment
5. Host Bacterial Relationships
5.1. bacteria metabolize indigestible compounds
5.2. supply essential nutrients and vitamins
5.3. defends against colonization by opportunistic pathogens
5.4. contributes to the formation of intestinal architecture
6. Infectious diseases
6.1. New emerging infectious disease
6.1.1. HIV
6.1.2. Hepatitis B-related disease
6.2. treatments
6.2.1. antibiotics
6.2.2. immunosuppressive drugs
6.2.3. other new modern treatment technology
7. Complicit Microbes
7.1. promote carcinogenesis but are insufficient to cause cancer
7.2. immunomodulatory functions
7.3. bioactive metabolites
8. Immunomodulatory Functions
8.1. promote carcinogenesis but are insufficient to cause cancer
9. CRC risk factors
9.1. inflammation associated with inflammatory bowel disease
9.2. heritable genetic defects
9.3. 70-90% environmental factors - most notably diets that are low in fibre and high in red meat
10. Fecal Microbiota Transplantation
10.1. numerous clinical trials using FMT and other gut microbiota modulation strategies to treat diseases of the gut ( such as IBD) as well as other systemic diseases - including metabolic syndrome, autism, multiple sclerosis, Parkinson's disease and cancer
10.2. regulatory approval hurdle: the "Active ingredient" in FMT and its mechanisms are unknown
10.3. A single FMT administered colonoscopically together with PD-1 blockade
10.4. History
10.4.1. 4th century: a chinese practitioner reportedly used the stool of healthy subjects to treat patients with diarrhea
10.4.2. 1958 FMT reported as a treatment for antibiotics resistant CDI
10.4.3. 2013 FMT became an option for routine treatment for such infections
11. Maternal Microbiota
11.1. maternal nutrition affects the immune development in offspring
11.1.1. aids in expansion of gut innate immune cells
11.1.2. development of intestinal epithelial cells
11.1.3. mucus development
11.1.4. expression of antimicrobial peptides and secretion of antibodies
11.2. good nutrition aids in the translation of the endogenous microbiota
11.3. aids in avoiding of hyper-reactivity to microorganism-derived compounds
12. Brain Centric Perspective
12.1. interaction b/w animals microbiota aids in formation and function of the neurological system
13. Myelination
14. Neurotransmitters and Synaptic plasticity
14.1. increase in synaptic and neuronal plasticity
14.2. increase neuronal activity-related genes
14.3. decrease in BDNF
14.4. increase in serotonin
15. Microglia
15.1. decrease immune system related genes
15.2. normal microglia
15.2.1. short processes and limited branching
15.2.2. standard maturation and activation
15.2.3. inflammatory response to stimulation
15.3. dysregulated microglia
15.3.1. impaired response to LPS and LCMV exposure
15.3.2. increased branches, process length, and segments
15.3.3. increased expression of maturation and activation markers
15.3.4. decrease expression of genes for inflammation and response to stimulation
15.3.5. increase expression of cell cycle and proliferation markers
16. neurogenesis
16.1. increase volume
16.2. increase volume
17. Blood brain barrier
17.1. increase in membrane permability
17.2. decrease tight junction proteins expression
17.3. complex carbohydrates affect microbial fermentation by breaking down into SCFAs
17.3.1. increase claudin-5 occludin
18. Multiple Sclerosis
18.1. P.histoicola
18.1.1. decrease in pro-inflammatory TH1 and Th17 cells
18.1.2. increase in the frequencies of subset of regulatory T-cells, tolerogenic dendritic cells, and suppressive macrophages
18.2. IL-17
18.2.1. affects composition of gut microbiome
18.2.1.1. mice became resistant to MS development
18.3. Gut plasma cells
18.3.1. mobilize in the brian
18.3.1.1. produces IgA antibodies and dampens brain inflmmation
19. Stress
19.1. bidirectional
19.2. chronic stress leads to lasting alterations
19.3. transgenerational effect
19.3.1. prenatal stress in mice showed long-term effects on microbiota composition
20. Depression
20.1. bacteroidetes firmicutes and Firmicutes
20.2. changes in the gut microbiota coincides with alterations to the host physiology
20.2.1. activation of HPA axis
20.2.2. increase inflammatory activity
20.3. transplant of gut microbiota
20.3.1. showed that phenotypes was able to pass depression
20.4. bifidobacterium longum NCC3001
20.4.1. reduces depression
20.4.1.1. alters brain activity
21. Anxiety
21.1. by restoring the gut microbiome, it reversed learning deficits
21.2. gut microbiota may affect both baseline anxiety and resilience to stressful events
22. extreme aging
22.1. diverse microbiotaa
22.2. alpha diversity
22.3. unique microbial footprint in semi-supercentenarians
23. Host development
23.1. has to be tolerant toward the mutualistic microorganisms
23.2. beneficial microbiota composition by keeping pathobionts in check
23.3. Colonic mucus layer
23.3.1. inner and outer layer secreted by goblet cells
23.3.2. composed of highly glycosylated proteins
23.3.2.1. mucins
24. Lymphoid Structures
24.1. primary
24.1.1. thymus
24.1.2. bone marrow
24.2. secondary
24.2.1. lymph nodes
24.2.2. peyer's patches
24.2.3. tonsils
24.2.4. spleen
24.2.5. lymphoid follicles
25. Host Physiology
25.1. Biosynthetic enzymes
25.2. proteases
25.3. glycosidases
25.4. metabolic capability
25.4.1. metabolizing indigestible polysaccharides
25.4.2. producing essential vitamins
25.4.3. xenobiotic metabolism
26. Antiviral immunity
26.1. perturbation of the microbiome dampens antiviral type I IFN responses
26.2. restored by clostridium symbiont
26.3. colonization resistance
26.3.1. microbiota shields the host against infections
26.4. long-term
26.4.1. gut microbiota from previously infected hosts display enhanced resistance to infection
26.4.2. metaorganism memory
27. COVID-19
27.1. major dysbiosis of intestinal microbiome
27.1.1. enrichment by bacterial and fungal pathogens
27.1.2. depletion of beneficial symbionts
27.2. Medication
27.2.1. antimicrobial treatments
27.2.2. hydroxychloroquine-substantially
27.2.3. L-tyrosine
27.2.3.1. gut bacteria exhibit enhanced metabolism
27.2.3.1.1. by-product is p-cresol sulfate
27.2.3.2. protect against lung inflammation
27.2.3.2.1. Asthma
27.2.3.2.2. ARDS
27.3. Social Microbiomes
27.3.1. microbial transmission
27.3.1.1. shared social practices and interactions
27.4. IFNs role
27.4.1. antiviral host response
27.4.1.1. can influence microbiome composition
28. Definition of Biological Self
28.1. genome
28.1.1. microbiome functional genomic interaction
28.1.1.1. common p53 GOF mutations are only carcinogenic in the presence of microbially produced gallic acid and are otherwise protective in the gut
28.1.1.2. inability of Kras mutation and p53 loss to produce lung cancer in germ-free or antibiotic-treated mice
28.2. Brain
28.3. Immune System
28.4. challenges our concept of self
28.4.1. introduces new genome-based precision medicine
28.4.2. this is because of the genetic constitution of every human body is microbial
28.5. Metaorganism definition of self
28.5.1. extended to incorporate our microbiota
29. Human Microbiome
29.1. orchestrate adaptive immune system
29.2. influence the brain
29.3. contributes more gene function than our own genome
29.4. microbiome
29.4.1. the catalogue of these microbes and genes
30. Historical Accounts Linking Cancer and Microbes
30.1. William Cooley
30.1.1. vaccine of live or heat-killed streptococcus and serratia species on terminal cancer patients
30.1.2. later shown to yield >10-year disease free-survival in ~30% of the patients (60/210)
30.2. Viral Theory of Cancer (1911)
30.2.1. Discovery of Rous Sarcoma Virus
30.2.2. Failed to find a viral cause of most human cancer
31. Oncomicrobes
31.1. additional microbes initiate cancer through genotoxin-mediated mutagenesis
31.2. amplify tumorigenesis through E-cadherin-Wnt-beta-catenin signaling
32. Gut Dysbiosis
32.1. characterized by reduced microbial diversity and/or substantial shifts in resident species
32.1.1. disrupts the physiological interaction between epithelial cells and the microbiota
32.1.2. breach of the barriers - induces inflammatory pathologies
32.2. proteobacteria
32.3. lentisphaerae
32.4. bacteroides
33. Therapies
33.1. Antibiotics
33.2. Antiviral
33.3. Vaccines
33.4. Exogenous Microbiota
33.4.1. Oncolytic viral therapy
33.4.1.1. for advanced melanoma
33.4.2. bacterial cancer therapy
33.4.2.1. high-risk, non-muscle invasive bladder cancer using live attenuated mycobacterium bovis (BCG vaccine)
33.4.3. Immunotherapy options or Neoadjuvant
33.4.3.1. microbial chassis selection, payload options, and circut design
33.4.3.2. minimal systemic toxicities and sufficient antitumor efficacy
33.4.3.3. available routes of administration and effective biocontainment strategies
33.4.3.4. Ease of manufacturing, batch-to-batch quality controls, and distribution stability
33.4.3.5. Satisfactory patient dosing attributes (odor, colour, taste, refrigeration)
33.5. Microbiota is a key orchestrator of cancer therapy
33.5.1. chemotherapy
33.5.1.1. drug metabolism
33.5.1.1.1. nitroreduction of the radiation sensitizer misonidazole
33.5.1.1.2. hydrolysis of methotrexate (antineoplastic and immunosuppressive agent)
33.5.1.1.3. deconjugation of the liver-detoxified form of the topoisomerase I inhibitor irinotecan
33.5.1.2. Drug toxicity
33.5.1.2.1. irinotecan: transformed into its active form, SN-38, by liver and small intestine tissue carboxylesterase
33.5.1.2.2. detoxified in the liver by host UDP-gulcouronosyltransferases into inactive SN-38-G before being secreted into the gut
33.5.1.2.3. in the gut SN-38-G can be reconverted by bacterial beta-glucuronidases into active SN-38
33.5.1.3. Enhanced toxicity
33.5.1.3.1. genotoxic platinum compounds
33.5.1.3.2. commensal microorganisms and pathogens access the mesenteric lymph nodes and the blood circulation
33.5.1.3.3. septicaemia and systemic inflammation
33.5.2. radiotherapy
33.5.3. immunotherapy
33.5.4. bone marrow transplantation
33.5.5. gut microbiota affects
33.5.5.1. drug pharmacokinetics
33.5.5.2. anticancer activity
33.5.5.3. drug toxcity
34. Prenatal Period
34.1. Sterility Hypothesis
34.1.1. seman
34.1.2. placenta
34.1.3. aminotic fluid
34.1.4. umbilical cord blood
34.1.5. meconium
35. Postnatal period
35.1. critical period
35.1.1. early-life exposures immensely influences the morphological and functional development of the immune system
36. Chemicals
36.1. Betaine
36.1.1. improves long-term metabolic health by fostering growth of beneficial bacteria in the newborn gut
36.1.2. low lvls
36.1.2.1. childhood obesity
36.1.3. High lvls
36.2. Akkermansia
36.2.1. low lvls
36.2.1.1. obesity
36.2.1.2. other metabolic conditions
37. Early-Stage Maturation
37.1. 2-3 years old
37.1.1. introduction to solid food
37.1.2. decrease bifidobacterium
37.1.3. increases microbiome richness
38. Sexual Maturation
38.1. sex hormones
38.2. gender-specific microbial populations
38.3. establishment of secondary characteristics
38.4. resistome
38.4.1. antibiotic resistance genes
39. Microbiome stability
40. Neonatal period
40.1. Vaginal birth
40.1.1. increase lactobacillus
40.1.2. increase prevotella
40.2. C-section
40.2.1. increase in staphylococcus
40.2.2. increase corynebacterium
40.2.3. increase propionibacterium
40.3. Breast Milk
40.3.1. increase in bifidobacterium
40.3.2. increase in lactobacillus
40.3.3. increase staphylococcus
40.3.4. increase enterococcus
40.4. Formula Milk
41. Inflammaging
41.1. TNF-alpha
41.2. IL8
41.3. IL1-beta
41.4. CRP
42. Nutritional changes
42.1. Caloric restriction
42.1.1. inhibits toxins
42.1.1.1. increases BP
43. the gut microbiota-brain axis
43.1. interaction b/w the host, microbiome and the environment
43.2. shapes adaptive and dysfunctional neurological processes
43.3. influences of the microbiota on development and fxn of the nervous system
43.3.1. modulation of immune responses
43.3.2. impacts metabolism
43.3.2.1. hormones
43.3.2.2. neuropeptides
43.3.2.3. neurotransmitters
43.3.3. direct effects on neurons and neuronal signaling
44. Chemical Signalling
44.1. lactobacillus reuteri
44.1.1. increase oxytocin
44.1.1.1. regulates neuronal plasticity
44.1.1.1.1. increase social behaviour
44.1.1.1.2. increase oxytocin lvls and neurons
44.1.2. aids in ASD
44.1.2.1. this is because social behaviour deficits are mediated by gut microbiome
44.2. lactobacillus rhamnosus
44.2.1. increase in GABA
44.2.1.1. decrease stress
44.2.1.2. decrease anxiety
44.2.1.3. decrease depressive-like behaviour
44.2.1.4. increase vagal mesenteric nerve firing
44.3. bifidobacterium longum NCC3001
44.3.1. increase BDNF
44.3.1.1. decrease in anxiety-like behaviour
44.3.1.2. decrease in depressive behaviour
44.3.1.3. decrease in excitability ENS neurons
44.4. bacteroides fragilis
44.4.1. decrease in 4-EPS
44.4.1.1. decrease anxiety-like behaviour
44.4.1.2. decrease in repetitive behaviour
44.4.1.3. increase in communication
44.5. SCFA-producing bacteria
44.5.1. responds to increase in SCFA
44.5.1.1. Decrease stress
44.5.1.2. decrease anxiety and depressive-like behaviour
45. ASD
45.1. neurodevelopmental disorder
45.1.1. manifests early in life
45.1.2. prevalence in males
45.1.3. behavioural domains
45.1.3.1. social communication
45.1.3.2. social interaction
45.1.3.3. repetitive behaviour
45.1.4. gastrointestinal dysfunction
45.1.4.1. increased risk of intestinal inflammation
45.1.4.2. altered gut permeability
46. Maternal inflammation
46.1. infection
46.1.1. t-helper 17 cells become hyperactive
46.1.1.1. secrete Il-17
46.1.1.1.1. affects developing fetal brain
46.1.1.1.2. adult offspring shows ASD-like behaviour
47. Parkinson's disease
47.1. symptoms
47.1.1. tremors
47.1.2. stiffness
47.1.3. slowness of movements
47.2. biology
47.2.1. alpha-synuclein protein misfolds
47.2.2. harmful clumps form in the brain
47.2.3. gut inflammation
47.2.3.1. some gut bacteria are neuroprotection and increase signs of PD
47.3. E.coli
47.3.1. amyloid protein (curli)
47.3.1.1. promotes alpha-syn aggregation in the gut and brain
47.4. bidirectional
47.5. tyrosin decarboxylases
47.5.1. reduced drug absorption
47.6. Levodopa metabolism
47.6.1. increased rates of drug inactivation
48. Alzheimer's Disease
48.1. sodium oligomannate
48.1.1. remodells gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation
48.1.1.1. Inhibits Alzheimers
48.2. High blood levels of lipopolysaccharides and certain SCFAs
48.2.1. large amyloid deposits in the brain
48.3. Butyrate
48.3.1. associated with less amyloid pathology
49. ALS
49.1. progression depends
49.2. Vitamin B3 (nicotinamide)
49.2.1. improved ALS symptoms
49.2.1.1. done by eliciting neuroprotective transcriptional program
49.2.1.2. improves motor abilites
49.2.1.3. spinal cord gene expression
50. Huntington's disease
50.1. less gut richness and evenness
50.2. differences in gut microbiome structure
50.3. functional gut pathway and enzyme differences
50.4. Eubacterium hallii
50.4.1. cognitive performance
50.4.2. motor signs