Pathogenität of Mikroorganismen

• Species & number (Growth and Reproduction)

• Virulence factors

• Antibiotic resistance

• Genetic flexibility and variation

• Biofilm formation = communities of bacteria encased in a protective extracellular matrix -> enhance bacterial survival and resistance to antibiotics

1. Growth and Reproduction: can reproduce rapidly, with some species dividing every 20-30 minutes under optimal conditions. This rapid growth allows them to establish infections quickly.

2. Virulence Factors: toxins, adhesins (help bacteria attach to host cells), invasins (facilitate bacterial invasion of host tissues), other proteins or structures that enhance their ability to infect and damage host organisms

• Adhesins: Adhesion to host cells & surfaces by fimbria & cellwall associated proteins

• Toxins: Destruction of tissue

• Invasins: Invasion, Multiplication

1. Exposure: e.g. direct contact with contaminated surfaces, food/water, inhalation of respiratory droplets containing bacteria, or transmission via vectors like insects

2. Adhere to host cells & surfaces by fimbria & cellwall associated proteins

3. Toxin Production: damage host cells -> tissue damage

4. Invade the host tissues

5. Colonization

6. Multiplication and Growth

7. Immune Response of host's immune system -> activation of immune cells (white blood cells, production of antibodies, release of inflammatory molecules) -> eliminate the bacteria to protect the host

8. Symptoms: fever, inflammation, pain, ..

MGEs = segments of DNA that have the ability to move or transpose within a genome. They can move from one location in the genome to another, and in some cases, they can even move between different individuals of the same species or between different species. Types:

• Transposons = DNA sequences that can "jump" or transpose to new locations within the genome -> carry genes encoding enzymes necessary for their transposition

• Insertion Sequences (IS Elements) = specific type of transposon that consists of a minimal transposable unit

• Plasmids: Circular pieces of DNA that can replicate independently of the host genome and can be transferred horizontally between bacteria

• Integrons: Genetic elements that can capture and incorporate gene cassettes, including antibiotic resistance genes, through site-specific recombination

• Bacteriophages = Viruses that infect bacteria and can transfer bacterial DNA from one host to another during the process of infection. This is known as transduction.

Processes in which mobile genetic elements are involved:

1. Genomic Rearrangement by inserting themselves into new locations within the host genome -> changes in gene order, gene disruption, creation of new gene arrangements

2. Mutagenesis: introduce mutations into the host genome, potentially affecting the function of nearby genes. These mutations can be either deleterious or beneficial, depending on their impact on the host organism.

3. Horizontal Gene Transfer (HGT) genes between different organisms -> facilitate the spread of advantageous traits, such as antibiotic resistance genes, among bacteria or between different species

4. Antibiotic Resistance: MGEs frequently carry antibiotic resistance genes, allowing bacteria to rapidly acquire resistance to antibiotics through HGT

5. Virulence: Some pathogenic bacteria can acquire virulence factors, such as toxins or adhesins, through MGEs

6. Regulation of Gene Expression: MGEs can carry regulatory elements that affect the expression of nearby genes -> changes in gene expression patterns and phenotypic traits

1. Mutation: can alter the pathogen's characteristics, including its ability to infect new hosts or evade the host immune system

2. Recombination: Some pathogens can exchange genetic material with other related pathogens, resulting in a new hybrid pathogen with different characteristics

3. Zoonotic Transmission

4. Environmental Changes

5. Antibiotic Resistance

6. Inadequate Hygiene and Sanitation

1. Effective Prognosis & Treatment healthcare providers prescribe appropriate treatments, such as antibiotics, antiviral medications, or antifungal drugs

2. Prevention and Control the spread of the infection

3. Outbreak Management tracking of the outbreak source, identifying affected individuals, and implementing interventions to stop the spread

4. Research and Vaccine Development

5. Identification of Emerging Pathogens

6. Patient Isolation & Management to prevent further transmission

Hypothesis: living organisms could arise spontaneously from non-living matter —> life could emerge from inanimate materials under certain conditions without the need for pre-existing life

Outcome: hypothesis of spontaneous generation was incorrect

-> life did not spontaneously arise from non-living matter in sealed, swan-necked flasks. Instead, microorganisms in the air were the source of contamination and microbial growth in the control flasks with straight necks

-> microorganisms present in the air were not spontaneously generating in the nutrient broth, but were instead introduced from the external environment

1. The organism must be found on all the diseased host tissue but not on the healthy host

2. The organism can be isolated from the host and purified on artificial culture medium

3. The organism from pure culture, when inoculated on the susceptible host must reproduce the symptoms as in step 1

4. The organism can be re-isolated from the artificially inoculated host on pure culture medium

Limitations

1. Not All Pathogens Can Be Cultured: Some pathogens cannot be grown in pure culture or are challenging to culture in the laboratory

2. Chronic Infections: Koch's postulates were originally developed for acute infectious diseases, and they may not be well-suited for chronic infections where the relationship between a microorganism and disease is more complex

3. Multiple Pathogens: Some diseases are caused by multiple pathogens working together or by a combination of microbial and host factors

4. Antibiotic Treatment: In cases where antibiotics or other treatments have been widely used, the isolation and causation steps of Koch's postulates may be compromised because the pathogen may be eliminated before it can be re-isolated

1. Identification and Characterization: Genome sequencing allows researchers to definitively identify the pathogen and its species. It provides a complete genetic blueprint of the organism, aiding in accurate classification

2. Virulence Factors: The genome sequence reveals the presence of virulence factors, which are genes or proteins that contribute to the pathogen's ability to cause disease -> Understanding how the pathogen interacts with its host and causes infection

3. Drug Targets & Vaccine Development: Knowledge of the genome can help identify potential drug targets and potential vaccine candidates. Researchers can identify essential genes and proteins that are unique to the pathogen, which may serve as targets for the development of antibiotics or antiviral drugs

4. Antibiotic Resistance: Genome sequencing can identify genes associated with antibiotic resistance, helping in the surveillance and management of drug-resistant strains

5. Epidemiology: Genome sequencing allows for the tracking of outbreaks and the study of transmission patterns. By comparing the genomes of different isolates, researchers can determine the relatedness of strains and trace the source of infections.

6. Evolutionary Insights: The comparison of genomes from different strains or closely related species can provide insights into the evolutionary history of the pathogen. This includes information about its origins, diversification, and adaptation to different environments

• Global warming and climate change

• Animal infections become transmissible to humans

• Global travelers and tourism

• Mass migration

• Growth of urban slums

• Human sexual behavior and drug abuse

• Misuse and overuse of antibiotics

Diagnosis: Invasive & Non-Invasive Tests

• Biopsy check using endoscopy: quick urease test, histological examination +microbial culture

• Carbon urea breath test (14C or 13C-labelled urea is metabolized into CO2)

• Blood antibody test

• Stool antigen test

Treatment

• “Triple therapy”:

1. Proton pump inhibitors —> reduce stomach acid production and help create a less acidic environment in the stomach, allowing antibiotics to be more effective (e.g. omeprazole, lansoprazole, esomeprazole, pantoprazole)

2. Clarithromycin

3. Amoxicillin

• “Quadruple therapy”: + bismuth subsalicylate (Pepto-Bismol; coats ulcers) —> has both antibacterial and mucosal protective properties and can enhance the effectiveness of antibiotics

1. Urease Activity

-> H. pylori produces enzyme urease, which catalyzes the hydrolysis of urea into ammonia(NH3) and CO2

—> NH3 helps neutralize the acidic environment of the stomach by raising the pH around H. pyroli —> creates a more hospitable environment for H. pylori to survive and colonize the gastric mucosa

1. CagA & VacA Toxins: (Cytotoxin-associated gene A) & (Vacuolating cytotoxin A)

-> CagA is injected into gastric epithelial cells via a type IV secretion system --> interferes with cellular signaling pathways, leading to altered cell function and inflammation

-> VacA forms channels/pores in the host cell membrane, disrupting cell integrity and inducing vacuolization —> impair the host's defense mechanisms

1. Adhesive Proteins aka. Adhesins

-> BabA (Blood group antigen-binding adhesin) and SabA (Sialic acid-binding adhesin) —> enable H. Pyroli to adhere to the epithelial cells of the gastric mucosa -> preventing it from being swept away by gastric peristalsis and mucus turnover

—> Urease catalyzes the hydrolysis of urea into ammonia (NH3) and CO2

—> NH3 helps neutralize the acidic environment of the stomach by raising the pH around H. pyroli —> creates a more hospitable environment for H. pylori to survive and colonize the gastric mucosa

Molecular Mechanism: (NH2)2CO + H2O → CO2 + 2NH3

a. Periplasmic buffering

-> Urea crosses the outer membrane (OM) and then the inner membrane (IM) through the acid-activated urea channel (UreI)

-> Cytoplasmic urease forms 2NH3 + H2CO3, and the latter is converted to CO2 by cytoplasmic β-carbonic anhydrase (β-CA)

-> These gases cross the IM, and the CO2 is converted to HCO3− by the membrane-bound α-carbonic anhydrase (α-CA), thereby maintaining periplasmic pH at ∼6.1 (effective pKa)

-> Exiting NH3 neutralizes the H+ that is produced by carbonic anhydrase, as well as the entering H+, and can also exit the OM to alkalize the medium —> allows maintenance of a periplasmic pH that is much higher than the pH of the medium

b. FlgS TCS-mediated recruitment of urease to Urel

-> Activation of this TCS results in recruitment of the urease proteins to UreI

-> the resultant immediate access of urea to urease and the outward transport of CO2, NH3 and NH4+ through UreI increase the rates of periplasmic buffering and disposal of cytoplasmic NH4+

c. ArsRS TCE-mediated regulation of UreAB expression

-> At acidic pH: ArsS is activated and so ArsR is phosphorylated -> phosphorylated ArsR binds to the ureAB promoter to positively regulate the transcription of ureAB -> upregulation of the ureAB mRNA —> increase in urease activity

-> At neutral pH: ArsS not activated, unphosphorylated ArsR binds to the promoter of the gene encoding a small RNA that targets the ureB part of the ureAB mRNA (ureB-sRNA), leading to transcription of ureB-sRNA and consequent truncation of the ureAB mRNA —> decline in urease activity

1. Induction of vacuolation

-> forms channels in the host cell membrane, disrupting cell integrity and inducing vacuolation —> impair the host's defense mechanisms

2. Immunomodulation and Immune Evasion

-> suppress the immune response by inhibiting the activation and proliferation of T cells, particularly CD4+ T helper cells

-> induces apoptosis in immune cells (T lymphocytes, monocytes/macrophages)

3. Disruption of Epithelial Barrier Function

-> can weaken the integrity of the gastric epithelial barrier

-> affects the tight junctions between epithelial cells, leading to increased permeability of the epithelial layer

-> disruption allow H. pylori and its toxins to penetrate deeper into the gastric mucosa, contributes to tissue damage and inflammation

4. Mitochondrial Dysfunction

-> target mitochondria within host cells

-> disrupt mitochondrial function, leading to the release of cytochrome c and activation of apoptotic pathways

-> contributes to host cell damage and apoptosis

• Poultry (in the intestines, on the skin) -> Handling, preparation, or consumption of undercooked or raw poultry products can lead to infection

• Contaminated milk and dairy products, such as cheese

• Contaminated beef, water

1. Anatomical Location:

• In humans: C. jejuni primarily colonizes the lower part of the small intestine (ileum) and the colon

• In chickens: C. jejuni typically colonizes the ceca, which are pouches located at the junction between the small and the large intestine

2. Host Immune Response:

• Humans mount an immune response to C. jejuni infection, leading to inflammation and symptoms like diarrhea. The immune system recognizes the bacterium as pathogen

• Chickens develop tolerance to C. jejuni. The avian immune system may not respond as vigorously as in humans, allowing the bacterium to establish a commensal relationship in the chicken's gastrointestinal tract without causing severe disease

• C. jejuni adherence/secretion of virulence factors involves flagellar motility and a collection of outer membrane proteins (e.g. CapA) -> secreted by the flagellar machinery

• responsible cellular structure that resembles the type of secretion system is bacterial outer membrane

-> CapA acts as an adhesin and an autotransporter. CapA is synthesized and transported to the outer membrane

-> C. jejuni initially enters the host cell in an endocytic vacuole that matures to a specialized Campylobacter containing vacuole (CCV) —> CCV is trafficked to a perinuclear location in a process involving microtubules

Composition: 3 subunits

1. CdtA: helps CDT adhere to the surface of the target cell

2. CdtB = enzymatic subunit; has DNase I-like activity -> responsible for toxin's ability to damage host DNA

3. CdtC: function not fully understood

Mechanism of Action:

1. Binding to host cells: initially the surface -> then epithelial cells

2. Internalization into the host cell by endocytosis

3. Translocation of CdtB: from the endocytic vesicle into the cell's cytoplasm —> exact mechanism is not completely understood but may involve CdtC

4. DNA damage: in the cytoplasm CdtB exhibits its enzymatic activity -> acts as a DNase, cleaving the host cell's genomic DNA —> DNA double-stranded breaks

5. Cell Cycle Arrest: DNA damage triggers the activation of cell cycle checkpoint mechanisms —> cell cycle arrest, particularly in the G2 phase —> host cells temporarily unable to divide

6. Cellular Distension —> cells become enlarged, swollen and distorted due to the inability to divide properly

Phase Variation = a reversible on-off switching of gene expression that occurs through changes in the number of SSR within promoter regions or coding sequences of specific genes

• When the number of repeats in an SSR within a promoter region changes, it can affect the binding of RNA polymerase or transcription factors. An increase in the number of repeats may hinder transcription, leading to gene silencing, while a decrease can enhance transcription, leading to gene activation.

-> allows bacterium to rapidly switch between different phenotypes, enabling it to adapt to changing environments or evade host immune responses

Frameshift Mutations and Protein Variation

• SSRs located within coding regions of genes can cause frameshift mutations (deletion, insertion) when the number of repeats changes during replication or repair processes

-> Frameshift mutations alter the reading frame of a gene, leading to the translation of a protein with a different amino acid sequence

-> production of variant proteins with potentially altered functions

-> enabling to escape host immune recognition

3 surface structures contributing to the virulence:

1. Flagella: enable C. jejuni to move through the mucus layer of the intestinal epithelium and to penetrate the intestinal lining

2. Capsule: polysaccharide capsule that surrounds the bacterial cell -> protecting the bacterium from host immune defenses

3. Lipooligosaccharide (LOS)

4. Outer Membrane Proteins (adhesins and invasion proteins) —> involved in the attachment to and invasion of host epithelial cells

Lipooligosaccharide (LOS): structurally resemble human neuronal gangliosides on peripheral nerves = Molecular mimicry

-> During infection, host's immune system mounts an immune response against the bacterium, producing antibodies to combat the infection

-> Some antibodies produced against C. jejuni LOS can cross-react with gangliosides due to their structural similarity —> mistakenly target gangliosides on peripheral nerves

—> lead to inflammation and damage to the nerve cells —> characteristic symptoms of GBS (muscle weakness, tingling,..) = autoimmune disorders

• Induction of proliferation/Evading growthsuppression —> get access to replication machinery

• Avoiding immune destruction —> preventing immune eradication —> protection of replication niches

• Genome instability and mutation —> DNA damage frequent consequence of infection

• Tumor-promoting inflammation —> Inflammation as consequence of chronic infection

1. Selection of Sarcoma-Infected Chickens

2. Tumor Extracts: Removed sarcoma and broke up into small chunks of tissue —> extracted it from the tumors by grinding them up and creating a cell-free filtrate, which contained no intact tumor cells but still some type of agent capable of causing cancer

3. Injection into Healthy Chickens

4. Observation of Tumor Development in injected chicken

5. Recovery of Infectious Agent: repeated the process of isolating the cell-free filtrate from the newly formed tumors and injected it into more healthy chickens

   —> new chickens also developed tumors, demonstrating that the agent causing the tumors could be passed from one chicken to another

—> a transmissible agent present in the sarcoma tissue was capable of causing cancer in healthy chickens

1. Epidemiological Association

   • individuals with a history of chronic S. typhi infection (e.g. typhoid fever) are at a higher risk of developing gallbladder cancer compared to those who haven’t been infected

2. Presence of the Infectious Agent in Tumor Tissue

   • bacterium has been detected in the gallbladder tissue of affected individuals —> may contribute to the initiation or progression of the cancer

3. Mechanistic Understanding

   • S. typhi infection can lead to chronic inflammation of the gallbladder (chronic cholecystitis) —> Prolonged inflammation can result in cellular damage, DNA mutations and alterations in the tissue microenvironment —> can promote cancer development

   • S. typhi has been shown to interact with host cells, potentially affecting signaling pathways (e.g. MAPK) and cellular processes that play a role in tumorgenesis

Koch's postulates are not be entirely fulfilled in the case of H. pylori as the cause of gastric cancer

1. Isolation and Cultivation of the Microorganism

   • H. pylori can be isolated from the stomach lining of individuals with gastric ulcers or gastritis and be cultured in the laboratory —> fulfilled the postulate

2. Production of Disease in Experimental Animals

   • Most animal studies have shown that H. pylori infection leads to gastritis or gastric inflammation and ulcers but not cancer

3. Re-isolation of the same Microorganism from Experimentally Infected Animals

   • In animal models, H. pylori can often be recovered from the stomach lining after infection, but it typically does not lead to the development of gastric cancer

4. Recovery of the Same Microorganism from Naturally Infected Individuals

   • H. pylori can be re-isolated and cultured from the stomachs of individuals with gastric cancer —> fulfilled the postulate

1. Inflammation and chronic immune activation

• Connection: Dysbiosis, an imbalance in the composition and diversity of the gut microbiota —> lead to chronic inflammation in the intestinal mucosa —> associated with an increased risk of CRC

• Mechanisms:

  • Dysbiosis: overgrowth of pro-inflammatory bacteria or a decrease in anti-inflammatory microbes —> imbalances trigger an inflammatory response in the gut

  • Chronic inflammation promotes the release of pro-inflammatory cytokines (e.g. IL-6, TNF-α) -> can damage intestinal epithelial cells and stimulate cell proliferation

  • Proliferating cells are more susceptible to DNA damage and mutations, increasing the likelihood of oncogenic changes

  • Inflammatory responses can also lead to the production of reactive oxygen and nitrogen species -> can cause DNA damage and contribute to the development of CRC

2. Metabolite production and genotoxic effects

• Connection: Certain gut bacteria can produce metabolites that have genotoxic effects -> can damage DNA and increase the risk of CRC

• Mechanisms:

  • certain strains of E. coli can produce genotoxins, such as colibactin -> can directly damage DNA and lead to mutations in host cells

  • Fusobacterium nucleatum -> can adhere to and invade host cells, triggering an inflammatory response and promoting tumor growth

1. Inflammation and Chronic Immune Activation:

   • Bacterial infections can trigger the release of pro-inflammatory cytokines (TNF-α, IL-6) & recruitment of immune cells (neutrophils, macrophages) —> create a pro-tumorigenic microenvironment that supports the development of cancer cells

2. DNA Damage and Genomic Instability:

   • produce genotoxins that directly damage DNA, leading to mutations —> strains of E. coli produce colibactin with genotoxic effects

   • Inflammatory responses can lead to the production of reactive oxygen and nitrogen species -> can cause DNA damage and mutations

   • Bacterial infection-induced inflammation can activate DNA repair pathways in a way that may be error-prone, increasing the risk of DNA replication errors and genomic instability (C. trachomatis)

3. Promotion of Cell Proliferation and Survival

   • produce growth factors or activate host signaling pathways that stimulate cell division and proliferation

   • mechanisms to inhibit apoptosis in infected cells, allowing these cells to survive and potentially accumulate genetic mutations (cancerous cells survive)

Genotoxicity: a toxic agent that damages DNA molecules in genes, causing mutations and cytotoxicity

a. H. pylori: Infection -> DNA damage in gastric epithelial cells -> develops the gastric cancer

b. Certain strains of E. coli produce genotoxin colibactin -> directly damage the DNA of host cells -> implicated in colorectal cancer

Cytotoxicity the quality of being toxic to cells in general without necessarily affecting the genome directly

a. Clostridium botulinum produces botulinum toxin -> acts on nerve cells and inhibits neurotransmitter release —> muscle paralysis and potentially fatal respiratory failure

b. Streptococcus pneumoniae produces pneumolysin toxin -> forms pores and disrupts host cell membranes -> cell lysis & tissue damage -> characteristic of pneumococcal pneumonia

1. Oxidative Stress: Chlamydia infection can lead to the generation of reactive oxygen and nitrogen species within host cells —> cause oxidative damage to DNA by oxidizing DNA bases -> generating DNA adducts -> inducing single- and double-strand breaks

2. Activation of Host Immune Responses to Chlamydia infection involves the recruitment of immune cells (neutrophils and macrophages) —> release inflammatory cytokines and reactive oxygen and nitrogen species, contributing to oxidative stress and DNA damage in infected cells

3. Evolved effector proteins -> secreted them into host cells through a specialized secretion system to contribute to DNA damage —> e.g. CPAF (Chlamydial Protease-like Activity Factor) can cleave host cell proteins, including those involved in DNA repair processes —> disrupting DNA repair mechanisms

—> targets base excision repair (BER) pathway

1. H. pylori -> gastric cancer -> Signature 17

   • Signature 17 is characterized by a high frequency of C-to-T transitions, particularly in CpG dinucleotides

   • Presence of Signature 17 suggests that H. pylori infection contributes to the accumulation of specific DNA mutations in gastric epithelial cells, which may be involved in the carcinogenic process

2. Fusobacterium nucleatum -> colorectal cancer -> Signature 1

   • Signature 1 is characterized by a high frequency of C-to-T transitions, particularly in non-CpG sites

   • Presence of Signature 1 in colorectal tumors associated with F. nucleatum suggests a potential role for this bacterium in promoting specific mutational events in colorectal epithelial cells

Epithelial Phenotype Markers

1. E-cadherin (CDH1)

2. Cytokeratins

3. ß-Catenin

4. Zona Occludens-1 (ZO-1)

Mesenchymal Phenotype Markers

1. Vimentin

2. Laminin

3. ß-Catenin

4. α-SMA

1. Inhibition of Macrophage Activity: inside macrophages -> avoid destruction and replicate —> compromise the ability of macrophages to effectively eliminate the infection

2. Interference with Antigen Presentation: affecting the MHC II presentation pathway —> limit the ability of antigen-presenting cells (dendritic cells) to display Chlamydia-derived antigens to T cells —> hindering the activation of adaptive immune responses

3. Induction of Immune Tolerance: induce a regulatory T cell response, which helps dampen the host's immune response. Regulatory T cells can suppress the activity of other immune cells, contributing to immune tolerance and allowing the bacteria to persist

4. Manipulation the production of cytokines —> altering cytokine profiles -> create an environment that is less conducive to the elimination of the infection

5. replicates within host cells and forms inclusion bodies -> protect the bacteria from immune attack and antibiotic treatment

• Uropathogenic E. coli (UPEC)

• “Natural” treatments:

  - Cranberry juice/extract (proanthocyanidins→ antiadhesives for UPEC)

  - Plant extracts (e.g. Uva-ursis)

• Probiotics

1. Recurrent UTI

   • Frequency: having several separate UTIs over a specified period (~1 year), each of which is treated and resolved before the next one occurs

   • Cause: reinfection with a new strain of bacteria after the initial infection has been successfully treated

2. Chronic UTI

   • Duration: long-lasting or persistent UTI that does not seem to fully resolve despite repeated antibiotic treatments

   • Cause: variety of factors: underlying medical conditions (e.g., kidney stones, bladder dysfunction), antibiotic resistance, incomplete eradication of the infecting bacteria

• Consuming mannose as a supplement, it gets excreted in the urine and travels to the urinary tract

• E. coli have a natural affinity for binding to mannose

  -> GAG-rich proteoglycans form a gel-like mucus layer on the luminal surface of the bladder, which blocks FimH-mediated binding to mannosylated glycoproteins on the urothelium, inhibiting invasion into urothelial cells

  -> In the lumen, highly glycosylated THP protein has uroplakin-like mannose glycans, which bind FimH with high affinity, preventing UPEC adhesion

• —> UPEC get flushed out with the urine

  —> Mannose may help prevent the establishment of an infection or reduce the risk of recurrent UTIs —> effective in cases where E. coli is the causative agent

1. Gut Microbiota:

• Preventing uropathogenic bacterial translocation from the gut to the urinary tract

• Influence on immune system with Short-Chain Fatty Acids (SCFAs): Gut bacteria produce metabolites, including SCFAs -> have immune-modulatory effects —> help maintain a balanced immune response in the urinary tract

2. Vaginal Microbiota:

• helps maintain an acidic pH and produces substances that create a protective barrier in the vaginal environment -> help prevent the ascent of uropathogenic bacteria

• A healthy vaginal microbiota is often dominated by Lactobacillus species -> produce lactic acid and other compounds that help maintain vaginal acidity -> help prevent the ascent of uropathogenic bacteria

• Hormonal Changes occur during hormonal fluctuations (associated with menstruation, pregnancy, menopause) -> influence the risk of UTIs

Type 1 (fim) pili

-> bind mannosylated uroplakins in the bladder and mannosylated mucous components in the gastrointestinal tract using the two-domain FimH adhesin

• UPEC senses host immune responses and initiates escape by upregulating the phospholipase PldA

• PldA disrupts the vesicle membrane, allowing UPEC to escape into the cytoplasm

• UPEC infection causes an upregulation of the host phosphate transporter PIT1 via the nuclear factor NF-κB —> reduction of phosphate in the vesicles —> triggers the activation of pldA expression

—> beneficial for the host by shedding infected cells -> limit the spread of the infection

—> can also be exploited by UPEC to enhance their survival and dissemination

• UPEC can survive the exfoliation process and subsequently invade the underlying immature bladder cells and evade the host's immune response

—> double-edged sword

Lactoferrin

• inhibiting the adhesion of UPEC to bladder epithelium -> hinders the bacteria's ability to invade bladder cells

• immune response modulation in the bladder

• Iron Sequestration: limit the availability of iron to uropathogenic bacteria (Iron is an essential nutrient for bacterial growth)

Lipocalin

• Transport of small hydrophobic molecules, which include compounds with roles in the immune response or inflammation

• Inflammatory Response —> influence the balance between pro- and anti-inflammatory signals in the urinary tract

• recapitulate the in vivo environment more accurately

• Human Relevance: contain stem cells and differentiated cells

 1. Purulent (Eiternd)

· Pharyngitis (Rachenentzündung)

· Tonsillitis (Mandelentzündung)

· Necrotizing fasciitis

· Puerperal sepsis (Childbed fever)

2. Toxin-derived

· Scarlet fever (Scharlach) 

· Streptococcal toxic shock syndrome

3. Immuno pathological

· Acute rheumatic fever

· Acute glomerulonephritis

· Endocarditis

4. Others

· Skin infections (Impetigo, erysipelas)

· Meningitis

· Otitis media (Mittelohrentzündung)

1. Adherence and Colonization with surface proteins, fimbriae, particularly in throat and skin

2. Immune Evasion: M protein can mimic host proteins -> inhibits phagocytosis and complement activation

   -> Also can change its surface proteins through antigenic variation to avoid immune recognition

3. Toxin Production: Streptolysin O (SLO) lyses host cells; Streptolysin S (SLS) enhances tissue damage; streptococcal pyrogenic exotoxins (SPEs) cause toxic shock syndrome and scarlet fever

4. Superantigens: Some GAS toxins act as superantigens —> stimulate a massive and non-specific activation of T cells -> excessive immune response —> severe inflammation and tissue damage

5. Various antigens cause

   • immunological crossreaction with destruction of cardiac myosin

   • Deposition of immuncomplexes in kidneys and joints

6. Inflammatory Response: Secreted factors: Streptokinase trigger an inflammatory response —> lead to local inflammation/invasion

—> Vaccination

- Pneumococcal polysaccharide vaccine (PPV) (protective against 23 serotypes)

- Pneumococcal Conjugate Vaccine (PPV7) (7 serotypes, effective in infants and toddlers)

= is defined as a localized or systemic condition that results from

1) adverse reaction to the presence of an infectious agent or its toxin(s)

2) that was not present or incubating at the time of admission to the hospital

= ist definiert als ein lokalisierter oder systemischer Zustand, der daraus resultiert:

1) unerwünschte Reaktion auf das Vorhandensein eines Infektionserregers oder seiner Toxine(n)

2) das zum Zeitpunkt der Einlieferung ins Krankenhaus nicht anwesend war oder brütete

• Staphylococci (MRSA & Coagulase-negative staphylococci)

• E. coli, Klebsiella sp. & other enterobacteria

• Pseudomonas aeruginosa

• Vancomycin-resistant Enterococci

1. Adherence and Colonization by surface proteins and adhesins

2. Toxin Production:

   • Enterotoxins cause food poisoning

   • Exfoliative Toxins cause skin blistering in conditions like scalded skin syndrome

   • Toxic Shock Syndrome Toxin (TSST-1) characterized by fever, rash and organ dysfunction

3. Immune Evasion: production of surface proteins that inhibit phagocytosis and complement activation

4. Tissue Invasion leads to localized or systemic infections -> osteomyelitis (bone & joint infection)

5. Antibiotic Resistance: Acquisition of SCCmec elements renders S. aureus strains methicillin resistant (MRSA) —> resistant to many common antibiotics

1. Increased Antibiotic Resistance: Biofilms provide a protective barrier that makes it difficult for antibiotics to penetrate and reach the bacteria

2. Chronic Infections: can persist for extended periods -> lead to prolonged hospital stays

3. Persistent Inflammation: host immune response may be less effective at clearing biofilm-associated bacteria, leading to chronic inflammation and tissue damage

4. Transmission in Healthcare Settings: Healthcare workers and patients can inadvertently transfer MRSA between individuals or surfaces, contributing to the spread of MRSA. Biofilm formation on medical devices cause device-related infections

5. Challenges in Diagnosis: standard diagnostic tests may not detect the bacteria within the biofilm. This can result in delayed or missed diagnoses and hinder appropriate treatment

Genetic Mechanism:

1. mecA Gene encodes a modified penicillin-binding protein PBP2a

2. mecA gene is located on Staphylococcal Chromosomal Cassette (SCCmec) (a mobile genetic element)

   -> SCCmecs may carry other resistance genes

   -> SCCmec cassettes can be exchanged between staphylococcal strains and species

Functional Mechanism:

1. Production of PBP2a with a lower binding-affinity to ß-lactam antibiotics, also methicillin -> bacteria not effectively inhibited

2. in MRSA, PBP2a continues to function in cell wall synthesis despite the presence of methicillin --> survive and proliferate in the presence of antibiotics

1. Emergence of Resistant Strains: New strains of bacteria with resistance to multiple antibiotics continue to emerge -> threats in healthcare and community settings

2. Rising Rates of Multi-Drug Resistance: Multi-drug-resistant bacteria reduces the number of effective treatment options for infections

3. Antibiotic Use in Agriculture: overuse and misuse of antibiotics in food animal production can lead to the development of resistant bacteria that can potentially transfer to humans through the food chain

4. Resistance in Non-Pathogenic Bacteria: Resistance genes can potentially transfer to other pathogenic bacteria, also to non-pathogenic strains

5. Challenges in Antibiotic Discovery and Alternative Treatments Research-> development of new therapies, e.g. phage therapy, antimicrobial peptides, and immunotherapies

—> Addressing this issue requires a multifaceted approach that includes responsible antibiotic use, infection prevention measures, research into new therapies, and global collaboration to combat the spread of resistant bacteria

1. Increased Use of Broad-Spectrum Antibiotics can disrupt the balance of microorganisms in the body, including beneficial bacteria that help protect against fungal overgrowth -> create an environment favorable to fungal infections -> Candida species

2. Antifungal Resistance: Some fungal species, Candida and Aspergillus, have developed resistance to commonly used antifungal drugs

3. Growing Immunocompromised Populations

   -> populations living with conditions that compromise their immune systems: underlying diseases (HIV/AIDS, cancer, organ transplantation) and immunosuppressive therapies for autoimmune diseases —> they are more susceptible to opportunistic fungal infections

4. Global Travel and Migration can facilitate the spread of fungal pathogens to regions where they were previously less common -> can introduce new fungal strains and increase the incidence of fungal infections

• Candida albicans & Candida species

• Aspergillus fumigatus/species

• Cryptococcus neoformans

1. Superficial Fungal Infections (Oberflächliche Pilzinfektionen)

   • Dermatophytosis = tinea infections -> skin, hair, nails

   • Candidiasis: infections of the skin and mucous membranes, leading to conditions like oral thrush, vaginal yeast infections

2. Subcutaneous Fungal Infections (Dưới da)

   • Sporotrichosis

3. Systemic Fungal Infections:

   • Aspergillosis: cause invasive lung infections, particularly in immunocompromised individuals ->can lead to pneumonia and dissemination to other organs

   • Invasive Candidiasis can cause bloodstream infections, leading to systemic candidiasis -> affects immunocompromised patients

   • Cryptococcosis: can lead to respiratory infections and central nervous system involvement, particularly in individuals with compromised immune systems

   • Histoplasmosis: Inhalation of Histoplasma capsulatum spores can cause lung infections and dissemination to other organs

4. Opportunistic Fungal Infections in Immunocompromised individuals (deal with HIV/AIDS, organ transplant recipients, immunosuppressive therapies)

1. Adhesion and Colonization to different host tissues: Fungi adheres very well to many human cells, extracellular matrix, and medical devices, e.g. C. albicans

2. Iron uptake mechanisms Pathogenic fungi developed different strategies to obtain iron in host niches where it is restricted

3. Morphological Adaptations — Hyphal growth: switch between different morphological forms: yeast and hyphal forms -> Hyphae express genes encoding additional adhesins, secreted enzymes, toxin (candidalysin) that damages host cells

4. Production of Virulence Factors:

   • Toxins e.g. Aspergillus species produce mycotoxins that contribute to tissue damage

   • Enzymes: proteases and lipases -> degrade host tissues and facilitate invasion

5. Biofilm Formation: on surfaces, medical devices and mucous membranes (Candida species) -> protection from the host immune system and antimicrobial treatments

6. Immune Evasion & Antiphagocytic Mechanisms:

   -> Hyphal growth is also induced after phagocytosis of yeast cells by macrophages -> enables C. albicans to escape from the macrophage

   -> resist phagocytosis E.g. the capsular polysaccharide of Cryptococcus neoformans hinders phagocytosis by macrophages

7. Intracellular Pathogenesis: invade and replicate within host cells. E.g. Histoplasma capsulatum can replicate inside macrophages

8. Antifungal Resistance: particularly in Candida and Aspergillus species

1.) Extracellular reduction of Fe3+ to soluble Fe2+ by surface-localized iron reductases

2.) Reoxidization by a multicopper ferroxidase and internalization by a high-affinity Fe3+ permease

—> C. albicans can transport heme from hemoglobin (presumably after lysis of erythrocytes) into the cell with specialized carrier proteins

—> Aspergillus fumigatus synthesizes and secretes siderophores (small molecules that bind iron with high affinity and remove it from host proteins) and transports the iron-bound siderophores back into the cell to obtain iron from the host

1. Yeast Form:

   • Dissemination: can adhere to host tissues and persist as a commensal organism —> generally well-tolerated by the host's immune system in this state

   • Immune Evasion: due to their smaller size, yeast cells can evade immune detection and presence of surface proteins that mask recognition by phagocytic cells -> persist in host without causing an immediate immune response

2. Hyphal form:

   • Tissue Invasion: true hyphae express genes encoding additional adhesins, secreted enzymes, toxin (candidalysin) that damages host cells

   • Immune Evasion: Hyphal growth is induced after phagocytosis of yeast cells by macrophages -> enables C. albicans to escape from macrophage

3. White-opaque elongated yeast cell = the mating-competent form of C. albicans

   -> opaque cells are less visible to neutrophils and not attacked by them —> may avoid aggressive behaviour against the host, in order to be left in peace by its defense cells when they want to mate

1. Azoles (e.g., fluconazole)

   • inhibit the ergosterol synthesis (key component of fungal cell membranes) -> target sterol 14-α demethylase (involved in ergosterol biosynthesis) -> ergosterol depletion & production of toxic sterols from the accumulated lanostero -> fungal cell membranes become more permeable and unstable -> inhibits growth

2. Echinocandins (e.g. caspofungin, micafungin)

   • target the fungal cell wall by inhibiting the synthesis of ß-(1,3)-D-glucan (which synthesizes the major cell wall component β-1,3-glucan from UDP-glucose) -> cell lysis and death

3. Polyenes (e.g. amphotericin B)

   • bind to ergosterol in the fungal cell membrane, forming pores or channels that disrupt membrane integrity —> increased permeability and leakage of cellular components -> cell death

4. Flucytosine DNA & RNA synthesis —> inhibition of fungal growth

   • is converted inside fungal cells into 5-fluorouracil (5-FU), then to 5FUMP, which is phosphorylated to 5FUTP and incorporated into cellular RNAs —> aberrant RNAs production is toxic to the cells

   • 5FUMP is also converted to 5dUMP —> irreversibly inhibits thymidylate synthas, therby DNA synthesis

5. Antisense Oligonucleotide (e.g. Ancozan, Nikkomycin Z)

   • target specific fungal genes involved in cell wall synthesis or other essential processes —> binding to the fungal mRNA, interfere with protein production and disrupt fungal growth

6. Allylamines (e.g. terbinafine)

   • inhibit squalene epoxidase (involved in ergosterol biosynthesis) -> disrupting ergosterol production -> affect fungal cell membrane integrity and function

7. Thiabendazole and Benzimidazoles (e.g. albendazole)

   • disrupt microtubule formation and function in fungal cells, interfering with various cellular processes, including mitosis -> inhibit fungal growth and replication

1. Genetic Mutations: e.g. resistance to flucytosine by preventing its transport into the cell (mutations in cytosine permease) or its intracellular conversion to 5FUMP (mutations in cytosine deaminase or uracil phosphoribosyltransferase) —> synthesize nucleotides de novo and do not depend on the salvage pathway

2. Target Alteration/Mutation: e.g. target enzyme lanosterol 14-α demethylase can reduce the azole drugs binding, rendering them less effective

3. Target overexpression: e.g. Overexpression of the ERG11 gene increases the amount of 14-α demethylase for ergosterol synthesis

4. Overexpression of genes encoding multidrug efflux pumps: e.g. Cdr1/Cdr2 or Mdr1 are membrane proteins that actively pump antifungal drugs out of the fungal cell —> reduces the intracellular drug concentration, making it less effective

5. Mutation in cellwall synthesis: Mutations in β-1,3-glucan synthase that abolish drug binding —> echinocandin resistance

1. Upregulate the expression of Drug Efflux Pumps Gene (CDR1, CDR2, and MDR1):

   • mediated by transcription factors Tac1p (regulating CDR1 & CDR2), Mrr1 (regulating MDR1), Upc2 (ERG11) —> transcription factors are activated in the presence of azoles

2. Resistance mutations in MRR1, TAC1, UPC2, and ERG11. The strain becomes more resistant when it contained the mutation in only one allele —> selective advantage für cells in the drug presence as soon as they acquire such a mutation

   -> Resistance increased further when mutations also into the second allele

1. Diarrhea:

   • Clinical Symptoms: frequent, loose, watery bowel movements. Associated symptoms: abdominal cramps, bloating, dehydration

   • Pathogens

     • E. coli: enterotoxigenic E. coli (ETEC) and enterohemorrhagic E. coli (EHEC)

     • Salmonella species, Salmonella enterica

2. Gastroenteritis:

   • Clinical Symptoms: diarrhea, vomiting, abdominal pain, sometimes fever

   • Pathogens: Norovirus, Rotavirus

3. Dysentery:

   • Clinical Symptoms: bloody diarrhea, abdominal cramps and fever —> indicates inflammation and damage to the intestinal lining

   • Pathogens: Shigella spp., Entamoeba histolytica

4. Food Poisoning:

   • Clinical Symptoms: diarrhea, vomiting, abdominal pain and nausea

   • Pathogens: Staphylococcus aureus, Clostridium perfringens

= an infection or disease that is transmissible under natural conditions between animals and humans

—> These diseases can be caused by bacteria, viruses, parasites, fungi, or prions, and can be spread through direct contact with infected animals, their bodily fluids, tissues, or by consuming contaminated food or water

1. Metabolic Signals: e.g. bile acids, SCFA, fucose

   • proximity to epithelial surface (Vibrio cholerae, EHEC)

   • location to preferred regions along the GI tract (Campylobacter, S. enterica)

2. Physico-chemical Signals: pH, osmolarity, oxygen tension

   • transition from lumen to tissue (e.g. Salmonella)

   • proximity to epithelial surface (e.g. Salmonella)

3. Quorum sensing: cell density

   • securing enough bacteria before immune system is activated (e.g. S. aureus)

• = multi-protein complex

• has spanning inner/outer bacterial membrane

• the basal body consist of several protein rings anchored to the host membrane through the translocon,

• direct delivery of effector proteins through ATPase activity into host cytosol to induce uptake and modulate host physiology

• => e.g. invasion with T3SS1 or ability to survive/replicate in macrophages with T3SS2

• (e.g. Salmonella, pathogenic E. coli, Yersinia, Xanthomonas, Pseudomonas)

—> Salmonella enterica ssp. enterica (I) serovar Typhimurium

• Salmonella typhi

• Salmonella paratyphi A

= the characteristics of 2 species (e.g. wings from birds and from bats) evolve independently from each other but have the same function. It is not correct to conclude a close relation between them only because of this characteristics

—> S. paratyphi A and S. typhi acquire different mechanisms to prevent binding of IgM (same function)

S. paratyphi A produces very long O antigen chains contain the O2 antigen, which does not bind IgM naturally

-> S. paratyphi A gets a mutation in rfbE gene that normally converts CDP-Paratose into CDP-Tyvelose, which is part of O9-antigen, which normally can be bound by IgM

-> Through the mutation in rfbE, tyvelose is exchanged by paratose => O2 antigen => cannot be bound by IgM

CT-A = mono-ADP-ribosyltransferase -> consists 2 major domains A1 & A2

CT-B = pentamer, each subunit has receptor binding capacity

• CT-A binds to host cell receptors on the surface of intestinal epithelial cells through its B subunit, then internalizes into the host cell via endocytosis

• CT-B has a high affinity for specific carbohydrate receptors found on the surface of intestinal epithelial cells —> each CT-B binds to ganglioside GM1 receptors present in lipid rafts on the host cell membrane

• Inside, A1 domain with ADP-ribosyltransferase activity catalyzes the transfer of ADP-ribose from NAD+ to a specific target protein Gsα, a component of the host cell's adenylate cyclase complex

• ADP-ribosylation of Gsα results in its persistent activation, leading to increased levels of cAMP

• Elevated cAMP levels trigger the activation of protein kinase A (PKA) -> efflux of Cl- and HCO3- into the intestinal lumen and the inhibition of Na+ uptake

  -> disruption in ion transport leads to the massive secretion of water and electrolytes into the gut lumen, causing profuse, watery diarrhea characteristic of cholera

Because C. difficile is a gram positive bacterium, so it doesn´t own Lipopolysaccharide and also no O antigen.

cytotonic toxins —> secretory diarrhea

• no structural damage to the cell

• induce secretion of water and electrolytes

• inhibit fluid absorption (leading to net fluid secretion)

e.g. Vibrio cholerae, enterotoxigenic E. coli (ETEC)

cytotoxic toxins —> inflammatory diarrhea

• profound changes to cell morphology

• cell death

• bloody diarrhea

e.g. Clostridioides difficile, Shigella dysenteriae

• EPEC, ETEC, Vibrio cholera: Secretory diarrhea

• EIEC, Campylobacter jejuni, Salmonella Typhimurium: Inflammatory diarrhea

1)  Cholera toxin

2)  CdtA (clostridium difficile transferase A), is part of the binary Clostridium difficile toxin

—> Choleratoxin CT-B5-Domain binds to monosialganglioside GM1 receptor on epithelia cells of small intestine

=> induction of endocytosis

=> retrograde transport to ER and release of CT-A (catalytic activity) and retranslocation into cytosol

=> ADP-ribosylation of α-subunit of heterotrimeric G protein

=> permanently locked in GTP-bound active state

=> permanent activation of adenylate cyclase

=> cAMP concentration increases => PKA is activated

=> phosphorylation/activation of Chloride ion channel

=> secretion of Cl into lumen of small intestine

=> to maintain osmotic balance, water is also secreted

=> Diarrhea

· C. trachomatis modulates oncogenic signaling

· Epidemiological analysis gives evidence

· Persists for a long time without symptoms

· Induces DNA damage

1) Autophagy: recognizes intracellular bacteria and engulfs them in an autophagosom -> subsequently degrade

2) Nutrients restriction by host cells -> bacteria not able to survive. Bacteria dont have a discrete metabolism and have to uptake metabolic intermediates/molecules from host to survive => metabolic adaption

-> E.g. p53 is one of the factors, it inhibits the Glucose uptake to the host cell and also glycolysis and pentose phosphate pathway -> nutrients restriction

3) Apoptosis -> infected cell is destroyed together with the bacteria. If the bacteria survive, they are targets for the immune system, e.g. neutrophils

4) Proteasomal degradation

1. Intracellular Niche: Obligate intracellular bacteria adapte to reside within host cells in specialized vacuoles or compartments

   -> intracellular location provides protection from the host's immune system, including antibodies, complement proteins and immune cells

2. Inhibition of Phagolysosome Fusion (the vacuole formed during phagocytosis) with lysosomes (organelles containing antimicrobial enzymes) -> prevents the destruction of bacteria by lysosomal enzymes -> survive within the phagosome

3. Manipulation of Host Cell Processes: e.g. alter host cell signaling pathways, cytoskeletal dynamics or membrane trafficking to create a favorable environment for replication

4. Immune Evasion: modifying their surface molecules to avoid detection by pattern recognition receptors and inhibiting the presentation of antigens to immune cells, thereby dampening the host's immune response

—> Infection by direct contact with infected animals or inhalation of pathogen-containing dust or tick feces

—> Then it is uptaken by macrophages in phagosome

• Replication in phagolysosome

• Biphasic development in phagosom => maturation => switch to large cell variant, which is metabolic and replicative active => multiplying

—> Rickettsia rickettsii

-> the life cycle of the bacteria is coupled to rodents and ticks

• Larva/nymphall tick => selffeeds blood of infected rodent (horizontal transmission) => infected transstadial (the infection is maintained in every stage of life)

• During mating male ticks can transmit infection to female tick => transmission to next generation through transovarial transmission

• Mammals/human can be infected by faeces of infected ticks, e.g. if food is contaminated or through lesions

• Another pathway of transmission could be the bit of the tick

—> Rickettsia prowazekii

-> The bacteria enters through skin or the mucosa. (Faecal of flews, lice e.g. open wounds) -> Then invades endothelia cells

• Adherence through Adhesins e.g. rOmpB => interacts mit Ub-Ku70 (kinase predominantly in nucleus) => activates remodelling of actin cytoskeleton —> induces phago/endocytosis => invasion

• endosomal escape from phagosome through haemolysin and phospholipase => prior of lysosomal fusion/maturation

• Grow in the cytoplasm through binary fission

• Rickettsia rickettsii spread to the adjacent cells very early and uses Actin based movement (Rickettsia prowazekii most likely does not)

• Spread from cell to cell or by rupture of the cell

• They are able to modulate cell signalling pathways, secretion through T4SS, induce pro-inflammatory conditions and ROS production 

-> Cells damage causes disruption of tight junctions vascular permeability

-> They can be produced in a large amount

-> Transmitted through aerosol

-> Not a high mortality rate, but results in disabling disease

-> Low infectious dose

-> Builds spore-like environmental stability

Human: Granulocyten, Endothelia cells

Tick: salivary-gland cells, mid-gut cell

positive:

o Neutrophile: no competition with other bacteria=> no other bacteria replicate there

o Host cholesterol is introduced for membrane stability

• AnkA inhibits the CYBB expression (normally enzymes which produce ROS)

• Ats1 is translocated into the mitochondria => inhibits the apoptosis

• Anka and Ats are secreted by a T4SS

=> apoptosis is inhibited

—> monocytes & macrophages

• other pathogenic bacteria: Mycobacterium tuberculosis (macrophages), Listeria monocytogenes (both), Francisella tularensis (macrophages)

• Mechanisms

• Inhibition of Phagosome-Lysosome Fusion survive within modified vacuoles -> not subjected to lysosomal degradation

• Altering Host Cell Signaling to inhibit apoptosis and promote their own survival and replication

• Escape into the Host Cell Cytoplasm: e.g. Listeria, escape from the phagosome into the host cell's cytoplasm —> avoid immune detection

• Modulating Host Immune Responses: inhibiting the production of proinflammatory cytokines -> dampen the host's ability to mount an effective defense

Microbiome = Microbial community and its “theatre of activity”. —> involves the whole spectrum of molecules produced by the microorganisms, including their structural elements (nucleic acids, proteins, lipids, polysaccharides), metabolites (signaling molecules, toxins, organic and inorganic molecules), and molecules produced by the coexisting host and structured by the surrounding environmental conditions

Microbiota = Host-associated microbial community, including bacteria, archaea, viruses (phages), fungi, protozoa

16S Profiling

• focuses on a specific region of the 16S ribosomal RNA gene in all bacteria and archaea —> Sequence amplicons

• cheap, fast, low resolution (OTU)

Whole-Genome Sequencing (WGS)

• sequencing the entire genome DNA, including all genes, non-coding regions, and intergenic sequences

• expensive, longer turnaround, high res. (species + genes)

1. Firmicutes: important roles in the fermentation of dietary fiber and the production of short-chain fatty acids (SCFAs) —> involved in energy metabolism -> associated obesity and metabolic disorders

2. Bacteroidetes: important for the degradation of complex carbohydrates and the production of various metabolic byproducts

~ 300 species / individual

b) Is covered by a compact inner and loose outer mucus layer

d) Is the densest microbial ecosystem of the human body

a) metatranscriptomic profiles are be less individualized than metagenomic profiles because they capture the active functions and activities of the microbial community, which can show more commonalities in gene expression patterns across individuals.

b) Metatranscriptomic profiles, which capture the gene expression patterns of the gut microbiota, can be more variable over time within an individual compared to metagenomic profiles.

Metagenomic profiles, which represent the genetic potential of the microbiome, are relatively stable over shorter time frames because they are influenced by the genetic composition of the microbiota, which changes more slowly

1. The commensal microorganism must be consistently present in a healthy host

2. The microorganism's abundance or activity should change with a particular health condition

3. Experimental alteration of the commensal community (composition or abundance) should affect the health status

4. Restoring the commensal microorganism should reverse the health condition

= are laboratory animals that are bred and maintained in a controlled environment where their microbial colonization is well-defined and carefully controlled

—> e.g. ex-germ-free mice that were inoculated and colonized with a defined bacterial species or consortium

Akkermansia muciniphila

-> ability to thrive on the mucin layer that lines the intestinal epithelium, which is primarily composed of mucin glycoproteins -> role in mucin degradation

—> Propionate short-chain fatty acid (SCFA)

—> Acetate

—> Butyrate

Succinate promotes Salmonella growth

—-> double-edged sword for enteric infections