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Αντιβιοτικά και μικροβίωμα εντέρου - peptiko.gr
The document discusses the effects of antibiotics on the gut microbiota and its implications for human health, including emotional well-being, metabolic disorders, and the risk of diseases such as asthma and obesity. It highlights the unique communication between gut microbes and the brain and the potential of probiotics to mitigate depression. Furthermore, it stresses the need for antibiotic stewardship to minimize harmful impacts of antibiotic use on the gut microbiome and underscores the importance of understanding the human microbiome in relation to health and disease.
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Αντιβιοτικά και μικροβίωμα εντέρου - peptiko.gr
- 1. Ειρήνη Κουρμπέτη NHS Consultant Επίδρασητων αντιβιοτικών στο μικροβίωμα του εντέρου
- 3. “Gut feelings” andmelancholic microbes Unique role of our gut microbiota in influencing emotion Gut microbe- brain communication: metabolites produced by bacteria such as short chain fatty acids Patients with depression in bugs associated with butyrate production Gut microbiota: is it sculpting our behavior? Can probiotics attenuate depression? Can a psychiatric phenotype be transferred through fecal transplant? Friedrich MJ. JAMA 2015; 313: 1699- 1701
- 4. Gut Microbes andthe Brain Dinan TG et al. Neuropsychopharmacology 2017; 42: 178-92 Routes of communication include the vagus nerve, cytokines, short chain fatty acids and tryptophan Acting through some or all these routes, psychobiotics induce an anti-inflammatory response and alter behavioral responses to stress
- 5. The Microbiome Revolution BlaserMJ. J Clin Invest 2014; 124: 4162-5 Ley RE. Science 2008; 320: 1647-51 Diversity & complexity Descent into degenerative and neoplastic diseases
- 6. Gut Microbiota Composition ThroughoutLife Span Dinan TG, et al. J Physiol 2017; 15: 489-503
- 7. Factors influencing theassembly of the infant gut microbiota Heijtz RD et al. Semin Fetal Neonatal Med 2016 xxx 1-8 Dominguez-Bello et al. PNAS 2010; 107: 11971-5 GI tract: harbors a diverse and complex community of microbes termed gut microbiota Effects on host physiology and development outside the GI system Microbiome may be the missing link
- 8. Human Microbiome beforeBirth Blaser MJ. Cell Host & Microbe 20, November 9, 2016 Heijtz RD et al. Semin Fetal Neonatal Med 2016 xxx 1-8 Dominguez-Bello MG, et al. Nat Med 2016; 22: 250-3 Vertical transmission from mothers to the children Vaginal and gut microbiota Human milk oligosaccharides stimulate the growth of beneficial microbial communities Higher proportions of C.difficile Shifts between the 1st and 3rd trimester
- 9. Cox LM, etal. Nat Rev Endocrinol 2015; 11: 182-90
- 10. Stop killing thebeneficial bacteria Blaser MJ. Nature 2011; 476: 393-4 Hviid A, et al. Gut 2011; 60: 49-54 10-20 courses until she is 18 The “friendly flora” may never recover
- 11. Antibiotics and gutmicrobiota Effects of antibiotics on the indigenous microbes of the gut have been studied since their discovery in the 1940s Over the past decade the study of antibiotics and the gut microbiota has taken a more ecological and system-wide perspective Antibiotic resistant genes are ubiquitous in present day natural environments Francino MP. Front Microbiol 2016; 6:1543 Thiemann S. Curr Top Microbiol Immunol 2016; 398: 123-46
- 12. Francino MP. Front.Microbiol 2016; 6: 1543 Thiemann S et al. Curr Top Microbiol Immunol 2016; 398: 123-46
- 13. The effect ofantibiotics on microbial diversity Thiemann S et al. Curr Top Microbiol Immunol 2016; 398: 123-46 Korpela K et al. Nat Comm 2016; 7: 10410 Usually people with multiple courses of antibiotics Use of macrolides larger and longer impact The elderly microbiome seems to be less diverse
- 14. Francino MP. Front.Microbiol 2016; 6: 1543 Thiemann S. Curr Top Microbiol Immunol 2016; 398: 123- 46
- 15.
- 16. Microbiota and CDI Seekatzet al. JCI 2014; 120: 4182-9
- 17. Protective and susceptible microbialtaxa Seekatz et al. JCI 2014; 120: 4182-9
- 18. Clostridium difficile Spores may survivefor months 1/3 of the CDI cases are not health care associated +CDT •Antibiotics •PPI •IBD •Gut microbiota & colonization resistance Seekatz et al. JCI 2014; 120: 4182-9 Thiemann S. Curr Top Microbiol Immunol 2016; 398: 123-46
- 19. Francino MP. Front.Microbiol 2016; 6: 1543
- 20. Forslund K etal. Genome Res. 2013; 7: 1163-9
- 21. Antibiotics and thegut microbiota Modi et al. JCI 2014; 124: 4212-8 Francino MP. Front. Microbiol 2016; 6: 1543 Antibiotic mediated disruption of the highly organized population can open new niches for intrusion
- 22. Bacteria with acquiredARGs that interact with commensal bacteria Thiemann S et al. Curr Top Microbiol Immunol 2016; 398: 123-46
- 23. What about treatmentfor H. pylori? H. pylori protects against some metabolic and immunological diseases in which the development coincides with temporal or permanent dysbiosis What is the effect of H pylori eradication on the human gut microbiome? Microbial diversity were similar pre- and post-eradication Decrease in the relative abundance of Bacteroidetes and corresponding increase in Firmicutes Significant increase in short chain fatty acids –producing bacteria this could also be associated with increased risk of metabolic disorders Yap TW et al. PLoS One 2016; 11: e0151893
- 24. Francino MP. Front.Microbiol 2016; 6: 1543
- 25. Compromised immune homeostasis Atopic disease-links have been demonstrated with alterations in gut microbiota- A significant association has been demonstrated with Bifidobacteria deficiency High abundance of organisms such as Clostridium coccoides and E. coli and a microbiota of low diversity Risk for several atopic diseases is increased by maternal intake of antibiotics during pregnancy Asthma- dose dependent associations between asthma and early life antibiotic exposures Broad-spectrum antibiotics show a stronger association with asthma Francino MP. Front. Microbiol 2016; 6: 1543
- 26. Compromised immune homeostasis Necrotizing enterocolitis-A low abundance of Bifidobacterium accompanied by a generally low diversity has been detected before NEC onset- preterm infants and infants of the mothers who receive- incidence of NEC IBD in children who receive antibiotics <5 years In Crohn’s they have established a reduction in Firmicutes (particularly C. leptum) and an increase in some GNB (Porfiromonadacae) IBS associated with decreased diversity Often follows bouts of gastrointestinal infection Francino MP. Front. Microbiol 2016; 6: 1543
- 27. Francino MP. Front.Microbiol 2016; 6: 1543
- 28. Dysregulated metabolism Obesity phylumlevel changes in the gut microbiota, reduced bacterial diversity, altered representation of bacterial genes and metabolic pathways Long-term exposure to antibiotics is associated with increased BMI both in humans and in farm animals Antibiotic use is therefore emerging as an important risk factor for the development of obesity Metabolic syndrome: establishment of a state of low grade inflammation which could be exacerbated by antibiotics Increased risk for type I and type II diabetes Francino MP. Front. Microbiol 2016; 6: 1543 Boursi B et al. Eur J Endocrinol 2015; 172: 639-48
- 29. Antibiotics in earlylife and obesity By the age of 3 the microbiota is similar to the adult one Divergent metabolic outcomes Exposure to high dose antibiotics with extensive and sustained reductions in microbiota can stunt growth Antibiotics that alter the microbiota composition but have limited effects on the overall microbial population size can lead to weight gain Cox LM, et al. Nat Rev Endocrinol 2015; 11: 182-90 Mahara D, et al. Genome Medicine 2016; 8: 48
- 30. Possible interactions betweengut microbiome and immune system Semenkovich CF. Diabetes 2015; 64: 3967-77 Type I Type II
- 31. Gut microbiome andbreast cancer Increased risk of breast cancer in women who chronically receive antibiotics This disturbance in gut microbiota has also been associated with increased risk for recurrence Antibiotics may also affect the metabolizing function of cancer- protective substances Immune regulation plays a significant role Estrogen metabolism Yang J., et al. Breast Cancer 2017; 17: 70-5
- 32. Take Home Messages Knowledgeof the human microbiome will alter our views on health and disease and will likely lead us to novel ways to preserve health and better treat the disease Excessively widespread use of antibiotics has created many threats increasing resistance of bacterial pathogens to antibiotics which has become a global challenge for infection control Antibiotics have a tremendous impact on the composition of the microbiome imprinting in some, but not all, long term taxonomic and functional changes
- 33. Take Home Messages Evidencehas linked antibiotic-induced disturbances in specific functions of the microbiome to enhanced susceptibility for gastrointestinal infections such as CDI Numerous studies are being conducted to understand how the microbiota affects and contributes to other human diseases such as metabolic syndrome or IBD and whether they are induced or modulated by antibiotics Strategies are needed to minimize the negative consequences of antibiotics probiotic bacteria Antibiotic stewardship in human and veterinary medicine is the essential mean to prevent the spread of antibiotic resistances but also the damage to microbiome
- 34.
Editor's Notes
- #2 Mammals are metagenomic that means that they are not only of their own gene complements but also of their associated microbes. The mammals are colonized with hundreds of microbial species that provide many advantages to the host but they must also be properly contained in order to maintain health. Host diet and phylogeny both influence bacterial diversity. The gut microbiota of humans living a modern lifestyle is typical of omnivorous primates (Ley RE, Science) Human Microbiota is an ancient assembly that has been selected to optimize host fitness. All plants and animals including humans are colonized by complex microbial ecosystems termed microbiome or microbiota. These microbes contain 100 fold more genetic potential than our genome. They contribute significantly to the physiology of their host and disturbances in the composition may lead or contribute to disease to the host. Antibiotics have been identified as one of the most important factors that may affect the human microbiome. Bacteria have lived in and on animals. Bacteroides that swell in the colon synthesize the vitamin K. The microbiota can provide functions that the host alone cannot supply such as the breakdown of essential nutrients, drug metabolism, immune development and pathogen resistance Comparisons of the overall phylogeny of the fecal microbiota have shown a strong correspondence with host phylogeny Excessive and widespread antibiotic use of antibiotics has created many threats
- #4 If you manipulate the gut microbiota in a very subtle way you can pick up a fairly robust brain signal that affects mutiple brain regions
- #6 For a long time the microbiome was just referred as the “normal flora”, a collection of plants living with us humans aνd was treated as a black box. We also tended to believe that it is homeostatic. We did not think that microbiome had much relevance to disease There is increasing evidence that the microbiome touches many pathways that affect health, disease and aging. The composition of the microbiome are involved in most of the biological processes that constitute health and disease as we proceed thru our life cycle
- #8 Birth and thereafter: the newborn is colonized with trillions of bacteria Early brain development coincides with the development of gut microbiota (synaptogenesis)- also the myelination is affected by the development of gut microbiota Mode of delivery is crucial. Dr Dominguez Bello in 2010 (PNAS- they used 16S RNA sequencing): the delivery mode has a marked influence on the acquisition and structure of the bacterial community in the infant gut. Vaginally delivered babies harbor bacterial communities resembling their own mother’s vaginal microbiome (Lactobacillus, Prevotella). On the contrary infants delivered by C section without rupture of the membranes are colonized by microbiota acquired from the mother’s skin (Staphylococcus, Corynobacterium, Propionibacterium) and other environmental sources including the health care workers and the hospital environment. Microbial products confer odors, this dichotomy raises hypotheses about mother-baby bonding. It seems that the microbial communities do not become similar to the vaginally delivered babies until the first year. The effect of maternal stress on the gut microbiome of the infant probably happens through changes in the vaginal microbiome
- #9 Vertical transmission from mothers to the children. The intrauterine environment is not sterile. Recent studies have demonstrated the presence of bacterial DNA in the amniotic fluid, umbilical cord blood, meconium, placenta and fetal membranes from healthy pregnancies without any evidence of infection or inflammation. Satokari (2009) demonstrated the presence of bacterial DNA in the placenta of healthy women that gave birth through elective C section without having any rupture of the membranes. The placenta microbiome resembles that of oral microbiome (Proteobacteria, Fusobacteria). The composition is highly sensitive to antenatal infection, antibiotic exposure and preterm birth. So the data show that transfer of maternal microbiota to the fetus may occur in utero thereby initiating the colonization of the fetal gut. Whether this bacterial DNA may represent local viable organisms or translocation via the blood stream is not clear. Still all the studies do not agree on that. Most data argue against local placenta microbiome. In the USA &gt;50% of the pregnant women receive pre-partum antibiotics. Especially if the mother receives parenteral antibiotics for GBS, this is a selective force for the maternal microbiota. The levels in the fetus and then the newborn may affect the initial microbiota of the baby. Also the residual antibiotic in the breast milk is another selective force. Antibiotic exposure through pregnancy or delivery are associated with an increased risk of immunologic and metabolic diseases. 30% of the women receive antibiotics for group B strep. The NTT is 200. We should have a better method to detect which newborns are at risk and if a vaccine should be a better approach. The treatment with peri-partum antibiotics for GBS has been found to result to reduced abundance of Bifidobacteria and lactobacillus that are commonly seen in newborns. In turn, we see that the newborns are colonized by Enterococcus and Enterobacteriacae which are opportunistic pathogens. Similarly, treatment with antibiotics within the first week reduces the Bifidobacteria and the Lactobacillus with also an increase in Enterococcus and enterbacteriacae for at least 8 weeks. Even that childhood allergy to cow’s milk was associated with antibiotics+ pregnancy antibiotics + antibiotics even 1 year before pregancy The community structure of the intestinal microbiota shifts between the first and the third trimester of pregnancy. Certain populations are favored reflecting selection for taxa with particular functions. The changes are driven by hormonal and immunologic changes that accompany and facilitate early pregnancy, There is a tendency for increase of butyrate producing organisms like Faecalibacterium prausnitzii. Probably this shift works to increase immunoregulatory T cells which may reduce the likelihood for maternal rejection. During the third trimester there is an increase in the heterogeneity with expansion of the microbiome. Each mother to be becomes differentiated in her own personal way. In a mice model the microbiota of the third trimester the microbiota induced more inflammation and increased adiposity with hyperglycaemia and increased energy storage. The increase is basically noted in the representation of certain dominant taxa Enterbacteriacae, enterococci and streptococci and these are the main categories that dominate in the early days of the infant’s life. At the end of the pregnancy there is an increase in the diversity including bifidobacteria, Clostridia and Bacteroides. In babies born vaginally the initial microbiota is similar in a variety of niches reflecting the passage through the birth canal. Swabbing the cesarean born babies with their mothers’ contents helps the restoration in the first month of life. Breastfeeding is another very important source of bacterial exchange. Breast milk contains bacteria like Staphylococcus and streptococcus spp. The oligosaccharides stimulate the growth of beneficial bacteria including bifidobacteria. It is a very important part of the baby’s life. Clinical trials may teach us how restore our ancient inheritance and optimize the health of the next generation
- #11 A baby born today should reach 78 mainly because of antibiotics The long term suppression may increase our susceptibility to infections and other diseases. Overuse of antibiotics could be fuelling the dramatic increase in conditions such as obesity, type 1 diabetes, allergies, asthma and IBD The collateral damage is more evident with the H pylori. Early 20th century the pathogen was the predominant in the stomachs of almost all people. In the turn of 21st century &lt;6% of the children in Germany, Sweden and US harbor the pathogen. The courses that the little children receive for URTI etc. may be enough to eradicate the microorganism. Stomachs that lack H. pylori are immunologically much different than the ones who do not. Experiments in mice suggest that infection with H pylori protects against experimental asthma. Be aware: The alterations in our microbiome harbors the risk of intrusion with very pathogenic bacteria. In humans, eradicating H. pylori affects the regulation of two hormones produced in the stomach and involved in energy balance, ghrelin and leptin. And as we are eradicating H pylori we increase the incidence of GERD . Can we link these trends? And of cource we know that H pylori causes ulcers and gastric cancer but why should a pathogen be so pervasive if it did not carry some benefit to the host. As the mice do also in humans, large studies have proven that people without the bacterium are more prone to develop hay fever, asthma or skin allergies. There is even a thought that along with the standard vaccinations the children may be receiving inoculations of specific strains of H pylori in order to reduce their chance of developing asthma, then to be given narrow spectrum antibiotics later in life in order to lower the risks of peptic ulceration and gastric cancer Very important conclusions may come from the study of tribes that have never received antibiotics. These studies will reveal much more about the function of our microbiome.
- #12 Ecological principles and molecular approaches are now used in research laboratories The human microbiome is heavily exposed to antibiotics not only because of the human consumption but also because of the overuse in crops and animals The ubiquitous resistance genes reflect the widespread use of human antibiotics and the strong selective pressure this use has exerted over the last 70 years. However the resistance genes are ancient. DNA sequences predicting to encode for beta lactamases have been recovered from 30K old permafrost sediment in northern BC. They were significantly divergent than the present day genes, but in at least on case (vanA ligase),the gene expressed a protein with the expected function Bacterial isolates have been recovered from ancient, protected sites that were isolated for more than 4 million years have been shown to express multi drug resistance. The presence of these genes in isolated spaces strongly suggests that the antibiotics were widely distributed in the environment and the resistance genes have been circulated for thousands of years. Modern use of antibiotics enriches for resistant genes and from a host ecological prospective it may lead to uncoupling of mutualistic relationships that have evolved over the period of time between the gut microbiota and the human host. There are natural antibiotics in the environment, them and small molecules that display growth inhibitory properties may have evolved long ago in order to serve as interspecies signaling molecules. The diversity and number of small molecules and potential antibiotics produced by gut commensal bacteria are almost certainly far greater than previously recognized Host derived free sialic acid that it is increased by some antibiotics, can be utilized by opportunistic pathogens such as Salmonella or C. difficile
- #13 Antibiotic administration can result in gut microbiota dysbiosis, ie. Disturbances in gut microbiota composition and function. Broad spectrum antibiotics can affect the abundances of 30% of the bacteria causing rapid and significant drops in taxonomic richness, diversity and evenness Depletion of bacterial diversity- This was demonstrated with Cipro affected 30% of the microbiome of the intestine of healthy adults. This had not only affected the taxonomic richness (the number of species) but also the diversity (the structure of the community). The authors really questioned if the This was proved by multiple other studies with different antibiotics. The most long term effects with long term shifts were noted for clindamycin and cephalosporin. In the clindamycin study the results were prolonged. In a study by Zaura et al they studied several antibiotics, yet only clindamycin had got statistically significant effects 4 months after treatment. At the same time, the effects in the mouth- saliva were only noticed for a week (very briefly). In the clindamycin study there was a significant decrease in the clonal diversity of Bacteroides and then there was persistence of highly resistant strains Declines and expansions in the relative abundances of certain taxa Some degree of recovery in most individuals but persistent effect in others. Medications with strong activity against anaerobes have longest lasting effects on gut community composition. Jakobbson studied the impact of Clarithromycin, metronidazole, omeprazole for 7 days: broad taxonomic compositional effects with rapid but only partial recovery in some cases and persistent effects at least 4 years after exposure Ciprofloxacin- relatively little activity against standard cultivated anaerobes has been profound effects on the gut microbiota composition. Five days of ciprofloxacin influenced the abundance of about a third of the bacterial taxa in the gut and decreased taxonomic richness within days of initial exposure. Nearly complete recovery was seen in most cases by 4 weeks after exposure, although some compositional effects lasted for 6 months. Less complete recovery after repeated short exposures
- #14 Communities at different sites have potentially distinct resilience to disturbances, that means their ability to return to their original state is distinct. Once the treatment is stopped, the microbiota may still have a certain degree of resilience being able to return to the original state, but the initial state is not usually recovered. The gut microbiota develops through the first years and affects the maturation of the immune system Decrease in the gut microbiota diversity are detectable within days of antibiotic use, althoughcompositional changes may depend on the antibiotc used as well as the underlying microbiota of the organism. The cessation of the antibiotic may result in an altered community structure. The behavior of the microbiota likely to be different in populations that have a more unstable microbiota. Specific compositions of the microbiota may predict the expansion of the opportunistic pathogen E. cloacae when the patients receive cephalosporin. Similar to newborns, elderly population have potentially higher susceptibility to antibiotic-induced disturbances of the microbiome. The microbiome also has been found to recover better in elderly people that do need assistance. People in facilities face an increased risk of nosocomial infections, the impaired or delayed recovery may affect its function preventing infections with opportunistic pathogens. Microbiota changes in the elderly include a loss in protective species such as Bifidobacteria ehile there is an increase in Bacteroidetes an some more detrimental species such as Proteobacteria and it can be associated with a decrease in the immune function in the older age. Use of macrolides in the early age such as azithromycin and clarithromycin are associated with larger and long-lasting impact on the composition of the microbiome than use of penicillin. These perturbations are stronger in children since this is a period when the microbiome assembles and displays lower resilience. Macrolides cause a shift with depletion of Actinobacteria and increase in Bacteroides and Proteobacteria and also increase macrolide resistance
- #15 Loss of colonization resistance- Loss of “competitive exclusion” – Direct inhibition of invading pathogens- competition for nutrients Attention has turned to manipulate the microbiota to interfere with VRE colonization.
- #16 The human microbiota protects the host from exogenous pathogens through a process called colonization resistance. Loss of “competitive exclusion” – This was first manifested by the easiness for colonization and disease for Salmonella immediately following antibiotic treatment. The mice experiments showed that when treated with antibiotics, they have a 10000x susceptibility to Salmonella Enterica. Both resource and direct interference competition play roles in the resistance of the intact microbiota to colonization by pathogens. Antibiotics disrupt community structure sufficiently to cause large-scale disturbances in resources and species species interactions. Indirect methods include the induction of multiple innate immune responses and effector molecules Antibiotics lead to an increase in the abundance of host derived free sialic acid that can be utilized by opportunistic pathogens such as Salmonella and C. difficile. Inhibitory substances such as nicin (class I bactericin) produced by Lactococcus Lactis and it targets Gram negative pathogens but also C.difficile Other bacteria such as Bifidobacterium secrete galactooligosaccharides which inhibit the growth of Salmonella. As the years go by we understand that the colonization resistance is also immune-mediated The mucus layer consists of a single layer in the small intestine but a double layer in stomach and colon. The inner layer is a compact dense layer that is sterile. The outer layer is loose and pathogens may enter forming a distinct microbial niche. From the other side, the microbiota also help for the production of mucus by the goblet cells. Mucin bound fucose serves as a substrate for protective bacteria, enriching bacterial diversity. The commensal bacteria induce the production of Fucose (especially fucosyltransferase) by the activation of ILC3 and Il 22 which further enriches bacterial diversity A healthy gut is comprised of diverse bacteria supporting a tight and protective epithelial barrier. The antibiotic treatment affects diversity by the loss of antibiotic sensitive commensal bacteria and the outgrowth of resistant bacteria with altered functionality resulting in disruption of the epithelial barrier. Altered colonization resistance enables invasion of pathogens, induction of inflammatory responses, and local or systemic pathology In summary, Microbiota: 1. Prevents outgrowth of GI pathogen (classical colonization R) 2. Induction of the mucus layer as well by stimulation of multiple protective immune pathways. Antibiotic treatment acts with a shift in the composition of the microbial composition because they target not only pathogenic bacteria but also a wide range of commensals. They also alter the functions of specific commensal bacteria. Antibiotic resistant pathogens expand to the lumen and then penetrate the intestinal barrier. And then we end up with infections by C difficile, VRE and MDR GNB Blood stream infections in immunocompromized individuals is another life-threatening condition that increases in risk due to antibiotic treatment. In the clinical setting, intestinal domination by VRE has been shown to precede bloodstream infection by this pathogen. In premature infants who are heavily treated with broad spectrum antibiotics the risk of sepsis has also been related tp gut microbiotacomposition and length of antibiotic treatment
- #17 To explore the pathogenecity of C. difficile we have used mice model. As in patients, mice also require pre-exposure to antibiotics in order to develop C. difficile. Disease severity correlates with a loss of Lachnospiricae. The resistance is mediated by the conversion of host derived primary bile acids to secondary bile acids by commensals inhibiting vegetative growth of C. difficile. Except for the direct colonization resistance, there is also an immunologic mechanism that prevents from the colonization with C diff. The human microbiota consumes both microbial and host-derived metabolites in order to be able to suppress the germination of C difficile spores. The microbiota may also stimulate the production of antimicrobial peptides and sIgA that can stop the germination of C difficile spores. With the changes in microbiota as a result of antibiotics, there is a problem of the microbiota to consume microbial and host metabolites. That results in a different functional state that promote spore germination and vegetative outgrowth. An altered microbiota results in an imbalanced immune response through loss of immune regulation and a proinflammatory state. Toxin production can stimulate the production of inflammatory cytokines, neutrophils and antitoxin antibodies
- #18 It is very difficult to know the taxa that are correlated with protection since we do not have prospective feces collection in people before tey develop CDI. The infants are a special category of people.
- #19 CDI is the most common health care associated infection C difficile is an obligate anaerobe acquired by the ingestion via fecal-oral route. The spores may survive in the environment and they are even resistant to alcohol based cleaners. The disease development follows the consumption of antibiotics which leads to loss of colonization resistance and subsequent CDI Most of the cases are health care related , but a percentage occurs in the community and it is not even antibiotic related. About 1/3 of the cases are not health care related. The spores have been detected in various environmental sources. Including domesticated animals, water and food sources. A very important reservoir of C difficile is the infant population. There is an estimated 45% colonization with C difficile. The microbiome of the infants is distinct when compared to the one of the adults. This distinct microbiome plays an important role in both colonization resistance and disease development. The infants rarely develop disease. They may lack the receptor necessary for the development of the disease. A maternal IgA may be protecting against toxin binding. The germination of the spores depends on the presence of specific primary bile acids (such as taurocholate). On the contrary some secondary bile acids (such as deoxycholate) inhibit the growth of C.difficile. Since the bile acids are transformed by the microbiota, you may appreciate how important the changes that are caused by the antibiotics are TcdA & TcDB are produced through the stationary phase of the growth and are largely responsible for the damage that we encounter in the intesinal epithelium. CDT disrupts the actin cytoskeleton and its presence may increase the strain virulence, however its presence does not always correlate with disease severity. Other factors that may be associated with CDI development: PPI that increase the Ph in the stomach but they may also affect other areas of the GI tract. Through this mechanism, they may be capable of modulating the microbiota. In vitro studies have also shown that PPIs can affect the growth of Lactobacillus The microbiota of the people with IBD is slightly different and there are more Proteobacteria.
- #20 The dysbioses brought about by antibiotics have the added disadvantage of enriching the microbiota in R organisms. The microbiome has been established as a significant reservoir of antibiotic resistances. In the Jacobsson study patients treated with a clarithromycin containing combination antibiotic regimen for H pylori associated peptic ulcer exhibited 1000 fold increases in the ermB resistance gene which encodes the macrolide target modifying RNA methylase. There were comparable levels of the resistant genes even four years later. Subtherapeutic doses also appear to result in the enrichment of resistant genes. The use of ASP 40 growth enhancing cocktail in swine feed produced significant increases in resistant genes after only 3 days of exposure.
- #21 The microbiome has been established as a significant reservoir of antibiotic resistances. There is a very significant study that analyzed 252 fecal genomes from different countries and it identified resistance genes for 50/68 antibiotic classes and subclasses that were screened for with an average of 21 per sample. Resistance gene penetration is higher for antibiotics approved for use in animals, them or their analogs. Also, it is very important that there is more ARG carriage with antibiotics that are in veterinary usage, also it increases by time in use. Resistant genes are more abundant in samples from Spain, Italy and France than from Denmark, US or Japan. There is a very significant study that analyzed 252 fecal genomes from different countries and it identified resistance genes for 50/68 antibiotic classes and subclasses that were screened for with an average of 21 per sample. Importantly, european samples showed enrichment in resistances to vancomycin although an analog to treat animals has never been employed. Abundance in ARGs more in the southern Europe and that correlates with measures of total outpatient antibiotic use. This seems to confirm the notion that a higher exposure to antibiotics increases the likelihood of resistance acquisition by gut microbiota. Not only the microbiota of adults constitute s a resistance reservoir but children and infants also harbora variety of ARGs. Numerous ARGs can already be identified in feces of 1 week old babies and even in meconium. The worst is that ARGs have also been identified in infants and isolated human populations that have never been administered antibiotics. ARGs can be stably maintained in the human gut microbiome in the absence of direct antibiotic selectionnad it is consistent with the fact that ARGs can be detected in a large range of natural environments. In infants resistances may be vertically inherited as maternal gut microbe can be transmitted to the offspring. Several studies have demonstrated shared ARG pools between mothers and infants fecal samples. And in some cases there is presence of shared ARGs in meconium, colostrum and breast milk. These studies have also detected ARGs in infants that they were not present in the mothers. About the remote human populations, the presence of ARGs in their microbiota suggets two possibilities: 1. either they are ancestral and were present before the rampant spread of resistance, probably imposed by naturally occurring antibiotics. 2. they have been acquired recently by dispersion of antibiotic resistant strains from other areas and by horizontal transfer of genes from such strains.
- #22 Antibiotics disrupt community structure- large scale disturbances in resources and species-species interactions. They alter the the microbiota, reducing bacterial diversity and redistributing member composition in both transient and persistent effects. Changes in the microbial community architecture lead to changes in resource availability and species-species interactions opening niches available for pathogenic intrusion and leading to the loss of colonization resistance. Antibiotics select for antibiotic-resistant community members enriching the presence of resistance genes in the microbiome. Treatment with antibiotics promotes the transfer of genetic information among bacteria promoting conjugation, phage transduction and plasmid mobility. The pili not only serve as intercellular mating bridges but they also promote cell adhesion aiding in colonization of the GI tract. Conjugation, phage transduction and natural transformation Intercellular movement of DNA is further facilitated by its intracellular mobilization such as by transposons and mobile integrons.Transposons and integrons can translocate to plasmids facilitating their transfer Gene transfer is common in the gut. Human associated bacteria exhibit HGT in 20- 40% of all pairwise bacterial comparisons Donor and recipient cells physically connected through the formation of a pillus and DNA copied from one cell flows to the next. Cells can transfer plasmid DNA and chromosomal DNA 2. The phages can transduce DNA from one host cell to the other. 3. Certain bacterial species can take up free DNA for the environment using membrane protein complexes. Horizontal transfer of genes: transfer of ARGs between gut microbiota. Transfer of ARGs between gut microbiota isolates of the genus Bacteroides among them and between them and Gram positive bacteria. Identical ARG sequences have been identified in bacteria coexisting in the in the gut of a single individual, including different strains of E coli as well as distantly related organisms. The transfer conjugative transposons can be stimulated 100 or 1000x by low concentrations of antibiotics. Many ARGs that are present in the gut microbiota are identical at the nucleotide level to resistance genes from human pathogenic isolates. Human gut: not only a site of accumulation of ARGs but also an environment where these genes can spread across species boundaries In the clinical setting, in the immunocomprpmized patients, the colonization and intestinal outgrowth with VRE has been shown to precede blood stream infection with this pathogen. E faecalis and E. faecium are the two most prevalent enterococci in the human intestine. They comprise &lt;1% of the human microbiota. However administration of antibiotics to treat unrelated infections in humans can facilitate the expansion of VRE which can then translocate into the tissue and cause bloodstream infections, especially in older or immunocompromized individuals. Subsequent disruption of the microbiota by antibiotics in patients carrying antibiotic-resistant Enterococcus predisposes them to their expansion. New niches for occupation- co localization of pathogenic and commensal communities offers opportunities for the transfer of resistance to virulent species The complexity of these disturbances arising from antibiotic treatment highlights the importance for developing augmented or alternative antimicrobial therapies that minimize consequences to the microbiome It remains unclear how other mechanisms are utilized to mediate protection in the face of antibiotic perturbation
- #23 The intestinal microbiota serves as reservoir for ARGs which can be transferred to pathogens that enter the intestines via contaminated food or water. All these resistances may be transferred from baceria to bacteria through Horizontal gene transfer. The high cell density in the intestinal microbiota is favorable for horizontal gene transfer. The bacteria in the microbiota contain a pool of related ARGs although the encoding bacteria are not closely related to each other. This means that there is a high incidence of HGT between members of the microbiota, more over even bacteria that are taxonomically distinct can still share a group of related ARGs
- #25 The microbiota alterations caused by antibiotics can also affect basic immune homeostasis with body wide and long term repercussions. Atopic, inflammatory and autoimmune diseases have been linked to hut microbiota dysbiosis and in some cases significant associations have been established between these diseases and the intake of antibiotics in early life.
- #26 The associations suggest that early antibiotic use would likely increase the risk for atopic disease. The links have been controversial
- #29 Boursi et al demonstrated a higher adjusted risk for tyoe 2 diabetes among individuals with recurrent exposures to penicillin, cephalosporins, macrolides and quinolones. There was no increase in adjusted adjusted risk for exposure to anti-viral or anti-fungal medications. The results are consistent with the description of altered microbiota in obese individuals as well as in subjects with insulin resistance and increase in obesity among individuals exposed to antibiotics during the first year of life
- #30 As a result of its instability the microbiota in infancy is particularly to antibiotic disruption and having an altered microbiota can affect growth and development later in life The divergent metabolic outcomes may include excessive weight gain or stunted development In theory it is likely that these disruptions must pass a threshold in order to exert an effect and a limited perturbation with a rapid recovery might not result in altered weight or adiposity. The microbiota induced metabolic changes are layered on top of other factors that also can have a strong effect on metabolic development The growth stunt can be mediated through altered immunological signalling or decreased production of microbiota derived calories and nutrients This may happen by reducing key metabolically protective microbiota species, increasing the production of SCFA, altering hepatic function and levels of circulating metabolic hormones or by altering intestinal defences (lowering energy costs) There is a murine model that confirms that microbial gut perturbation caused by antibiotics leads to obesity and NASH
- #31 For Type I diabetes: The microbial composition may be impacted by sex or sex steroids which can also affect the autoimmunity. The altered bacterial products may directly promote inflammation and lead to what we call a “leaky gut” leading to a higher accumulation of microbes in the bloodstream and conribute to increased inflammation. Also on the mucosa, the balance between pro and anti inflammatory responses can also lead to severe inflammation. A severe inflammation can induce autoimmunity Again in the development of type II diabetes, the metabolites and products may directly promote inflammation. They may also lead to increased leakage leading to increased gut and metabolites in the blood . This ends up in increased inflammation and inflammation in adipose tissue promotes obesity that ends up to type II diabetes. Inflammation may favor the maintenance of specific gut microbes that may produce inflammation promoting metabolites leading to a vicious cycle