THE HUMAN MICROBIOME: THE INFECTION

THE HUMAN MICROBIOME:THE INFECTION PREVENTIONIST’SBEST FRIENDMichigan Communicable DiseaseConferenceMay 4, 2017Richard A. Van Enk, Ph.D., CICDirector, Infection Prevention and Epidemiologyvanenkr@bronsonhg.org

What you will learn Describe the new science of human microbiomestudies Define the terms and techniques used inmicrobiome science Identify important characteristics of the humanmicrobiome Identify ways we harm the patient’s microbiomethrough medicine List things we can do to protect the patient’smicrobiome2

Why study the humanmicrobiome? 90% of the cells in the humanbody are bacteria– Some viruses and fungi– 3% of body mass 99% of the genes in the humanbody are microbial 10,000 unique species, mosthave never been cultured Our microbiome has evolvedwith us, is in constantinteraction with us andcontributes to health anddisease Understanding our microbiomewill open up a new world ofmedicine3

The human microbiome project http://www.hmpdacc.org/ Started in 2008 as a 5-yearproject Modeled on the humangenome project that mapsevery gene on the humanchromosome Focused on five body sites;mouth, skin, vagina, gut, andrespiratory tract Uses 16s rRNA andmetagenomic sequencing todevelop a map of the entirehuman microbiome4

What do we know about the humanmicrobiome? It is like another organ Can be core and transient Parts of the body we thoughtwere sterile have a microbiome Can change over time Differences within thepopulation Similarities with race and family Relationship to health anddisease Unstable up to age 2-3, thenstabilizes Protects us from infection5

Human Microbiome Project goals Develop a reference set of microbial genomesequences and characterize the normal humanmicrobiome (finished 6/13/2012) Explore the relationship between disease andchanges in the microbiome Develop new technologies and tools forcomputational analysis Establish a resource repository Study the ethical, legal and social implications ofhuman microbiome research6

Microbial ecology definitions Diversity; how many different strains live in a community Invasion; establishment of a foreign organism in acommunity Metagenomics; a culture-independent method used forfunctional and sequence-based analysis of a community Microbiome; the sum of microbial genes in a community Microbiota; the sum of the microorganisms in a community Metabolome; the microbiota’s metabolic capability Stability; the ability of a community to maintain its structureover time Resilience; the ability of a community to return to its nativestate after a perturbation Dysbiosis; disruption of the normal microbiome structure7

Ways to study the human microbiome The Human Microbiome Project uses new methodsto study complex microbial communities and theirecological relationships– Simple metagenomics; what species are present– Taxonomic diversity; how many different types andwhich types of microorganism are present; thecommunity structure, described as alpha, beta andgamma– Functional metagenomics; the metabolic capability ofthe population, regardless of the species All of these are very important to health8

How the human microbiota begins The fetus is almost sterile, has a small microbiome Most colonization begins at birth– Vaginal delivery gives the baby the mother’s vaginal andintestinal flora immediately, becomes stable quickly– Cesarean delivery deprives the baby of normal flora,acquires normal flora randomly and incompletely, longerperiod of instability and less colonization resistance As the baby encounters new microorganisms, theirmicrobiome matures, depending on their environment– Breast-fed babies have very different gut microbiota thanformula-fed babies The human microbiota is quite mature by about age 2and remains stable for life9

Benefits of the human microbiota Protection from infection by competitiveexclusion (colonization resistance)– By occupation of binding sites, receptors– By consuming or sequestering essential nutrientsfrom pathogens (siderophores)– By production of bacteriocins Development of a healthy immune system– Normal flora in infancy induce T supressor cells thatdown-regulate the immune response, producingimmune tolerance and avoiding hypersensitivity10

Unexpected findings Effects on the immune system– More, and more types of bacteria are better Effects on nutrition– Microbiome changes with diet– Proposed three human enterotypes based on thepredominant microbiota– Microbiota metabolize nutrients, produce vitamins Effects on the neurologic system– Proposed neurologic microbiome-gut-brain axis ofcommunication– Gut bacteria produce neural signals that may beconnected to autism, depression, anxiety, stress11

The vaginal microbiota The microbiomes ofnormal and vaginosispatients are drasticallydifferent The normal microbiomeis dominated byLactobacillus The vaginal microbiomecontributes to the baby’smicrobiome Vaginitis is mostly adisease of dysbiosis12

The gut microbiota The intestinal microbiome correlates more than otherswith health and disease (largest microbiota) Gut flora have 150 times more DNA and enzymes thanhuman enterocytes– Key to nutrition; synthesize vitamins and amino acids,harvest energy Three enterotypes Pronounced differences in the gut microbiomes ofnormal humans and those with obesity, malnutritionand inflammatory bowel disease– Currently an association; causation is not clear– Transplanting normal GI flora into diseased patients curessome diseases13

Question The effect of an antibiotic on a patient ends:1. When the drug level in the patient drops belowthe minimum inhibitory concentration forbacteria (hours)2. When all the antibiotic is metabolized orexcreted (days)3. When the patient’s insurance pays the bill(weeks)4. When the patient’s microbiota returns to normal(months to years, maybe never)14

Antibiotics and the microbiome The effects of antibiotics on the humanmicrobiome are drastic and long-lasting– One dose of antibiotic can change the microbiome for amonth, sometimes for 2 years– The number of doses and courses matters A study showed that the patients’ microbiome recovered afterone course of ciprofloxacin but not two– Antibiotics kill components of the normal flora Reducing the total numberReducing the susceptible strainsReducing the population diversitySummarized as dysbiosis– Some taxa are difficult to recover15

Antibiotics and the microbiome16

Antibiotics and the microbiome The effect is cumulative; combinations of antibioticscause more dysbiosis than monotherapy Subclinical antibiotics also do this (antibiotics in ourfood; how does that happen?) Many common infections are caused by dysbiosis or therisk increases with antibiotics––––Antibiotic-associated diarrheaClostridium difficile colitisBacterial and yeast vaginitisFoodborne bacterial infections (Salmonella, Shigella,Campylobacter)17

Antibiotic resistance and themicrobiome Exposure of the human microbiome to antibioticsdoes shifts the community to a more resistantpopulation; increases the prevalence of resistancegenes in the population; the resistome– Resistance genes can be on mobile genetic elements(plasmids) and hide in non-culturable bacteria– Macrolide resistant genes persisted in the intestinemicrobiome for up to 4 years following macrolidetreatment Antibiotic resistant bacteria do not have anadvantage and will not spread in the absence ofantibiotics18

Example of microbiota management inclinical medicine Fecal MicrobiotaTransplantation (FMT)– FDA-approved for C. difficilecolitis– Replace dysbiotic GImicrobiota with healthymicrobiota through an NJ tube– Cures much better, faster andsafer than antibiotic– Patient improves the same day,has normal GI function in 24hours19

Question The most important factor preventinghospital-acquired infections in patients is:1.2.3.4.5.How clean their room is at admissionHandwashing by staffGiving prophylactic antibiotics for surgeryDaily chlorhexidine bathingReducing dysbiosis20

What does this mean for infectionprevention? The dominant belief in infection prevention hasbeen that microorganisms are the threat and theanswer to infection is to kill them all The answer to multi-drug-resistant pathogens ismore, and more powerful antibiotics Now, we need to change our paradigm:– Cleaner is not necessarily better– Antibiotics, disinfectants, hand sanitizer, haveunintended consequences– Fighting antibiotic resistance with more antibiotics isdoomed to fail21

What does this mean for infectionprevention? One of the mostimportant things we cando to reduce the risk ofinfection in our patientsis to supportantimicrobialstewardship programsin our hospitals– Your pharmacist is yourfriend– Optimize antibiotic useto minimize exposure22

Who is more susceptible to infection(and allergies)?23

Changes in medical practice Reduce antibiotic exposure to patients– Non-therapeutic courses (surgery, dental procedures,empiric use)– Shorten the course– Look at surgical prophylaxis Target antibiotic treatment as narrowly aspossible (versus “broader is better”) Discontinue using antimicrobial soap for bathingand handwashing Discontinue antibiotics in animal feeds24

Changes in medical practice Consider the role ofprebiotics and probiotics– Prebiotics; functionalfoods; vegetable fiber thatchanges the microbiota Asparagus, artichokes,bananas, oatmeal, legumes.– Probiotics; consuming livegood bacteria to displaceunwanted species yogurt25

Changes in medical practice Fecal Microbiota Transplantation (FMT, stooltransplant) for microbiota-related entericdisease– Accepted for C. difficile colitis– Antibiotics are not the answer to perturbedintestinal flora, they are the problem– Procedure has become mainstream– Extremely effective– Approved by the FDA, there is a billing code for it– Doctors still don’t know about it or recommend it26

Human microbiome future directions We will better understand the effects of themicrobiome on health and disease by comparinghealthy controls with disease patient data to identifydifferences We may be able to reverse some diseases byrestoring healthy microbiomes We will understand the effect of antibiotics on thepatient and develop more targeted therapies towardpathogens that protect more of the microbiome27

Human microbiome researchapplications to medicine The treatment and prevention of infectiousdiseases may evolve to include not just usingantibiotics and vaccines but using probiotics andprebiotics to manage the patient’s microbiome The diagnosis of some diseases may involvemetagenomic microbiome analysis instead ofdoing cultures for specific pathogens– Stool analysis for microbiome to assess the gut ecologyrather than looking for a few pathogens– The “normal flora” we ignore in the clinical laboratorymay have the answer to the patient’s disease, not the“pathogens”28

What do physicians need to do? Own the patient’s microbiome and protect it asmuch as you can Realize that all antibiotics are toxic Do not give antibiotics when not absolutelynecessary; consider other approaches Use the most narrow spectrum and shortestcourse you need to cure the infection Remember the resistome29

Thank you!bronsonhealth.com30

intestinal flora immediately, becomes stable quickly – Cesarean delivery deprives the baby of normal flora, acquires normal flora randomly and incompletely, longer period of instability and less colonization resistance As the baby encounters new microorganisms,