BIO3124 - The Human Microbiome 2023 PDF

Microbial symbiosis with humans Norton textbook Chap. 23 Picture taken from Huffpost Chapter Overview § Human microbiome § Benefits and risks of harboring microbiota § Overview of the immune system § Physical and chemical host defenses § Innate immunity: Surveillance, cytokines, and inflammation § C...

Microbial symbiosis with humans Norton textbook Chap. 23 Picture taken from Huffpost Chapter Overview § Human microbiome § Benefits and risks of harboring microbiota § Overview of the immune system § Physical and chemical host defenses § Innate immunity: Surveillance, cytokines, and inflammation § Complement and fever 2 ”We … proceed through our lives in their presence. When we eat so do they. When we travel, they come along. When we die they consume us." Ed Yong, I contain multitudes. Introduction § The human body teems with microbial hitchhikers. Most are harmless. Many are beneficial to the host. § All sites on a human that contain microorganisms are part of a microbiome. § A microbiome is a functional collection of different microbes in a particular environmental system (e.g., the human microbiome). § Scientists use the term microbiota to describe all the microbes in a microhabitat (e.g., skin microbiota). § Different microhabitats support different microbes, so the skin will have very different microbes than the mouth. 4 23.1 The Human Microbiome Our bodies carry about as many bacterial cells as human cells (1013 to 1014 microbes ), and about 100 times more nonredundant bacterial genes than human genes. https://www.college-de-france.fr/media/philippesansonetti/UPL5651126360200390895_Cours_Psansonetti_11122014.pdf 5 Overview of our different microbiota niche § Skin microbiota § Oral cavities and airways microbiota § Urogenital tract microbiota § Gastro-intestinal microbiota 6 Skin microbiota The skin is difficult to colonize (dry, salty, acidic, protective oils) Regardless, there are approximately 1 million resident bacteria per square centimeter of skin for a total of about 1010 skin microorganisms covering the average adult, especially in moist areas (scalp, ears, armpits, genital, and anal areas). Composition is influenced by: § § § environmental factors (e.g., weather, pets) host factors (e.g., age (puberty), personal hygiene) Each microenvironment shows a unique microbiota. Source: The Scientist Three main microenvironments: § § § dry skin (Proteobacteria) moist skin (Corynebacterium and Staphylococci) sebaceous skin (Propionibacteria (causes acne) and Staphylococci) 7 Skin physiology/anatomy Two distinct layers: § Epidermis: Keratinocytes Squames (enuclated keratinocytes crosslinked to fortify the skin barrier) § Dermis: Sub-cutaneous tissues, include sebaceous and sweat glands, hair follicles and immune cells. § Mostly Gram-positive bacteria More resistant to salt and dryness Staphylococcus epidermidis Cutibacterium acnes (formerly Propionibacterium acnes) ― Degrades skin oil ― Inflames sebaceous glands ― Causes acne Byrd, A., Belkaid, Y. & Segre, J. The human skin microbiome. Nat Rev Microbiol 16, 143–155 (2018). https://doiorg.proxy.bib.uottawa.ca/10.1038/nrmicro.2017.157 8 Skin microbiota is shaped by physiological characteristics (Forehead) Byrd, A., Belkaid, Y. & Segre, J. The human skin microbiome. Nat Rev Microbiol 16, 143–155 (2018). https://doiorg.proxy.bib.uottawa.ca/10.1038/nrmicro.2017.157 9 Immunology in the skin Immunology in the skin, Nature video, 2014, 7:23min https://www.youtube.com/watch?v=_VhcZTGv0CU Skin commensal interactions with S. aureus Abx produced by coagulase-negative Staphylococcus prohibit colonization of S. aureus. S. epidermidis can inhibit S. aureus biofilm formation with production of the serine protease glutamyl endopeptidase (Esp). Esp-expressing S. epidermidis induces keratinocytes to produce antimicrobial peptides via immune cell signalling, killing S. aureus. S. hominis-produced lantibiotics synergize with human antimicrobial peptide LL-37 to decrease S. aureus colonization. Propionibacterium acnes produces a small molecule, coproporphyrin III, that promotes S. aureus aggregation and biofilm formation. Byrd, A., Belkaid, Y. & Segre, J. The human skin microbiome. Nat Rev Microbiol 16, 143–155 (2018). https://doi-org.proxy.bib.uottawa.ca/10.1038/nrmicro.2017.157 11 Oral cavities and airways microbiota The oral cavity is a complex, heterogeneous microbial habitat. § Saliva contains antimicrobial enzymes. § But high concentrations of nutrients near surfaces in the mouth promote localized microbial growth. Canadian Dental Association position on prevention of infective endocarditis The oral microbiota are normally harmless, but they can cause disease. Dental procedures, for instance, will often cause these organisms to enter the bloodstream, producing what is called bacteremia. § This can ultimately lead to subacute bacterial endocarditis. 12 Respiratory track anatomy Microbes thrive in the upper respiratory tract. Bacteria continually enter the upper respiratory tract from the air during breathing. Most are trapped in the mucus of the nasal and oral passages and expelled with nasal secretions or swallowed and then killed in the stomach. The lower respiratory tract has a limited microbiota in healthy adults. Ciliated mucosal cells move particles up and out of the lungs. Wikipedia 13 Oral and Nasal Cavities At first, a human infant’s mouth is colonized with: § Nonpathogenic Neisseria (Gramnegative) § Streptococcus, Lactobacillus, Actinomyces (Gram-positive) As teeth emerge, other bacteria start growing: § Prevotella; Fusobacterium: between gums and teeth § Streptococcus mutans: tooth enamel Nasopharynx and oropharynx are populated by Staphylococcus aureus and S. epidermidis. § Also by harmless streptococci 14 Lower Respiratory Tract § Originally thought to be sterile, the lungs and trachea harbor normal microbiota. Most prominent: Prevotella, Streptococcus, and Veillonella § The ciliated mucous lining of the trachea, bronchi, and bronchioles makes up the mucociliary escalator. Sweeps foreign particles up and out of the lung 15 Particularities of the lungs § The anatomy of the lungs, allowing gas exchange, is very delicate. A strong immune response causes tissue damage that could kill. The immune response must therefore be particularly well controlled and almost surgeon-like in its precision. § The epithelial cells are able to defend themselves largely by themselves! Secretion of mucus Secretion of surfactants that normally decrease surface tension but can also be microbicides Can detect pathogens and secrete microbicidal polypeptides, or cytokines such as IL-25 and IL-33, following their activation § A large population of resident alveolar macrophage constantly clear debris and intruders by phagocytosis. § Dendritic cells (DCs), present in the respiratory epithelium, also seem to set the tone for the immune response with their ability to present Ag to cells of adaptive immunity. 16 Alveolar structure in the lungs Respiratory epithelial cells orchestrate pulmonary innate immunity. Jeffrey A Whitsett & Theresa Alenghat, Nature Immunol. Vol16 (1) Jan 2015 Immunology of the lung (asthmatic response) https://www.youtube.com/watch?v=rgphaHmAC_A 6:28min Urogenital tract microbiota § Kidney and bladder normally sterile. § Altered conditions can cause potential pathogens in the urethra (such as Escherichia coli and Proteus mirabilis) to multiply and cause disease. § E. coli and P. mirabilis frequently cause urinary tract infections in biological women, for example, when the pH changes. § Urinary tract infections (UTIs) are one of the most common infections worldwide affecting over 100 millions people each year1. 12-15% of biological women annually, 50% by their 32nd birthday2. In Canada, in the top ten most common reason for consulting a doctor (GP or emergency)2. (Is there a place for pharmacists to alleviate the pressure on the Health System?) 1 (Microbiology 2nd ed Openstax Rice University) (Sanyal, C., Husereau, D.R., Beahm, N.P. et al. Cost-effectiveness and budget impact of the management of uncomplicated urinary tract infection by community pharmacists. BMC Health Serv Res 19, 499 (2019). https://doi.org/10.1186/s12913-019-4303-y 2 19 Urogenital tract microbiota § Sexually transmitted disease (STIs) sometimes included in UTIs, although UTIs generally refer to bladder infections. § STIs also primarily affect the urogenital system and are an important cause of patient morbidity.1 (CDC) estimates that there are approximately 20 million new cases of reportable STIs annually in the United States.1 half of which occur in people aged 15–24 years old.1 1 (Quoted directly or slightly modified from Microbiology 2nd ed Openstax Rice University) 20 The microbiota of the genital tract of biological women § The vagina of the adult female is weakly acidic and contains significant amounts of glycogen. § Lactobacillus acidophilus, a resident organism in the vagina, ferments the glycogen, producing lactic acid. § Lactic acid maintains a local acidic environment (pH~5.0). § L. acidophilus only colonizes the vagina at puberty and disappears during menopause. Before puberty and after menopause, pH is neutral (no lactic acid being produced), so the microbiota changes as biological women become fertile or lose their fertility. § Yeasts like Candida are commensals that can cause opportunistic infections, for example, when L. acidophilus is displaced and can’t protect the mucosa anymore (after Abx trx, douching, or sexual intercourse (semen is alkaline)). Microbiology 2nd ed., Rice University OpenStax Figure 23.4 L. acidophilus 21 The microbiota of the genital tract of biological men § § § § § § § § Male genitalia microbiota understudied. Circumcision is the largest influence on the composition of the penis microbiome, fewer anaerobic bacteria within six months after the men in a study were circumcised. https://doi.org/10.1371/journal.pone.0008422 Age and sexual activity are other factors affecting microbiota composition. Species found resemble that of the gut (Bacteroidetes and Firmicutes) Unknown yet if commensal microbiota present is preventative of diseases like chlamydia or contributes to its colonization by providing nutrients for C. trachomatis. Female and male partners seem to share genital microbiota. Anaerobes associated with bacterial vaginosis also found on https://www.aboutkidshealth.ca/Article?contentid=461&language=English uncircumcised penises. Anal receptive intercourse in both homo- and heterosexuals can For more information: contribute to the spread of anorectal STIs or other microbial infections. https://www.the-scientist.com/news-opinion/parsing-theRead more about it here. penis-microbiome-37436 Safe anal sex practices considerably reduce potential negative health effects. Read more about that here. 22 Gastro-intestinal microbiota § Humans are monogastric and omnivorous. § Microbes in gut affect early development, health, and predisposition to disease. § Colonization of gut begins at birth. § Consists of stomach, small intestine, and large intestine § Responsible for digestion of food, absorption of nutrients, and production of nutrients by the indigenous microbial flora 23 As pH increase, so does the # of cells More and more anoxic 1-4h to transit from stomach to the large intestine 24h from mouth to anus Source: Brock Biology of Microorganisms, 15th ed., Pearson. Gastrointestinal Microbiota Overview § The vast majority (~98 percent) of all human gut phylotypes fall into one of three major bacterial phyla: Firmicutes, Bacteroidetes, and Proteobacteria. § Individuals may have mostly Firmicutes, or mostly Bacteriodetes, or a mix of the two. § In contrast to the limited phylum-level diversity, the species diversity in the mammalian gut is enormous (3,500 to 35,000 species but no more then ~200 in one individual). § Archaea, yeasts, fungi and protists are either absent or form a very little part of the gut community in humans. McCallum, G., Tropini, C. The gut microbiota and its biogeography. Nat Rev Microbiol (2023).. https://doi.org/10.1038/s41579-023-00969-0 Stomach and small intestine § The acidity of the stomach and the duodenum of the small intestine (~pH 2) prevent many organisms from colonizing the GI tract. Few microbes survive. Helicobacter pylori Survives stomach at pH 1 ― Burrows into protective mucous lining ― Occasionally may causes gastric ulcers § Helicobacter pylori was discovered in the 1980s and has since been found in ~50% of the world’s population! When present, it is found in the gastric mucosa. § Decreased stomach acidity = Hypochlorydia Caused by malnourishment Vibrio cholerae survives stomach passage. ― Establishes infection in less acidic intestine 26 Large Intestine § The intestine contains 1011–1013 bacteria/gm of feces. Ratio of 1,000 anaerobes:1 facultative organism The small amount of oxygen that diffuses from the intestinal wall into the lumen is immediately consumed by facultative bacteria such as E. coli. § Intestinal microorganisms carry out a variety of essential metabolic reactions that produce various compounds. vitamin production modification of steroids amino acid biosynthesis § The Large Intestine: The colon is essentially an in vivo fermentation vessel (anoxic so no respiration using O2 as final electron acceptor), with the microbiota using nutrients derived from the digestion of food. Most organisms are restricted to the lumen of the large intestine, while others are in the mucosal layers. 27 Effect of gut microbiota on its human host Development of innate and adaptive immunity Microbial barrier Maintain epithelial integrity Source of energy Vitamin biosynthesis, transformation of bile salts, catabolism of complex plant sugars (cellulose, pectins) and mucins. Metabolism of xenobiotics Modified from https://www.college-de-france.fr/media/philippesansonetti/UPL5651126360200390895_Cours_Psansonetti_11122014.pdf Microbial and gut interactions differ depending on intestine anatomy SFB: segmented filamentous bacteria McCallum, G., Tropini, C. The gut microbiota and its biogeography. Nat Rev Microbiol (2023). https://doi.org/10.1038/s41579-023-00969-0 29 Mucus is your friend – mucins are heavily glycosylated proteins Yong Hua Sheng and Sumaira Z. Hasnain, Front. Cell. Infect. Microbiol., 14 June 2022, Vol.12. https://doi.org/10.3389/fcimb.2022.856962 Mucus depletion in inflammatory bowel disease Healthy Inflamed McCallum, G., Tropini, C. The gut microbiota and its biogeography. Nat Rev Microbiol (2023). https://doi.org/10.1038/s41579-023-00969-0 31 GALT (the gut-associated lymphoid tissue) Vangoitsenhoven, Roman & Cresci, Gail. (2020). Role of Microbiome and Antibiotics in Autoimmune Diseases. Nutrition in Clinical Practice. 35. 10.1002/ncp.10489. Illustration by Dave Schumick, BS, CMI. Cleveland Clinic Center for Medical Art & Photography © 2020. All Rights Reserved. 32 Immune response to a gut infection By constantly monitoring intestinal antigens, the immune cells of the gastric mucosa are always on the alert and eliminate threats locally, without our knowledge. For there to be an immune response the following conditions must be present: 1- There must be stimulation of the innate cells. Physical barriers must be broken The balance between pathogenic and commensal must be broken (ecological niche favorable to pathogens) Or a deregulation of the innate system favorable to pathogens 2- The severity of the pathology is a consequence of the host / pathogen relationship Virulence of microΦ influence immune response Aggressiveness, opportunistic microΦ, toxin, quantity of pathogens ingested? Quality and number of commensals Presence of immune deficiency (over or under activation) Break in tolerance (overreactive immune response) 33 Dysbiosis and/or virulence = pathogenesis No curli fiber = no disease With curli fiber = disease Rice University Microbiology 2ed, OpenStax Figure 24.1 E. coli O157:H7 causes serious foodborne illness. Curli fibers (adhesive surface fibers that are part of the extracellular matrix) help these bacteria adhere to surfaces and form biofilms. Pictured are two groups of cells, curli non-producing cells (left) and curli producing cells (right). (credit left, right: modification of work by USDA) 34 Dysbiosis vs commensalism How the Interplay Between the Commensal Microbiota, Gut Barrier Integrity, and Mucosal Immunity Regulates Brain Autoimmunity, Antonini Martina, Lo Conte Marta, Sorini Chiara, Falcone Marika, Frontiers in Immunology , VOL. 10, 2019, P.1937, DOI=10.3389/fimmu.2019.01937 35 Clostridium difficile Prevalence on the rise Nosocomial (80% according to CDC) Old age Immunosuppressed Exposed to Abx Serious underlying disease Severity and mortality related to infection have increased. Development of antibiotic resistance, use of Abx can perpetuate dysbiosis. Symptoms: Strong diarrhea Fever Loss of appetite Nausea Abdominal pain Current Status of Clostridium difficile Infection Epidemiology. Fernanda C. Lessa, Carolyn V. Gould, and L. Clifford McDonaldClin Infect Dis. Aug 1, 2012; 55(Suppl 2): S65–S70. doi: 10.1093/cid/cis319 Clostridium difficile infection Fecal microbiota transplantation (FMT) 4:33min Mayo Clinic (2014) FMT, 4:33min https://www.youtube.com/watch?v=Awn3haOpfcI In shorts: A lot of these are observational studies and not mechanistic. I.e., we do not know whether the dysbiosis is the cause or effect of a symptom, physiological status, pathogenicity, etc… Gut dysbiosis caused by pathogenic microorganisms Some consequences of gut dysbiosis § § § § § § § § § https://epidemicanswers.org/about-theepidemic/why-are-we-so-sick/gut-dysbiosis/ Localized gut inflammation Systemic inflammation Increased oxidative stress Increased production of endotoxins and other biotoxins Intestinal permeability Impaired energy metabolism Impaired nutrient synthesis (vit, scFAs…) Impaired enzymatic activity Autoimmunity Immune response in the gut mucosa Immunology in the gut mucosa, Nature video, 2013, 6:51min https://www.youtube.com/watch?v=gnZEge78_78 Microbiome Acquisition § Recent evidence suggests that the microbiome begins to develop before birth. The source of those microbes may be the placenta, which some say has its own microbiome. § Once the baby breaks out of the embryonic membrane, however, it is exposed to a dizzying array of microbes residing in the birth canal and the outside world. Early colonizing microbes are a source of vitamins and tend to be facultative rather than obligate anaerobes. § Indeed, young babies have microbiomes that are more diverse than those of adults. By the time babies are 3 years old, diversity assumes adult composition. 42 Vaginal vs C-section birth Vaginally born infants have a microbiome more like that of their biological mother than those born via C-section (72% matched sp vs 41% in C-section neonates). At 4 months, vaginally born infants are colonized by lactose digesting bacteria. No data on Csection infant. At 12 months the difference between the gut microbiota is not as important but there are still differences. Do these variables have immediate and/or long-term health impacts? Uncertain. https://learn.genetics.utah.edu/content/microbiome/changing/ 43 Vaginal vs C-section birth Ed Yong, I contain multitudes. Microbes form mom: Vaginal Birth vs. C-section, 9:13min 44 Breastfed vs bottle fed Breastfed infants have more commensal bacteria, as breast milk has a variety of complex oligosaccharides that promote their colonization. At 4 months, clear difference still between breast-fed and bottle-fed infants, with breast-fed microbiota including taxa commonly associated with probiotics and gut lining protection and immune system education, particularly Bifidobacterium longum, whilst bottle-fed infants have a greater abundance of C. difficile and Citrobacter and Enterobacter. Do these variables have immediate and/or longterm health impacts? Uncertain. 45 The Hygiene Hypothesis For millennia, human microbiota were shaped by an intimate contact with natural environments composed of animals, caves, dirt, poop, and bugs. Today we are an indoor species spending most of our time inside closed buildings, segregated from nature. § Our use of soaps, antibiotics, and disinfectants has severely restricted our access to microbes. As a result, our microbiota appear less diverse than those of our long-ago ancestors. § Because our microbiome helps train our immune system, narrowing the diversity of our microbiome could potentially contribute to inflammatory and autoimmune diseases. “some experts now speak of “targeted hygiene”—eliminating the spread of pathogens while promoting steps to restore a diverse microbiome.” Megan Scudellari, Cleaning up the hygiene hypothesis, PNAS, February 14, 2017, 114 (7) 1433-1436. https://www.pnas.org/doi/10.1073/pnas.1700688114 46 The raw water trend https://www.cbsnews.com/new s/raw-water-trend-tourmalinespring-at-the-source/ 47 Infectious diseases vs immune/inflammatory diseases over time Megan Scudellari, Cleaning up the hygiene hypothesis, PNAS, February 14, 2017 114 (7) 1433-1436. https://www.pnas.org/doi/10.1073/pnas.1700688114 48 Diversity depletion rather than hygiene? Targeted hygiene. Our immune system, like an AI system, may need wide and varied inputs to deliver the best response. Perhaps it is a lack of microbial diversity, rather than a clean environment, that under stimulate our immune system, making it less effective at decerning what is dangerous and what isn’t. Farmers, pet owners, and what we would call underdeveloped countries, seem less likely to develop immune disorders. https://www.freepik.com/premium-ai-image/immune-system-complex-networkorgans-cells-proteins-that-defends-body-against-infection-whilst-protectingbody39s-own-cells-virus-healthy-medical-bacteria-generative-ai_43051605.htm Method of birth and feeding less so. 49 Stability of the Adult Microbiome and Transitions with Age § Individual adult microbiota seems to be stable (~70% match over 5 years). So far, for an individual, geographical location and age are stronger determinants then physiological or demographic variables.1 § Firmicutes and Proteobacteria seems to be much less stable. § Early experiences determine gut microbiome (?) Seems to indicate that parental transmission of microbiota very early in life determinant for the rest of adult life. § Aging is associated with decreased microbial diversity. Increased proportion of Bacteroidetes. Individuals living at home rather then in residential facilities have a more diverse microbiota. 1 Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012). https://learn.genetics.utah.edu/content/microbiome/changing/ What happens when we die? Ed Yong, I contain multitudes, Solving Crimes with the Necrobiome, 7:10min 51 What happens when we die? Alpha diversity: diversity within-sample Beta diversity: diversity between samples First few days to week, bacteria and fungi participate in putrefaction (tissue breakdown) and act as decomposers. The microbiota stays relatively stable during these 24-48h, relative to their body niche and age. Past 48h, the microbial ecology start to alter to a point that is no longer recognizable as a human microbiota (unless the body is cooled or frozen). Martino, C., Dilmore, A.H., Burcham, Z.M. et al. Microbiota succession throughout life from the cradle to the grave. Nat Rev Microbiol (2022). 52 Disorders attributed to the Gut Microbiota § Inflammatory Bowel Disease (IBD) § Obesity 53 Inflammatory Bowel Diseases: Crohn’s disease and UC Source: CDC https://www.cdc.gov/ibd/what-is-IBD.htm 54 Inflammatory Bowel Diseases: Crohn’s disease and UC § Chronic inflammation of the gut and disruption of homeostasis (dysbiosis). § Epidemiology: 4X more frequent then in the 50’s, genetic risk cannot explain this increase. Emergence greater in countries that are actively “westernizing”. Diagnosed at anytime during life. Incidences rather high in Canada compared to other countries. § Potential causes: Failure to develop a tolerance to commensal bacteria in the gut early in life (breastfeeding vs not, vaginal birth vs C-section, hygiene hypothesis)? Leaky gut? Antibiotic use increases the risk of developing IBD Links with Western diet (rich in animal proteins which can produce harmful metabolites also associated with colon cancer, food additives), high fiber diet seems to be beneficial Read more on IBD from the Crohn’s and colitis foundation of America: https://www.crohnscolitisfoundation.org/sites/default/files/2019-02/Updated%20IBD%20Factbook.pdf 55 Inflammatory Bowel Diseases : Crohn’s disease and UC § Once developed, IBD may be transmissible between family members. § Presence of an adaptive T cell response against commensal gut bacteria is detected when it should not (break in tolerance). § Individuals with IBD seem to have lower gut microbiome diversity. Data inconsistent with recent meta-analysis suggesting more studies need to be done to associate microbial diversity to IBD1. 1 Differences in Gut Microbiota in Patients With vs Without Inflammatory Bowel Diseases: A Systematic Review. Rapat Pittayanon et al, Gastroenterology, Dec 05, 2019, DOI:https://doi.org/10.1053/j.gastro.2019.11.294 Figure 24.18 Reduced functional capacity of the gut microbiome of patients with inflammatory bowel disease. Metagenomic analysis of human gut microbiota in healthy subjects and patients with inflammatory bowel disease (IBD) revealed a tendency toward fewer nonredundant bacterial genes in patients with IBD. Brock Biology of Microorganisms, Pearson. 56 The gut microbiota and human obesity Mouse Models Normal mice have 40% more fat than germ-free mice with the same diet. When germ-free mice were given normal mouse microbiota, they started gaining weight. Mice that are genetically obese have different microbiota than normal mice. Obese mice have more Firmicutes. VFA: volatile fatty acids Figure 24.19 Differences in gut microbial communities between lean and obese mice. Obese mice have more methanogens, a 50% reduction in Bacteroidetes, and a proportional phylum-wide increase in Firmicutes. Nutrient production from fermentation is higher in obese mice due to removal of H2 by methanogens. Brock Biology of Microorganisms, Pearson. 57 The gut microbiota and human obesity A landmark study from Jeffrey Gordon et al. demonstrated that obesity in humans is clearly linked to their microbiomes. Like the mouse model, obese humans have more Firmicutes than non-obese humans.1 The nature and transferability of gut microbiota is dependent on diet as well as genetics. Figure 24.20 Transfer of an obese condition by fecal transplant. Transplanting fecal material from the gut contents of a paired identical human twin study group (one twin was obese and the other lean) to germ-free mice showed that the obese twin microbiota made the mouse obese. Conversely, transfer of gut contents from the lean twin did not contribute to an obese phenotype. Adapted by Pearson from Ridaura, V.K., et al. Science 341: DOI:10.1126/science.1241214. 1 Crovesy L, Masterson D, Rosado EL. Profile of the gut microbiota of adults with obesity: a systematic review. Eur J Clin Nutr. 2020 Sep;74(9):1251-1262. doi: 10.1038/s41430-020-0607-6. Epub 2020 Mar 30. PMID: 32231226. Brock Biology of Microorganisms, Pearson. 58 The Link between Obesity and Dysbiosis § Microbiota seems to influence obesity in two major ways. Harvesting of energy from ingested foods Triggering of intestinal inflammation § The metabolic dexterity of intestinal microbes allows them to digest many foods that we cannot. In the process, these microbes produce short-chain fatty acids (SCFAs) that our cells use in many ways. Numerous investigations suggest that the amounts and ratios of these SCFAs influence obesity. 59 The Link between Obesity and Dysbiosis 60 The Link between Obesity and Dysbiosis § Archaea in the gut might also tilt metabolic balance toward obesity. About 50% of humans have significant numbers of methaneproducing archaea, primarily Methanobrevibacter smithii. § Inflammation induced by gut microbes also may influence the development of obesity and diabetes. Lipopolysaccharide (LPS, or endotoxin) produced by Gramnegative species promotes inflammation. A high-fat diet can promote absorption of endotoxin across the intestinal epithelium. 61 Modulation of the microbiome Antimicrobials Probiotics and pre-biotics 62 Use of antibiotics § Oral antibiotics decrease most microbes in the human gut (both target and non-target). § Use of antibiotics during the first few months of life increases the risk of developing IBD and other disorders related to dysbiosis. § Clostridium difficile infections are associated with antibiotic use. Clostridium difficile is a spore-former and generally antibiotic resistant. A newer therapy for Clostridium difficile infection is a fecal transplant. 63 Modulation of the microbiome Probiotics are living microbes that are ingested to restore the natural microbial balance. The most used genera are : Bifidobacterium Lactobacillus. 64 Modulation of the microbiome § Probiotics are live organisms that confer a health benefit to the host. Species of Bifidobacterium and Lactobacillus bacteria are commonly used probiotics found in yogurt and probiotic drinks. The caveat is that ― most are destroyed by acid pH conditions in stomach and ileum, ― enzymes or bile acids and ― they are obligate anaerobe, ie oxygen is toxic to them, so numbers in product diminish a lot between freshly made and expiry date. They may work by taking up space or nutrients, limiting the ability of pathogens to colonize the gut. ― Still a theory, we don’t know how they work (if they do work) ― Vast majority do not colonize the gut, the strains ingested disappear in the feces when you stop eating them. So, if they work, it’s temporary. 65 The low down on probiotics as of 2017 Contraindicated for immunosuppressed patients or for patients with comorbidities Rule of 3 “Ds”: Diversity Dose (10 billion CFUs per species) Delivery (enteric-coated capsules, powders, gel caps, gummies, liquids, and foods such as yogurt) NOT considered medicine, but food supplements or complementary medicine Probiotics for Gastrointestinal Conditions: A Summary of the Evidence. Thad Wilkins et al, Am Fam Physician. 2007 Aug 1;96(3):170-178. https://www.aafp.org/afp/2017/0801/p170.html#commenting http://www.probioticchart.ca/ DISCLAIMER The statements made regarding products listed here have not been evaluated by the Food and Drug Administration or Health Canada (unless otherwise indicated). These products are not intended to diagnose, treat, cure or prevent any disease. Products, services, information and other content provided on this Site, including information that may be provided on this Site directly or by linking to third-party websites are provided for informational purposes only. Please consult with a physician or other healthcare professional regarding any medical or health related questions. Manufacturer indications for use can be found on product labels. This chart is reflective of published evidence available to date. It does not represent an endorsement of any specific product. Work on this guide is done independently and without financial conflict. In order to minimize bias, publishing and distribution efforts are coordinated via Alliance for Education on Probiotics (AEProbio). We are grateful for unrestricted publishing grant AEProbio is providing for continuous efforts to translate science into clinically applicable form. Modulation of the microbiome § Prebiotics are typically carbohydrates that are indigestible by human hosts, but provide nutrition for fermentative gut bacteria, presumably to promote the growth of “good” bacteria. 68