MBS2002 Engineering the Immune System & Treatment of Disease Week 7 Lecture Notes PDF

Week 7: Approaches to Modulate the Immune System – The Microbiome as Target for Therapy MBS2002 Engineering the Immune System & Treatment of Disease Kaatje Lenaerts, PhD Department of Surgery 7 themes Focus: current and future Therapies & Treatment 1. Immune modulation 7. Microbiome 6. Allergy, hype...

Week 7: Approaches to Modulate the Immune System – The Microbiome as Target for Therapy MBS2002 Engineering the Immune System & Treatment of Disease Kaatje Lenaerts, PhD Department of Surgery 7 themes Focus: current and future Therapies & Treatment 1. Immune modulation 7. Microbiome 6. Allergy, hypersensitivity & auto-immune disease 2. Innate immunity 5. Immune therapy in oncology mental/neurological modifiers 4. Sterile inflammation & CVD 3. Viral disease 2 Week 7: Overview Introductory Lecture – The microbiome as target for therapy (K. Lenaerts) Meet the expert session – Microbial short chain fatty acids and metabolic health (E. Canfora) Tutorial – Week assignment on exploiting the gut microbiome to prevent and treat human disease (K. Lenaerts) Journal club – Yang et al. Intestinal microbiota-derived short chain fatty acids regulation of immune cell IL-22 production and gut immunity. Nature Commun 2020:11:4457. (K. Lenaerts) 3 Week 7: Overview Additional Lecture – Interaction immune system and nervous system > Psycho-neuro-immunology (G. Kenis) 4 Introductory Lecture The microbiome as target for therapy Contents Terminology Tools for microbiota analysis Current understanding of gut microbiota functions Factors influencing gut microbiota Modulation of the gut microbiota 6 Terminology Microbiota: The types of microorganisms (bacteria, fungi, archaea, protists, algae) that are present in an environmental habitat Microbiome: A collection of different microbes and their functions or genes found in an environmental habitat (i.e. microbiota and their structural elements, metabolites, signaling molecules, and surrounding environment) Dysbiosis: A disturbance in a biological system, e.g. changes in types and numbers of bacteria in the gut which may lead to developing different diseases Pathobiont: A commensal microorganism that can cause or promote disease only when specific genetic or environmental conditions are 7 altered in the host Terminology Metagenomics is the genomic analysis of microbial communities by extraction and sequencing or cloning of their DNA that allows studying communities of organisms directly in their natural environment The metagenome consists of the genomes of many individual microorganisms present in an environmental sample Platform: metagenomic DNA sequencing > microbial diversity as well as functional potential https://youtu.be/RcYXTpNS_XU 8 Terminology Metabolomics is the systematic study of the small molecular metabolites in a cell, tissue, biofluid, or cell culture media that are the tangible result of cellular processes or responses to an environmental stress The metabolome is the complete set of small-molecule chemicals found in a biologic sample; this profile represents a snapshot in time Platform: LC-MS or GC-MS 9 Tools for microbiota analysis 10 From: Environmental Chemicals, the Human Microbiome, and Health Risk: A Research Strategy (2018) DNA-Based approach OTU: Operational taxonomic unit 11 Milani et al. Microbiol Mol Biol Rev. 2017 Microbiota composition in different regions 12 Hou et al. Signal Transduction and Targeted Therapy. 2022 Current understanding of the gut microbiota 100 trillion bacteria within the human gut (colon) 9.9 million microbial genes across fecal microbiome Comprised of two major phyla Firmicute and Bacteroidetes, followed by the phyla Actinobacteria and Verrucomicrobia Function is more important than identity 13 Lynch et al. NEJM. 2016 Gut microbiota functions Role in maturation and education host immune response Provide protection against pathogen overgrowth Influence host cell proliferation and vascularization Regulate intestinal endocrine function Regulate neurologic signaling Provide source of energy biogenesis [5-10% of daily host energy requirement] 14 Lynch et al. NEJM. 2016 Gut microbiota functions Biosynthesize vitamins Produce neuroactive compounds such as neurotransmitters serotonin, dopamin Metabolize bile salts Modify drugs Eliminate exogenous toxins Ferment undigestible carbohydrate => SCFA 15 Lynch et al. NEJM. 2016 Induction of mucosal immune responses 16 Allaire et al. Trends Immunol. 2018 Gut microbiota functions 17 Rios-Covia et al. Front. Microbiol. 2016 SCFA production dictates epithelial cell homeostasis 18 Allaire et al. Trends Immunol. 2018 Gut microbiota-associated diseases Metabolic Neurologic / psychiatric Respiratory Cardiovascular Gastrointestinal / hepatic Autoimmune Oncologic 19 Lynch et al. NEJM. 2016 Hou et al. Signal Transduction and Targeted Therapy. 2022 Factors contributing to gut microbiota composition 20 Early life 21 Tamburini et al. Nature Med. 2016 Early life 22 Tamburini et al. Nature Med. 2016 Diet Vegetable and meat-restricted diets - Rapid and reproducible gut microbiota responses - Meat -> bile-metabolizing microbiota - Vegetable -> plant polysaccharide-fermenting organisms Individuals have very different metabolic responses to identical meals - Postprandial glycemic responses (PPGRs) are associate with multiple person-specific clinical and microbiome factors - Clinical and microbiome factors could be integrated into an algorithm that predicts individualized PPGRs 23 Lynch et al. NEJM. 2016 Diet 24 Zeevi et al. Cell. 2015 Diet 25 Zeevi et al. Cell. 2015 Diet Postprandial variability is associated with clinical and microbiome profiles 26 Zeevi et al. Cell. 2015 Diet 27 Zeevi et al. Cell. 2015 Environmental factors House dust microbiota - Different microbiota in residences associated with protection against, or development of childhood allergic disease - Oral supplementation or nasal exposure of mice to protective house dust prevents airway sensitization 28 Lynch et al. NEJM. 2016 Environmental factors Parasitic helminths can promote protective microbiota and block inflammatory diseases such as IBD Inflammatory bowel disease is less prevalent in regions where helminth colonization is endemic Populations in rural area of Malaysia vs those living in an urban area [96% vs 5.3% helminth colonization] - Increased microbial diversity and Clostridiales species - Reduced abundance Bacteroidales 29 Ramanan et al. Science. 2016 Environmental factors Manipulating helminth microbiota axis could be a viable therapeutic strategy 30 Giacomin et al. Trends in Parasitol. 2016 Challenges of human studies in this field c i t u e p a r s e e i h t T i n u t r o p p o Major intra-individual variability of the microbiome with changes in lifestyle Reproducibility issues Statistically underpowered case–control studies Phenotypically, etiologically, and microbiologically heterogeneous cases and controls Lack of statistically powered longitudinal and interventional studies involving study participants with well-defined diseases or preclinical at-risk conditions in order to explore causality 31 Microbiome-mediated therapeutics 32 Vieira et al. Clin Transl Immunology. 2016 Microbiome-mediated therapeutics 33 Tamburini et al. Nature Med. 2016 Modulation of the gut microbiota 34 Vieira et al. Clin Transl Immunology. 2016 Antibiotics Germ-free mice are protected from diet-induced obesity (Bäckhed et al., 2004) Use of antibiotics has been associated with increased metabolic impairments, mainly when exposure occurs in early life (Cox and Blaser, 2015) Antibiotics may improve peripheral insulin sensitivity in a small number of obese subjects (Vrieze et al., 2014) Modulation of the gut microbiota may provide a promising avenue to target obesity-related metabolic disorders 35 Antibiotics Randomized DoubleBlind PlaceboControlled Trial Broad-spectrum antibiotic amoxicillin 57 obese, pre-diabetic men Narrow-spectrum antibiotic vancomycin (directed against Grampositive bacteria) 36 Reijnders et al. Cell Metabolism. 2016 Antibiotics Antibiotic exposure, during cancer therapy, negatively correlates with patients’ response to immune checkpoint blockade (Routy et al., 2018) 37 Probiotics Live microorganisms that, when administered in adequate amounts, confer a health benefit on the host The primary actions: - Antimicrobial effects - Enhancement of mucosal barrier integrity - Host immunomodulation Experimental studies - Positive results in animal models - Ambiguous results in human studies - Poor study design / choice of strain / … 38 Gibson et al. Nat Rev Gastroenterol Hepatol. 2017 Probiotics 39 Lynch et al. NEJM. 2016 Probiotics in anxiety – gut-brain axis Maternal immune activation (MIA) model - Mirrors behavioral and neuropathological changes of human autism spectrum disorder - Gut microbiota dysbiosis, increased gut permeability Feeding Bacteroides fragilis - Ameliorated intestinal dysbiosis - Restored mucosal barrier integrity - Diminished behavioral abnormalities Effect via microbial metabolite 4-ethylphenylsulphate 40 Hsiao et al. Cell. 2013 Probiotics in cancer Commensal bacteria can modulate tumor microenvironment Certain microbes enhance the efficacy of cancer immunotherapy - Bifidobacterium supplementation improved tumor control to the same degree as anti–PD-L1 (programmed cell death ligand 1) therapy (checkpoint blockade) in an animal model (Sivan et al., 2015) - Combination treatment (Bifidobacterium supplementation and anti–PD-L1 therapy) almost completely eliminated tumor expansion 41 Probiotics in obesity Negative correlation between A. muciniphila abundance and overweight, obesity, untreated type 2 diabetes mellitus Administration of A. muciniphila in obese subjects 42 Depommier et al. Nat Medicine. 2019 Prebiotics A substrate that is selectively utilized by host microorganisms conferring a health benefit 43 Gibson et al. Nat Rev Gastroenterol Hepatol. 2017 Prebiotics Double-blinded, placebo-controlled, parallel intervention study 12-weeks GOS supplementation in 44 overweight or obese, prediabetic men and women 44 Canfora et al. Gastroenterol. 2017 Prebiotics 45 Canfora et al. Gastroenterol. 2017 Prebiotics 46 Canfora et al. Gastroenterol. 2017 Prebiotics 47 Canfora et al. Gastroenterol. 2017 Prebiotics 12-week supplementation of the prebiotic GOS - Consistently increased bifidobacteria - Did not alter SCFA concentrations - Did not alter insulin sensitivity - Did not alter energy metabolism 48 Canfora et al. Gastroenterol. 2017 Postbiotics Preparation of inanimate microorganisms and/or their components that confers a health benefit on the host Deliberately inactivated microbial cells with or without metabolites or cell components that contribute to demonstrated health benefits Bypass the complex modulation of microbial ecology and directly exert an effect on the host 49 Salminen et al. Nat Rev Gastroenterol Hepatol. 2021 Postbiotics Purified microbial metabolites and vaccines are not postbiotics The site of action for postbiotics is not limited to the gut, they must be administered at a host surface, such as the oral cavity, gut, skin, urogenital tract or nasopharynx Might be applicable in a wider range of populations compared to pre- and probiotics, whose effectiveness depends in part on the microbial community present prior to the intervention 50 Salminen et al. Nat Rev Gastroenterol Hepatol. 2021 Postbiotics Postbiotics 51 Salminen et al. Nat Rev Gastroenterol Hepatol. 2021 Adult Salminen et al. Nat 52 Rev Gastroenterol Hepatol. 2021 Child Salminen et al. Nat 53 Rev Gastroenterol Hepatol. 2021 Synbiotics Mixture comprising live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on the host 54 Swanson et al. Nat Rev Gastroenterol Hepatol. 2020 Synbiotics 55 Swanson et al. Nat Rev Gastroenterol Hepatol. 2020 Swanson et al. Nat Rev Gastroenterol 56 Hepatol. 2020 Fecal microbiota transplantation (FMT) FMT is the most radical form of microbiome-based therapy; attempt to replace the entire microbial ecosystem in the intestine with the fecal matter of a healthy donor 57 Fecal microbiota transplantation Results from small, open-label, randomized, controlled trial in patients suffering from recurrent Clostridium difficile infection 58 Van Nood et al. New Engl J Med. 2013 Fecal microbiota transplantation 59 Routy et al. Science. 2018 Fecal microbiota transplantation FMT is a highly effective treatment against recurrent Clostridium difficile infection (van Nood et al. 2013 and many others) Recently introduced into routine clinical practice for this indication Promising strategy for other conditions; e.g. acute graft-versushost disease of the gut (Kakihana et al. 2016) 60 Crosstalk Intestine Diet Immunity