Microbiome Study PDF

The Human microbiome Dr. Corinne Maurice [email protected] MIMM211, Nov. 20th, 22nd, and 25th  Wednesday: The human microbiome – What is it? – How is it studied? – Major questions in the field Friday: The human microbiome, health, and disease – The gut mi...

The Human microbiome Dr. Corinne Maurice [email protected] MIMM211, Nov. 20th, 22nd, and 25th  Wednesday: The human microbiome – What is it? – How is it studied? – Major questions in the field Friday: The human microbiome, health, and disease – The gut microbiome and obesity – Antibiotics, the gut microbiota, and C. difficile – The gut-brain axis Today: Manipulating the gut microbiome with – Probiotics – The other members of the microbiome The other members of the gut microbiome Important to identify and characterize for therapeutic manipulations Rowan-Nash et al., 2019, Microbiol Mol Biol Rev Manipulating the gut microbiome with bacteria Probiotics: live microorganisms which when administered in adequate amounts confer a health benefit to the host Current issues with probiotics Inadequate studies: low sample size, quality of study design, lack of in vivo data, self-reported diagnostics and measurements, lack of details about probiotic strains used, … Limited mechanistic understanding of effects of current probiotics Probiotic industry largely unregulated Publication of negative results required Need for a standardized and validated measure of “health benefit to the host” No adequate tests to predict functionality of probiotics in the human body Current issues with probiotics Information still required: strain(s)of probiotics, dose, duration, frequency, timing, indications, and side-effects Rare cases of infections associated with probiotics Transferrable microbial properties (antibiotic resistance genes, virulence genes, …) Effectiveness of probiotic for altering a disease state is not provided currently Probiotics vs. FMT Antibiotics: ciprofloxacin and metronidazole 7-day treatment in humans, 14 days in mice Resulted in significant decrease in gut bacterial diversity Bi-daily probiotics administration (same 11-strain cocktail) to 21 human volunteers Suez et al., Cell, 2018 Probiotics vs. FMT Mice with a native gut microbiota are not colonized by probiotics. Antibiotics mildly enhance probiotic colonization in mucosal layers. In humans, probiotic colonization is site- and person-specific. Antibiotics significantly enhance probiotic colonization in mucosal layers After antibiotics exposure, probiotics delay gut microbiome reconstitution and its metabolism. In contrast, FMT from the same person (autologous FMT) restores mucosal microbial diversity and metabolism The other members of the gut microbiome Can they be used to manipulate gut bacterial communities and alter disease progression or outcome? Manipulating the gut microbiome with helminths Helminth = worm Free-living organisms and parasites of most animals (almost universal feature of vertebrate animals) and plants Three major assemblages of parasitic helminths recognized: nematodes, cestodes, and trematodes Helminth infection concerns 25% of the world population Helminths, disease, and health Symptoms of helminth infections: diarrhoea, abdominal pain, weakness, reduced nutritional input, chronic intestinal bleeding (causing anemia), intestinal obstruction and rectal prolapse, death Co-infection common Modulate host immune response (induce Th2 response), allowing for decade-long infections. Conflicting reports that helminths protect from malaria (Plasmodium sp.) The hygiene hypothesis Helminths in the gut Intestinal helminths possess immunomodulatory capacities and can alleviate bleeding in IBD. Have been shown to decrease the number of Bacteroides species involved in intestinal inflammation (Ramanan et al., 2016, Science 352). Giacomin et al., 2016, Trends in parasitology Body-wide effects of gut helminths Their interactions with the gut bacteria can alleviate asthma symptoms (Zaiss et al., 2015, Immunity 43). Reynolds and Finlay, 2015, Immunity Worm therapy Frequency, duration, which worm(s)? Is the whole/live worm needed? What are the direct effects of the helminths on the (human) host? Interaction with other chronic or acute diseases? Bacteriophages Viruses infecting bacteria Exist everywhere bacteria are present Typically outnumber bacteria 10:1 Bacteriophages (phages) Self-replicating obligatory parasites without inherent metabolism High morphological diversity Several molecular tools used in the lab (DNA polymerase, restriction enzymes, CRISPR) come from phage research Clokie et al., Bacteriophage, 2011 Phage diversity DNA and RNA phages (circular, linear, ss and ds) Phages with capsid or envelope Highly mosaic structure No common genetic marker (no 16S rDNA equivalent) Limited, incomplete Edwards and Rohwer, 2005 databases Most phages remain unknown Replication cycles Khan Mirzaei and Maurice, Nat. Rev. Microbiol., 2018 Our tiny phriends Majority of DNA phages Phage to bacteria ratio lower than other systems (between 0.1 and 3) Caudovirales (Myoviridae, Podoviridae, Siphoviridae), Microviridae, crAssphage, Lak phages (Dutilh et al., 2014, Nature; Devoto et al., 2019, Nature Microbiol) Khan Mirzaei and Maurice, 2018, Nat. Rev. Microbiol. Our tiny phriends Most phages are integrated in bacterial cells (prophages) Unique communities, temporally stable, high similarity between relatives and household members (“core phageome” – Manrique et al., 2016, PNAS) Can directly/indirectly modulate immune response (Barr et al., 2013, Bacteriophages; Sinha Shkoporov and Hill, Cell Host Microbe, 2019 and Maurice, 2019, Mediators Inflamm.; Hsu et al., 2019, Cell Host Microbe) Phage populations are dynamic Sinha and Maurice, 2019, Mediators Inflamm. Phage populations are dynamic Healthy adult gut Inflamed gut Disease-specific changes in virome diversity, increased phage richness, increased abundance of free phages Sinha and Maurice, 2019, Mediators Inflamm. Phages regulate bacterial: Abundance Diversity Phenotype (Breitbart et al., 2018, Nature Microbiology) Current questions in the field: Can phages be used as biomarkers? Can we use phages to manipulate gut bacterial communities? Are phages shaping the microbiota- immune cross-talk? (Hsu et al., 2019, Cell Host Microbe; Khan Mirzaei et al, 2020, Cell Host Microbe; Reyes et al., 2013, PNAS; Sinha et al., 2022, Microbiome) Are phages implicated in child stunting? Stunting: height-for-age > 2 STDEV below the WHO Child World Food Program USA Growth Standards median. Stunting affects 22% of children