GUT MICROBIOTA AS AN EMERGING TARGET TO ATTAIN LONGEVITY

Transcription

1 Symposium Nutrition for the Ageing Brain MOVING TOWARDS CLINICAL APPLICATIONS 30 th 31 st August 2018, Madrid, Spain GUT MICROBIOTA AS AN EMERGING TARGET TO ATTAIN LONGEVITY

2 MICROBIOTA ROLE IN HOST PHYSIOLOGY our bacterial counterpart provides essential features we have not evolved enhancement of the digestive efficiency and modulation of energy homeostasis vitamin synthesis (K, B9, B12, B2) competitive barrier against colonization/invasion development, education and function of the immune system strengthening of the intestinal epithelium impermeability central nervous system modulation endocrine system modulation programming of the circadian epigenetic and transcriptional landscape detoxification of xenobiotics (role in anticancer immuno-chemotherapy)

3 The gut microbiota is a dynamic system allowing host adaptive responses to environmental and endogenous changes Candela M, Biagi E, Maccaferri S, Turroni S, Brigidi P. Intestinal microbiota is a plastic factor responding to environmental changes. Trends Microbiol Aug;20(8): MUTUALISM n different compositional layouts OPTIMIZATION OF SUPERORGANISM S METABOLIC AND IMMUNOLOGICAL PERFORMANCES

4 MUTUALISM INTERRUPTION - DYSBIOSIS MUTUALISM Switch-like behavior, making sudden jumps from different steady states IMMUNE ABNORMAL DEREGULATION ANTIBIOTIC INTAKE DIETARY INTAKE INFECTION INFLAMMATION RUPTURE OF THE MICROBIOTA-HOST MUTUALISTIC RELATIONSHIP AND COMPROMISED HOST ENERGY BALANCE AND IMMUNE HOMEOSTASIS

5 A PARTIAL LIST OF DISEASES AND THEIR LINKS TO THE MICROBIOME Knight et al., Annu Rev Genomics Hum Genet IS AN ALTERED MICROBIOME THE CAUSE OF A DISEASE STATE OR A CONSEQUENCE??

6 THE CHICKEN OR THE EGG: A COMMON GROUND HYPOTHESIS Lynch and Pedersen, N Engl J Med. 2016

7 META-ANALYSIS OF GUT MICROBIOME STUDIES IDENTIFIES DISEASE-SPECIFIC AND SHARED RESPONSES Duvallet et al., Nat Commun LOSS OF BENEFICIAL MICROBES (e.g., butyrate-producing Clostridiales) probiotics replacing missing taxa 2. ENRICHMENT OF PATHOGENS (e.g., Fusobacterium) narrow-spectrum antimicrobials 3. BROAD RESTRUCTURING (e.g., diarrhea) fecal microbiota transplantation

8 GUT MICROBIOME CHANGES FROM INFANCY TO ADULTHOOD Kundu et al. Cell. 2017

9 WE ARE BORN STERILE IN A MICROBIAL WORLD vaginal flora (mother) Lactobacillaceae environmental microorganisms Proteobacteria mother s milk microorganisms fecal flora (mother / father) Gut microbiota skin flora (mother / father) Streptococcus, Staphylococcus mouth flora (mother / father) Streptococcus, Staphylococcus, Proteobacteria, Actinobacteria, Bacteroidetes -Streptococcus -Staphylococcus -Lachnospiraceae -Ruminococcaceae -Bacteroidaceae -Bifidobacteriaceae -Proteobacteria (dead) mother s milk INDIVIDUAL GENOME INFANT MICROBIOTA WEANING - low diversity - highly dynamic - Bifidobacterium-dominated - presence of aerobes - Bacteroidetes and Veillonella as minor components Nuriel-Ohayon et al., Front Microbiol ADULT INDIVIDUAL MICROBIOTA (from 1 st 3 rd year to all life)

10 HUMAN GUT COLONIZATION MAY BE INITIATED IN UTERO Collado et al., Sci Rep Placenta and amniotic fluid harbor a distinct microbiota characterized by low richness, low diversity and the predominance of Proteobacteria Shared features with the meconium, suggesting microbial transfer at the feto-maternal interface At the age of 3-4 days, the infant gut microbiota composition begins to resemble that of colostrum

11 AMNIOTIC FLUID FROM HEALTHY TERM PREGNANCIES DOES NOT HARBOR A DETECTABLE MICROBIAL COMMUNITY Lim et al., Microbiome THE BACTERIAL MICROBIOTA OF AMNIOTIC FLUID IS INDISTINGUISHABLE FROM CONTAMINATION CONTROLS

12 THROUGH PUBERTY TOWARDS ADULTHOOD A robust core microbiome that adds flexibility and reduces vulnerability to external and internal challenges GUT MICROBIOME CHANGES FROM INFANCY TO ADULTHOOD Kundu et al. Cell. 2017

13 AND BEYOND.? When does the gut microbiome start to change in healthy elderly people? Are the occurring changes to be considered DYSBIOSIS or ADAPTATION to the aged condition?

14 Studies investigating ageing and the gut microbiome in humans Buford, Microbiome. 2017

15 THE AGED-TYPE GUT MICROBIOTA Candela M, Biagi E, Turroni S, Maccaferri S, Figini P, Brigidi P. Dynamic efficiency of the human intestinal microbiota. Crit Rev Microbiol Jun;41(2): DETERIORATION IN NUTRIENT INTAKE AND ABSORPTION (including dentition, salivary function and intestinal transit time) SENSORY CHANGES IN TASTE AND SMELL PHYSICAL CHANGES TO THE INTESTINAL EPITHELIAL BARRIER (leaky gut) INFLAMMAGEING IMMUNOSENESCENCE

16 Community-dwelling elderly people show a microbiota structure overall comparable to that of young adults VS Elderly people living in long-term residential care show a (more) compromised microbiota structure Claesson et al., Gut microbiota composition correlates with diet and health in the elderly. Nature Aug; 488(7410):

17 Dietary changes and frailty-related factors force a microbiome dysbiotic state that compromises the health of the elderly Claesson et al., Nature POOR DIET HOSPITALIZATION IMMUNO SENESCENCE LOW SCFA PRODUCTION INFLAMMATION FRAILTY MARKERS

18 THE LONGEST AVAILABLE TRAJECTORY OF THE HUMAN GUT MICROBIOTA ALONG AGEING Centenarians and semisupercentenarians (i.e. 105 yrs) as THE BEST MODEL OF HEALTHY, SUCCESSFUL AGEING AND LONGEVITY (low incidence of chronic illness, reduced morbidity, increased lifespan and healthspan) Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R, Turroni S, Consolandi C, Quercia S, Scurti M, Monti D, Capri M, Brigidi P, Candela M. Gut Microbiota and Extreme Longevity. Curr Biol Jun 6;26(11):

19 The gut microbiota of centenarians and semi-supercentenarians: signatures of longevity?? Biagi et al., Curr Biol A CORE MICROBIOTA of highly occurring, symbiotic bacterial groups (e.g. Coprococcus, Roseburia and Faecalibacterium) remains approximately constant during ageing but VARIES IN THE CUMULATIVE RELATIVE ABUNDANCE of its members along with age Ageing is characterized by INCREASING CONTRIBUTION OF SUBDOMINANT BACTERIA (e.g. Enterobacteriaceae, Desulfovibrionaceae), as well as a rearrangement in their cooccurrence network The microbial ecosystem found in extremely old people is invaded by microbes typical of other niches (e.g. Mogibacteriaceae) and ENRICHED IN THE HEALTH-ASSOCIATED TAXA Akkermansia, Bifidobacterium and Christensenellaceae

20 Ageing-supportive / longevity-adapted microbial communities?? BIFIDOBACTERIUM, a well-known probiotic agent with antiinflammatory and immunomodulatory properties, and long history of use AKKERMANSIA, a mucin-degrading bacterium recently proposed as a next-generation probiotic or live biotherapeutic for the treatment of obesity and related complications CHRISTENSENELLACEAE, whose relative abundance is significantly influenced by host genetics. An heritable component of longevity? O Toole et al., Nat Microbiol Both Akkermansia and Christensenella harbor genes coding for deglycases, which alleviate the ageing-related burden of Advanced Glycation End-products (AGEs) Danchin, Environ Microbiol. 2018

21 Functional metagenomics profiling of the gut microbiome in extreme ageing Rampelli S, Candela M, Turroni S, Biagi E, Collino S, Franceschi C, O Toole PW, Brigidi P. Functional metagenomic profiling of intestinal microbiome in extreme ageing. Aging Dec; 5(12): Collino et al., PLoS One PROTEOLYTIC METABOLISM (trp, phe, tyr, val, lys) REDUCTION OF SERUM TRP BIOAVAILABILITY (cognitive deficit, immune activation, but also increased lifespan in rodents) INCREASED URINARY LEVELS OF PHENOLIC METABOLITES, e.g. PCS (cancer, depression, diabetes) CENTENARIANS SHOW A DISTINCTIVE MICROBIOME STRUCTURE THAT MATCHES A DISTINCTIVE METABOLIC PROFILE

22 Evidence in favor of an adaptive functional microbiome response to extreme ageing REDUCTION OF FOLATE BIOSYNTHESIS INCREASE OF POLYAMINE BIOSYNTHESIS INCREASE OF α KETOGLUTARATE BIOSYNTHESIS elimination of excess folate restoring of intestinal barrier function anti inflammatory activity anti oxidative properties autophagy partial suppression of electron transport chain via ATP synthase binding LIFESPAN INCREASE IN ANIMAL MODELS AND HUMAN CELLS

23 The gut microbiota of centenarians from different continents: ITALIANS vs CHINESE vs JAPANESE Biagi E, Rampelli S, Turroni S, Quercia S, Candela M, Brigidi P. The gut microbiota of centenarians: Signatures of longevity in the gut microbiota profile. Mech Ageing Dev Jul;165(Pt B): Santoro et al., Cell Mol Life Sci DIFFERENCES, possibly attributable to geographic, genetic and lifestyle factors SIMILARITIES, including - the decrease in butyrate producers (e.g. Coprococcus, Roseburia, Faecalibacterium) - the increase in pathobionts (e.g. Enterobacteriaceae) - the enrichment in health-associated Akkermansia, Bifidobacterium and Christensenellaceae SIGNATURES OF LONGEVITY, regardless of lifestyle, dietary habits, geographic/population/social factors, as well as host genetics, and probably a NEW, BENEFICIAL AND SYMBIOTIC MICROBIOTA EQUILIBRIUM

24 Some lessons from the animal world on the lifelong value of commensal bacteria to their host Mogibacteriaceae was also found in the gut microbiome of the naked mole-rat (Debebe et al., Sci Rep. 2017) and the sea turtle (Biagi et al., Environ Microbiol Rep. 2018), notoriously long-living animals Bifidobacterium also accumulates in the gut of queen honey bees, which can live over ten times as long as workers (Anderson et al., Microbiome. 2018) Nitric oxide produced by commensal bacteria regulates worm longevity, by inducing heat shock response and thermotolerance (Gusarov et al., Cell. 2013) The anti-diabetic medication metformin is a potent C. elegans longevity factor, by disrupting the folate cycle of commensal bacteria (Cabreiro et al., Cell. 2013) Colanic acid, a bacterial polysaccharide, promotes lifespan increase in worms, by regulating mitochondrial dynamics and unfolded protein response in the host (Han et al., Cell. 2017)

25 Altering the gut microbiome to activate major host longevity signaling and promote healthy ageing DIET, by increasing the consumption of dietary fiber for increased abundance of healthassociated taxa and high levels of SCFAs CALORIE RESTRICTION, for a more efficient metabolism, higher protection against cellular damage and increased abundance of Akkermansia LIFESTYLE, e.g. physical exercise for increased microbiota diversity and abundance of Akkermansia ADMINISTRATION OF TRADITIONAL OR NEXT-GENERATION PROBIOTICS, e.g. bifidobacteria promote longevity in mice, possibly through the suppression of chronic low-grade inflammation in the colon induced by higher microbiota-derived polyamine levels FMT, the most direct means to manipulate the microbiota POSTBIOTICS (i.e. bacterial products), PHAGE THERAPY (for targeted microbial disruption)

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