Han B, Sivaramakrishnan P, Lin CJ, Neve IA, He J, Tay LW, Sowa JN, Sizovs A, Du G, Wang J, Herman C, Wang MC.
Microbial Genetic Composition Tunes Host Longevity.
Cell. 2017 Jun 15;169(7):1249-1262.e13.
PubMed.
These findings add to rapidly mounting data that point to a role for micro-organisms in Alzheimer's disease (AD). Recent findings from both mouse models and human nutrition studies suggest the gut microbiome modulates brain β-amyloidosis (Minter et al., 2016). Here, Han et al. suggest the microbial polysaccharide colanic acid may mediate the beneficial host outcomes that appear associated with specific gut microbes, including ameliorating the harmful effects of Aβ fibrillization.
These findings are consistent with the emerging antimicrobial protection hypothesis for AD that we (Kumar et al., 2016), and others (Bourgade et al., 2016), recently proposed. In this model, Aβ is an antimicrobial peptide (AMP) of innate immunity that protects against infecting pathogens and, pertinent to the Han et al. study, microbial products. Fibrillization mediates Aβ’s antimicrobial activities and leads to protective sequestration of pathogens or microbial endotoxins in β-amyloid deposits (Kumar et al., 2016). Aβ contains an AMP heparin-binding motif (XBBXBX) that mediates microbial targeting and binding (Kumar et al., 2016). Soluble host sugars inhibit microbial binding of Aβ and other AMPs, regulating their activities. However, bacteria also secret exopolysaccharides that target AMPs and inhibit their activities, including polysaccharides that specifically inhibit microbial agglutination.
Aβ microbial agglutination pathways lead to generation of β-amyloid. Colanic acid and other exopolysaccharides, as well as a plethora of additional secretory products, are generated by the gut microbiome and enter the CNS, either from the periphery or via the vagus nerve. A key role for AMPs in the immunoprivileged brain is the agglutination and neutralization of potentially harmful microbial products. We suspect this may also emerge as a key innate immune role for Aβ in brain. Thus, the antimicrobial protection model provides a plausible pathway in which microbial molecules bind to Aβ, directly modulating β-amyloid deposition. Importantly, the microbial molecules need not be generated in the brain, but can be translocated from the gut microbiome or sites of infection.
The protective effect of colanic acid observed by Han et al in Aβ-expressing transgenic CL2006 nematodes is consistent with this model. It is worth noting that the transgenic CL2006 nematode model used in the Han et al. study has been reported to express only Aβ3-42, and not full-length Aβ1-42 (McColl et al., 2009). In vitro analysis demonstrates that Aβ3-42 self-aggregates like Aβ1-42, but more rapidly, forming fibrillar structures. Thus, confirmation of the new findings with a line expressing Aβ1-42 will be useful in future studies.
In summary, we believe there is much to be gained by considering the data of Han et al., as well as similar related findings, in the context of the antimicrobial protection model in which β-amyloid deposition is part of an innate immune response driven by immunochallenge. This approach may lead to alternative therapeutic strategies for effective modulation of β-amyloid generation that take into account Aβ’s normal function and do not necessarily target the peptide directly.
References:
Minter MR, Zhang C, Leone V, Ringus DL, Zhang X, Oyler-Castrillo P, Musch MW, Liao F, Ward JF, Holtzman DM, Chang EB, Tanzi RE, Sisodia SS.
Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer's disease.
Sci Rep. 2016 Jul 21;6:30028.
PubMed.
Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD.
Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease.
Sci Transl Med. 2016 May 25;8(340):340ra72.
PubMed.
Bourgade K, Le Page A, Bocti C, Witkowski JM, Dupuis G, Frost EH, Fülöp T Jr.
Protective Effect of Amyloid-β Peptides Against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model.
J Alzheimers Dis. 2016;50(4):1227-41.
PubMed.
McColl G, Roberts BR, Gunn AP, Perez KA, Tew DJ, Masters CL, Barnham KJ, Cherny RA, Bush AI.
The Caenorhabditis elegans A beta 1-42 model of Alzheimer disease predominantly expresses A beta 3-42.
J Biol Chem. 2009 Aug 21;284(34):22697-702.
PubMed.
Gut microbial landscapes undergo a drastic change with age, and this is thought to impact age-related decline (Bischoff, 2016; Clark et al., 2015). Recently, several papers have also highlighted the importance of probiotics in suppressing chronic inflammation, enhancing immunity in humans (Ibrahim et al., 2010; Moro-Garcia et al., 2013) and in preventing insulin resistance as well as obesity in model organisms (Vincent et al., 2013). But the component of probiotics responsible for longevity is largely unknown.
In this study, Han and colleagues took an unbiased approach to identify longevity-promoting microbial factors from a library of single-gene knock-out E. coli. Using this screen as a platform, they went on to identify several E. coli mutants that use known lifespan-modulating pathways such as IGF1 and mTOR to exert their effect. However, two E.coli strains, Δlon and Δhns, did not use these conventional pathways. The authors further identified colanic acid (CA), a mannose containing extracellular polysaccharide made by several enterobacterial species, as the key molecule that extends healthspan and lifespan. Colanic acid seems to regulate mitochondrial homeostasis through fission, which in turn influences longevity.
This is a relevant study in the field given that most studies with microbial gut communities, probiotics and aging have been largely correlative. Furthermore, the study brings to the forefront the communication between microbial factors and mitochondria, which are known to have evolved from bacteria, that ultimately impacts host health.
This study sparks many exciting avenues for follow up.
1. Mechanism of function: The authors suggest that the mitochondrial unfolded protein response is required for CA-mediated longevity. However, whether hsp-6 or UPRmt dynamics are altered with age in response to CA, and if this is important for extension of lifespan, is unanswered. Other studies have shown that the mitochondrial unfolded protein response plays a role in longevity via cell-autonomous and non-cell-autonomous functions (Durieux et al., 2011). Does colanic acid exert its effect similarly? Does it change mitochondrial function with age, or substrate utilization?
2. Healthspan in other species: In the current study, colanic acid reduces amyloid toxicity and germline tumors in worms, and also activity and lifespan of D. melanogaster. Does colanic acid supplementation increase healthspan/ lifespan in mammals? If so, is supplementation required through life or intermittently? These questions will help determine the therapeutic potential of colanic acid, as well as uncover novel pathways that can be fine-tuned to extend healthy life.
Clark RI, Salazar A, Yamada R, Fitz-Gibbon S, Morselli M, Alcaraz J, Rana A, Rera M, Pellegrini M, Ja WW, Walker DW.
Distinct Shifts in Microbiota Composition during Drosophila Aging Impair Intestinal Function and Drive Mortality.
Cell Rep. 2015 Sep 8;12(10):1656-67. Epub 2015 Aug 28
PubMed.
Durieux J, Wolff S, Dillin A.
The cell-non-autonomous nature of electron transport chain-mediated longevity.
Cell. 2011 Jan 7;144(1):79-91.
PubMed.
Ibrahim F, Ruvio S, Granlund L, Salminen S, Viitanen M, Ouwehand AC.
Probiotics and immunosenescence: cheese as a carrier.
FEMS Immunol Med Microbiol. 2010 Jun 1;59(1):53-9. Epub 2010 Feb 11
PubMed.
Moro-García MA, Alonso-Arias R, Baltadjieva M, Fernández Benítez C, Fernández Barrial MA, Díaz Ruisánchez E, Alonso Santos R, Alvarez Sánchez M, Saavedra Miján J, López-Larrea C.
Oral supplementation with Lactobacillus delbrueckii subsp. bulgaricus 8481 enhances systemic immunity in elderly subjects.
Age (Dordr). 2013 Aug;35(4):1311-26. Epub 2012 May 30
PubMed.
Vincent M, Philippe E, Everard A, Kassis N, Rouch C, Denom J, Takeda Y, Uchiyama S, Delzenne NM, Cani PD, Migrenne S, Magnan C.
Dietary supplementation with Agaricus blazei murill extract prevents diet-induced obesity and insulin resistance in rats.
Obesity (Silver Spring). 2013 Mar;21(3):553-61.
PubMed.
Comments
Massachusetts General Hospital & Harvard Medical School
These findings add to rapidly mounting data that point to a role for micro-organisms in Alzheimer's disease (AD). Recent findings from both mouse models and human nutrition studies suggest the gut microbiome modulates brain β-amyloidosis (Minter et al., 2016). Here, Han et al. suggest the microbial polysaccharide colanic acid may mediate the beneficial host outcomes that appear associated with specific gut microbes, including ameliorating the harmful effects of Aβ fibrillization.
These findings are consistent with the emerging antimicrobial protection hypothesis for AD that we (Kumar et al., 2016), and others (Bourgade et al., 2016), recently proposed. In this model, Aβ is an antimicrobial peptide (AMP) of innate immunity that protects against infecting pathogens and, pertinent to the Han et al. study, microbial products. Fibrillization mediates Aβ’s antimicrobial activities and leads to protective sequestration of pathogens or microbial endotoxins in β-amyloid deposits (Kumar et al., 2016). Aβ contains an AMP heparin-binding motif (XBBXBX) that mediates microbial targeting and binding (Kumar et al., 2016). Soluble host sugars inhibit microbial binding of Aβ and other AMPs, regulating their activities. However, bacteria also secret exopolysaccharides that target AMPs and inhibit their activities, including polysaccharides that specifically inhibit microbial agglutination.
Aβ microbial agglutination pathways lead to generation of β-amyloid. Colanic acid and other exopolysaccharides, as well as a plethora of additional secretory products, are generated by the gut microbiome and enter the CNS, either from the periphery or via the vagus nerve. A key role for AMPs in the immunoprivileged brain is the agglutination and neutralization of potentially harmful microbial products. We suspect this may also emerge as a key innate immune role for Aβ in brain. Thus, the antimicrobial protection model provides a plausible pathway in which microbial molecules bind to Aβ, directly modulating β-amyloid deposition. Importantly, the microbial molecules need not be generated in the brain, but can be translocated from the gut microbiome or sites of infection.
The protective effect of colanic acid observed by Han et al in Aβ-expressing transgenic CL2006 nematodes is consistent with this model. It is worth noting that the transgenic CL2006 nematode model used in the Han et al. study has been reported to express only Aβ3-42, and not full-length Aβ1-42 (McColl et al., 2009). In vitro analysis demonstrates that Aβ3-42 self-aggregates like Aβ1-42, but more rapidly, forming fibrillar structures. Thus, confirmation of the new findings with a line expressing Aβ1-42 will be useful in future studies.
In summary, we believe there is much to be gained by considering the data of Han et al., as well as similar related findings, in the context of the antimicrobial protection model in which β-amyloid deposition is part of an innate immune response driven by immunochallenge. This approach may lead to alternative therapeutic strategies for effective modulation of β-amyloid generation that take into account Aβ’s normal function and do not necessarily target the peptide directly.
References:
Minter MR, Zhang C, Leone V, Ringus DL, Zhang X, Oyler-Castrillo P, Musch MW, Liao F, Ward JF, Holtzman DM, Chang EB, Tanzi RE, Sisodia SS. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer's disease. Sci Rep. 2016 Jul 21;6:30028. PubMed.
Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Sci Transl Med. 2016 May 25;8(340):340ra72. PubMed.
Bourgade K, Le Page A, Bocti C, Witkowski JM, Dupuis G, Frost EH, Fülöp T Jr. Protective Effect of Amyloid-β Peptides Against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model. J Alzheimers Dis. 2016;50(4):1227-41. PubMed.
McColl G, Roberts BR, Gunn AP, Perez KA, Tew DJ, Masters CL, Barnham KJ, Cherny RA, Bush AI. The Caenorhabditis elegans A beta 1-42 model of Alzheimer disease predominantly expresses A beta 3-42. J Biol Chem. 2009 Aug 21;284(34):22697-702. PubMed.
View all comments by Robert MoirUniversity of Pittsburgh School of Medicine
Gut microbial landscapes undergo a drastic change with age, and this is thought to impact age-related decline (Bischoff, 2016; Clark et al., 2015). Recently, several papers have also highlighted the importance of probiotics in suppressing chronic inflammation, enhancing immunity in humans (Ibrahim et al., 2010; Moro-Garcia et al., 2013) and in preventing insulin resistance as well as obesity in model organisms (Vincent et al., 2013). But the component of probiotics responsible for longevity is largely unknown.
In this study, Han and colleagues took an unbiased approach to identify longevity-promoting microbial factors from a library of single-gene knock-out E. coli. Using this screen as a platform, they went on to identify several E. coli mutants that use known lifespan-modulating pathways such as IGF1 and mTOR to exert their effect. However, two E.coli strains, Δlon and Δhns, did not use these conventional pathways. The authors further identified colanic acid (CA), a mannose containing extracellular polysaccharide made by several enterobacterial species, as the key molecule that extends healthspan and lifespan. Colanic acid seems to regulate mitochondrial homeostasis through fission, which in turn influences longevity.
This is a relevant study in the field given that most studies with microbial gut communities, probiotics and aging have been largely correlative. Furthermore, the study brings to the forefront the communication between microbial factors and mitochondria, which are known to have evolved from bacteria, that ultimately impacts host health.
This study sparks many exciting avenues for follow up.
1. Mechanism of function: The authors suggest that the mitochondrial unfolded protein response is required for CA-mediated longevity. However, whether hsp-6 or UPRmt dynamics are altered with age in response to CA, and if this is important for extension of lifespan, is unanswered. Other studies have shown that the mitochondrial unfolded protein response plays a role in longevity via cell-autonomous and non-cell-autonomous functions (Durieux et al., 2011). Does colanic acid exert its effect similarly? Does it change mitochondrial function with age, or substrate utilization?
2. Healthspan in other species: In the current study, colanic acid reduces amyloid toxicity and germline tumors in worms, and also activity and lifespan of D. melanogaster. Does colanic acid supplementation increase healthspan/ lifespan in mammals? If so, is supplementation required through life or intermittently? These questions will help determine the therapeutic potential of colanic acid, as well as uncover novel pathways that can be fine-tuned to extend healthy life.
References:
Bischoff SC. Microbiota and aging. Curr Opin Clin Nutr Metab Care. 2016 Jan;19(1):26-30. PubMed.
Clark RI, Salazar A, Yamada R, Fitz-Gibbon S, Morselli M, Alcaraz J, Rana A, Rera M, Pellegrini M, Ja WW, Walker DW. Distinct Shifts in Microbiota Composition during Drosophila Aging Impair Intestinal Function and Drive Mortality. Cell Rep. 2015 Sep 8;12(10):1656-67. Epub 2015 Aug 28 PubMed.
Durieux J, Wolff S, Dillin A. The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell. 2011 Jan 7;144(1):79-91. PubMed.
Ibrahim F, Ruvio S, Granlund L, Salminen S, Viitanen M, Ouwehand AC. Probiotics and immunosenescence: cheese as a carrier. FEMS Immunol Med Microbiol. 2010 Jun 1;59(1):53-9. Epub 2010 Feb 11 PubMed.
Moro-García MA, Alonso-Arias R, Baltadjieva M, Fernández Benítez C, Fernández Barrial MA, Díaz Ruisánchez E, Alonso Santos R, Alvarez Sánchez M, Saavedra Miján J, López-Larrea C. Oral supplementation with Lactobacillus delbrueckii subsp. bulgaricus 8481 enhances systemic immunity in elderly subjects. Age (Dordr). 2013 Aug;35(4):1311-26. Epub 2012 May 30 PubMed.
Vincent M, Philippe E, Everard A, Kassis N, Rouch C, Denom J, Takeda Y, Uchiyama S, Delzenne NM, Cani PD, Migrenne S, Magnan C. Dietary supplementation with Agaricus blazei murill extract prevents diet-induced obesity and insulin resistance in rats. Obesity (Silver Spring). 2013 Mar;21(3):553-61. PubMed.
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