Pryor, R. et al. (2017) International Worm Meeting "Metabolic superbugs regulate the effect of drugs and diet on host health and lifespan."

Temmerman, L., Bryson, K., Maier, L., Pryor, R., De Haes, W., Norvaisas, P., Typas, A., Bala-Krishnan, K., Cabreiro, F.

[International Worm Meeting, 2017]

Animals are typically colonised by a diverse community of commensal and symbiotic microorganisms. Recent studies have linked perturbations to the gut microbiota with several nutrition-associated pathologies including obesity, type-2 diabetes and potentially ageing1. Therefore, in order to fully understand the physiology of an organism, it is important to consider both the host and its microbiota as a unique metabolic entity- collectively referred to as the holobiont. Metformin has been found to extend lifespan in C. elegans by altering the metabolic profile of the gut bacteria2. Similarly, a role for the microbiota in mediating the therapeutic effect of the drug has been uncovered in both mice and humans3,4. Nevertheless, precisely how the microbiota mediates the effects of metformin on the host remains unclear. To this purpose, we have created 35 biguanide-resistant bacterial strains which regulate the effects of metformin on C. elegans lifespan. To systematically elucidate which bacterial mechanisms confer resistance against metformin we utilised a chemical genomics approach and screened a genome-wide overexpression and deletion library in E. coli. This strategy allowed us to identify novel bacterial genes regulating the effects of metformin on the host. In order to establish how bacterial-dependent effects of metformin regulate host heath, we have employed a combination of diverse "omic" techniques at the holobiont level using C. elegans and germ-free mice. Utilising metformin-sensitive and resistant bacterial strains we have disentangled the bacteria-dependent effects of metformin from those that result from direct action of the drug in C. elegans. This has led to the identification of a unique pro-longevity signature mediated by the effects of metformin on bacterial metabolism. Finally, we have discovered a "legacy effect" whereby microbial exposure to metformin triggers long-lasting metabolic rearrangements that have beneficial or detrimental consequences in the host in a nutrient-dependent manner. Ultimately these findings underscore the importance of microbes as molecular integrators of the effects of drugs and diet on host physiology. 1- Pryor R., & Cabreiro F. Biochem J (2015); 2- Cabreiro F. et al. Cell (2013); 3- Shin N.R. et al. Gut (2014); 4- Forslund K. et al. Nature (2015)

Quintaneiro, L. et al. (2017) International Worm Meeting "Host-microbe co-metabolism dictates cancer drug efficacy in C. elegans."

Bryson, K., Cabreiro, F., Greene, N. D. E., Norvaisas, P., Typas, A., Quintaneiro, L., Lui, P. P., Herrera-Dominguez, L., Scott, T. A.

[International Worm Meeting, 2017]

Fluorouracil (5-FU) is a fluoropyrimidine and uracil analogue commonly used in the treatment of colorectal cancer. 5-FU exerts cytotoxicity by inhibiting nucleotide synthesis and by misincoorporating into RNA and DNA, leading to cancer cell damage and death1. Despite the widespread use of this drug, new approaches are needed to boost efficacy and decrease toxicity. Furthermore, 5-FU treatment outcome is variable between patients and cannot be completely explained by genetic factors, suggesting that environmental factors could contribute to its efficacy. The gut microbiota is defined as the collective community of microbes that reside a host gastrointestinal tract, and have recently been linked to other elements of host fitness, such as immunity2 and metabolism3. However, not much is known about the interplay between drug, gut microbes and the host. To unravel the mechanism by which the microbiota is affecting the metabolism of 5-FU, we used the nematode C. elegans as a host model and microbe E. coli as a gut microbe model. Via high-throughput screens and metabolomic approaches we found that microbes can affect drug conversion and efficacy in the host. We discovered this effect to be influenced by bacterial metabolism and synthesis of ribonucleotides and vitamins B9 and B6. Additionally, we find deoxynucleotide pools imbalances in bacteria increased autophagy and cell death on host cells upon 5-FU treatment. Interestingly, this effect was found to be dependent and regulated by the host gene nucleoside diphosphate kinase ndk-1. In summary, our data suggests bacteria can contribute to drug efficacy on host metabolism through two distinct but complementary processes4. These findings emphasize the importance of the gut microbiome in the co-metabolism of host-targeted drugs. Moreover, this study reveals the potential therapeutic power of manipulating gut microbial communities to help treat disease and improve treatment outcomes. References: 1. Longley, D.B., et al. Nat. Rev. Cancer (2003) 2. Nicholson, J.K., et al. Science (2012) 3. Cabreiro, F., et al. Cell (2013) 4. Scott, A.T., Quintaneiro, L. M., et al. Cell (in press)

Quartey MO et al. (2021) Sci Rep "The A(1-38) peptide is a negative regulator of the A(1-42) peptide implicated in Alzheimer disease progression."

Pennington PR, Heistad RM, Nyarko JNK, Barnes JR, Bolanos MAC, Parsons MP, Knudsen KJ, De Carvalho CE, Leary SC, Mousseau DD, Buttigieg J, Maley JM, Quartey MO

[Sci Rep, 2021]

The pool of -Amyloid (A) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A peptides. We examined how a naturally occurring variant, e.g. A(1-38), interacts with the AD-related variant, A(1-42), and the predominant physiological variant, A(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A(1-38) interacts differently with A(1-40) and A(1-42) and, in general, A(1-38) interferes with the conversion of A(1-42) to a -sheet-rich aggregate. Functionally, A(1-38) reverses the negative impact of A(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A(1-42) phenotype in Caenorhabditis elegans. A(1-38) also reverses any loss of MTT conversion induced by A(1-40) and A(1-42) in HT-22 hippocampal neurons and APOE 4-positive human fibroblasts, although the combination of A(1-38) and A(1-42) inhibits MTT conversion in APOE 4-negative fibroblasts. A greater ratio of soluble A(1-42)/A(1-38) [and A(1-42)/A(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A(1-42).

Danielle Thierry-Mieg et al. (2003) Worm Breeder's Gazette "www.wormgenes.org , a new gene centered database"

Vahan Simonyan, Michel Potdevin, Mark Sienkiewicz, Yuji KOHARA, Jean Thierry-Mieg, Danielle Thierry-Mieg, Tadasu SHIN-I

[Worm Breeder's Gazette, 2003]

Wormgenes is a new resource for C.elegans offering a detailed summary about each gene and a powerful query system.

Scott TA et al. (2017) Cell "Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C.elegans."

Clayton PT, Herrera-Dominguez L, Cabreiro F, Wilson MP, Scott TA, Typas A, Quintaneiro LM, Pessia A, Sudiwala S, Norvaisas P, Velagapudi V, Leung KY, Mills PB, Greene NDE, Bryson K, Lui PP

[Cell, 2017]

Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variablebetween patients. We queried whether gut microbes,a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E.coli and the nematode C.elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B6, B9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potentialtherapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease.

Tangrodchanapong T et al. (2020) Front Pharmacol "Frondoside A Attenuates Amyloid- Proteotoxicity in Transgenic Caenorhabditis elegans by Suppressing Its Formation."

Tangrodchanapong T, Sobhon P, Meemon K

[Front Pharmacol, 2020]

Oligomeric assembly of Amyloid- (A) is the main toxic species that contribute to early cognitive impairment in Alzheimer's patients. Therefore, drugs that reduce the formation of A oligomers could halt the disease progression. In this study, by using transgenic <i>Caenorhabditis elegans</i> model of Alzheimer's disease, we investigated the effects of frondoside A, a well-known sea cucumber <i>Cucumaria frondosa</i> saponin with anti-cancer activity, on A aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 M significantly delayed the worm paralysis caused by A aggregation as compared with control group. In addition, the number of A plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of A species in the transgenic <i>C. elegans</i> were significantly reduced upon treatment with frondoside A, whereas the level of A monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of A. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express A. Taken together, these data suggested that low dose of frondoside A could protect against A-induced toxicity by primarily suppressing the formation of A oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-A aggregation should be studied and elucidated in the future.

Hodgkin JA (1998) International Journal of Developmental Biology "Seven types of pleiotropy."

Hodgkin JA

[International Journal of Developmental Biology, 1998]

Pleiotropy , a situation in which a single gene influences multiple phenotypic tra its, can arise in a variety of ways. This paper discusses possible underlying mechanisms and proposes a classification of the various phenomena involved.

Tuck S (2011) Curr Biol "Extracellular vesicles: budding regulated by a phosphatidylethanolamine translocase."

Tuck S

[Curr Biol, 2011]

Recent work on a Caenorhabditis elegans transmembrane ATPase reveals a central role for the aminophospholipid phosphatidylethanolamine in the production of a class of extracellular vesicles.

Viney ME et al. (2004) Naturwissenschaften "Is dauer pheromone of Caenorhabditis elegans really a pheromone?"

Viney ME, Franks NR

[Naturwissenschaften, 2004]

Animals respond to signals and cues in their environment. The difference between a signal (e.g. a pheromone) and a cue (e.g. a waste product) is that the information content of a signal is subject to natural selection, whereas that of a cue is not. The model free-living nematode Caenorhabditis elegans forms an alternative developmental morph (the dauer larva) in response to a so-called 'dauer pheromone', produced by all worms. We suggest that the production of 'dauer pheromone' has no fitness advantage for an individual worm and therefore we propose that 'dauer pheromone' is not a signal, but a cue. Thus, it should not be called a pheromone.

Schaeffer JM et al. (1990) J Antibiot (Tokyo) "Cochlioquinone A, a nematocidal agent which competes for specific [3H]ivermectin binding sites."

Williamson JM, Schaeffer JM, Bergstrom AR, Liesch JM, Goetz MA, Frazier EG

[J Antibiot (Tokyo), 1990]

Cochlioquinone A, isolated from the fungus Helminthosporium sativum, was found to have nematocidal activity. Cochlioquinone A is a competitive inhibitor of specific [3H]ivermectin binding suggesting that cochlioquinone A and ivermectin interact with the same membrane receptor.