Staff Advice Report

11 January 2021

Advice to the Decision-making Committee to determine the new organism status of 18 gut bacteria species

Application code: APP204098

Application type and sub-type: Statutory determination

Applicant: PSI-CRO

Date application received: 4 December 2020

Purpose of the Application: Information to support the consideration of the determination of 18 gut bacteria species

Executive Summary

On 4 December 2020, the Environmental Protection Authority (EPA) formally received an application from PSI-CRO requesting a statutory determination of 18 gut bacteria species, Anaerotruncus colihominis, Blautia obeum (aka Ruminococcus obeum), Blautia wexlerae, Enterocloster aldenensis (aka Clostridium aldenense), Enterocloster bolteae (aka Clostridium bolteae), Clostridium innocuum, Clostridium leptum, Clostridium scindens, Clostridium symbiosum, Eisenbergiella tayi, Emergencia timonensis, Flavonifractor plautii, Holdemania filiformis, Intestinimonas butyriciproducens, Roseburia hominis, ATCC PTA-126855, ATCC PTA-126856, and ATCC PTA-126857.

In absence of publicly available data on the gut microbiome from New Zealand, the applicant provided evidence of the presence of these bacteria in human guts from the United States, Europe and Australia. The broad distribution of the species in human guts supports the global distribution of these gut bacteria worldwide.

After reviewing the information provided by the applicant and found in scientific literature, EPA staff recommend the Hazardous Substances and New Organisms (HSNO) Decision-making Committee (the Committee) to determine that the 18 bacteria are not new organisms for the purpose of the HSNO Act.

Recommendation

1. Based on the information available, the bacteria appear to be globally ubiquitous and commonly identified in environments that are also found in New Zealand (human guts).

2. There is sufficient weight of evidence for the Committee to agree that the 18 bacteria species were present in New Zealand prior to 29 July 1998 and continuously after that, and therefore are not new for the purpose of the Act.

Purpose of this document

3. This document has been prepared by the EPA staff to advise the Committee of our assessment of application APP204098 submitted under the HSNO Act (the Act). This document discusses information provided in the application and other sources.

4. The decision path for this application can be found in Appendix 1.

The application

5. On 4 December 2020, PSI-CRO applied to the EPA under section 26 of the HSNO Act seeking a determination on the new organism status of 18 gut bacteria species. 6. The applicant provides evidence that these bacteria naturally occur in human guts from various countries and have a ubiquitous global distribution. Therefore, the applicant considers these bacteria to be not new for the purpose of the HSNO Act. 7. EPA staff have also investigated information on these species in scientific literature and other local sources for evidence of the existence of these organisms both before and after 29 July 1998 in New Zealand. Moreover, we have considered the histories of these organisms from the perspective of the taxonomic literature and the state of scientific knowledge regarding these species and their classification prior to 29 July 1998.

8. The EPA considered the ubiquity argument as evidence for the presence of a microorganism in New Zealand based on a commissioned report ‘The Biogeography of Environmental Microorganisms’, by Clark Ehlers and Gavin Lear of the University of Auckland . This report considers and discusses global phenomena that cause the distribution of Archaea and Bacteria to widely dispersed on the globe (Ehlers C & Lear G 2014). Among these are natural phenomena, such as the intercontinental transport of dust particles by wind and rain clouds, as well as unintentional transport by human beings, for example in ship ballast water or via air travel.

Organism description

Family Lachnospiraceae

Table 1: Taxonomic description of Blautia wexlerae, B. obeum, Eisenbergiella tayi, Roseburia hominis, Enterocloster aldensis and E. bolteae.

Taxonomic Unit Classification

Order Eubacteriales

Family Lachnospiraceae

Genus Blautia Eisenbergiella Roseburia Enterocloster

Species Blautia wexlerae Liu Eisenbergiella tayi Roseburia Enterocloster aldenensis et al. 2008 Amir et al. 2014 hominis corrig. (Warren et al. 2007) Blautia obeum Duncan et al. Haas and Blanchard 2020, (Moore et al. 1976) 2006 aka Clostridium aldenense Lawson and Enterocloster bolteae Finegold 2015, aka (Song et al. 2003) Haas Ruminococcus and Blanchard 2020, aka obeum Clostridium bolteae Blautia wexlerae and B. obeum (aka Ruminococcus obeum) 9. Blautia wexlerae and B. obeum are gram-positive, non-motile, anaerobic bacteria isolated from animal and human faeces (MOORE et al. 1976; Liu et al. 2008). 10. Blautia obeum is also known as Ruminococcus obeum (Moore et al. 1976). However, taxonomic authorities are waiting for a second deposit of R. obeum in a different collection and country to be recognised as a new species (LPSN ND).

Eisenbergiella tayi 11. Eisenbergiella tayi is the only species in the genus Eisenbergiella. The bacteria is strictly an anaerobic, non-motile bacterium with thin elongated rods. The main fermentation end product produced by the bacterium is butyric acid suggesting a beneficial effect in the human gastrointestinal tract (Amir et al. 2014).

Roseburia hominis 12. Species in the genus Roseburia are butyrate-producing bacteria. Roseburia hominis cells are gram- variable to gram-negative, slightly curved rods. They are motile thanks to the presence of multiple flagella. The species has been isolated from human faeces (Duncan et al. 2006).

Enterocloster aldenensis (aka Clostridium aldenense) and E. bolteae (aka Clostridium bolteae) 13. Following their complete genome sequencing, the species, C. aldenense and C. bolteae, were recently reclassified under the genus Enterocloster. Their basonym names, C. aldenense and C. bolteae, are validly published, however, their preferred names are E. aldenensis and E. bolteae (Haas & Blanchard 2020). 14. Species in this genus are anaerobic fusiform rods that rarely produce spores.

Family Ruminococcaceae

Table 2: Taxonomic description of Flavonifractor plautii and Anaerotruncus colihominis

Taxonomic Unit Classification

Order Eubacteriales

Family Oscillospiraceae

Genus Flavonifractor Anaerotruncus

Species Flavonifractor plautii (Seguin Anaerotruncus colihominis 1928) Carlier et al. 2010 Lawson et al. 2004

Flavonifractor plautii 15. The bacteria Flavonifractor plautii is a gram-positive anaerobic bacterium of the family Clostridiales commonly found in the human gut microbiome. This bacterium seems to play a role in the immune system and could be used as an anti-allergy probiotic (Ogita et al. 2020).

Anaerotruncus colihominis 16. Anaerotruncus is a newly described bacterial genus in the family Clostridiaceae. The species, A. colihominis, is a gram-positive, anaerobic, thin rod bacterium. It does not produce spores and forms colonies of 2-3 mm diameter. It has been isolated from human faeces (Lawson et al. 2004).

Family Clostridiaceae

Table 3: Taxonomic description of Clostridium innocuum, C. scindens, C. symbiosum and C. leptum.

Taxonomic Unit Classification

Order Eubacteriales

Family Clostridiaceae

Genus Clostridium

Species Clostridium innocuum Smith and King 1962 Clostridium scindens Morris et al. 1985 Clostridium symbiosum (Stevens 1956) Kaneuchi et al. 1976 Clostridium leptum Moore et al., 1976

Clostridium species 17. Species in the genus Clostridium are gram-variable rod-shaped bacteria widely distributed in the environment. They are found in soils, water, intestinal tracts of humans and animals (Elsayed & Zhang 2004). Most species are anaerobic. They produce bottle-shaped endospores1 (Maczulak 2011).

1 Endospore: a dormant, tough, and non-reproductive structure produced by certain bacteria. The primary function of most endospores is to ensure the survival of a bacterium through periods of environmental stress.

18. The bacterium C. leptum was recognised by the EPA as present in New Zealand (PNZ1000141) due to its natural occurrence in the human colon (Lay et al. 2007) and identification in New Zealand patients (Stebbings et al. 2002).

Family Oscillospiraceae

Table 4: Taxonomic description of Intestinimonas butyriciproducens.

Taxonomic Unit Classification

Order Eubacteriales

Family Oscillospiraceae

Genus Intestinimonas

Species Intestinimonas butyriciproducens Kläring et al. 2013

Intestinimonas butyriciproducens 19. Species in this newly described genus within the family Oscillospiraceae are gram-positive and anaerobic (Kläring et al. 2013). They have unique metabolic features such as the production of butyrate from sugars and amino acids. There is a lack of data on their diversity, however, the species I. butyriciproducens appears to be the most commonly found (Bui et al. 2016). It has been isolated from mouse intestines (Kläring et al. 2013) as well as human stool samples (Bui et al. 2015).

Family Erysipelotrichaceae

Table 5: Taxonomic description of Holdemania filiformis and the new strain in the family Erysipelotrichaceae.

Taxonomic Unit Classification

Order Erysipelotrichales

Family Erysipelotrichaceae

Genus Holdemania Unknown

Species Holdemania filiformis ATCC PTA-126855 Willems et al. 1997

Holdemania filiformis 20. The genus Holdemania was recently described with currently only two species. The species H. filiformis, previously known as Eubacterium-like strains, is a gram-positive bacterium, strictly anaerobic and non-spore-forming rods (Willems 2015). It has been isolated from human faeces (Willems et al. 1997).

ATCC PTA-126855 21. An isolate that was detected in the Ceres study was classified as a novel member of the family Erysipelotrichaceae. It has been isolated from stool samples from human subjects from the United States, Europe and Australia (Appendix 1 of the application). The strain was deposited in the ATCC collection and is now identified by the number ATCC PTA-126855.

22. Species in this family are known to play an important role in the human gut microbiome. Some species seem correlated to inflammation while others are immunogenic that could help to combat metabolic disorders (Kaakoush 2015).

Family Ruminococcaceae

Table 6: Taxonomic description of the two new strains in the family Ruminococcaceae.

Taxonomic Unit Classification

Order Clostridiales

Family Ruminococcaceae

Genus Unknown

Species ATCC PTA-126856 ATCC PTA-126857

ATCC PTA-126856 and ATCC PTA-126857 23. Two isolates detected in the Ceres study were classified as novel members of the family Ruminococcaceae. They have been isolated from stool samples from human subjects from the United States, Europe and Australia (Appendix 1 of the application). The strains were deposited in the ATCC collection and are now identified by the numbers ATCC PTA-126856 and ATCC PTA- 126857. 24. Ruminococcaceae is known as one of the most abundant family from the order Clostridiales found in the mammalian gut environment (Biddle et al. 2013).

Family Eubacteriales

Table 7: Taxonomic description of Paenibacillus macerans.

Taxonomic Unit Classification

Order Eubacteriales

Family not assigned to a family

Genus Emergencia

Species CSUR number P2260 “Emergencia timonensis” Bessis et al. 2016

“Emergencia timonensis” 25. A recently described species in the genus Emergencia. The species is gram-positive, rod-shaped bacilli, strictly anaerobic (Bessis et al. 2016).

26. We note that the species is not recognised by taxonomic authorities such as the List of Prokaryotic names with Standing in Nomenclature (LPSN). Therefore, we linked the species name with the culture collection where it was deposited, the Collection de Souches de l'Unité des Rickettsies (CSUR), World Data Centre for Microorganisms 875 (WDCM 875) and identify the species as CSUR number P2260 “Emergencia timonensis”.

Distribution of the 18 gut bacteria

Evidence regarding the globally ubiquitous distribution of the 18 gut bacteria

27. The applicant provided evidence that all the 18 bacteria have been found in the stool of healthy human donors from the United States (USA), the European Union (EU), and Australia (Appendix 1 of the application form). The bacteria were isolated and purified from 199 donors in the USA and 34 in the EU. In Australia, 114 stool samples were processed and analysed but only the presence or absence of individual species was considered. 28. The applicant argues that since each region represents a significant source of travellers into New Zealand, these bacteria are not new organisms and are likely to have been present in New Zealand prior to 1998. 29. In addition, we found more evidence of the global distribution for the 15 bacteria identified at the species level in the scientific literature (summarised in table 8).

Table 8: Global isolations of APP204098 bacterial species. Species Where What reference Japan Human faeces Touyama 2015 Spain Obese children gut microbiota Benitez-Paez 2020 Blautia wexlerae Indonesia, New Infant faecal microbiotas Lawley et al 2019 Zealand

Clostridium innocuum USA Human empyema fluid, blood cultures Gorbach, Sherwood 1975 UK Human faeces DSMZ, ND Taiwan Stool cultures Chia 2018 Japan Human faeces Hattori 1985 Stool from children with late-onset USA Song 2003 autism

Enterocloster bolteae Japan Patients Daimon et al 2008 (previously known as 531 individuals representing healthy Amerindians from the Amazonas of Clostridium bolteae) Venezuela, Venezuela, residents of rural Malawian Yatsunenko, 2012 Malawi and USA communities, and inhabitants of USA metropolitan areas India Human faeces Gupta 2019 Patients aged 3-18 years with Crohn’s Canada Armstrong 2019 Flavonifractor plautii disease or ulcerative colitis Stool sample from a healthy 28-year-old France Hosny, 2016 man USA Human faeces Lawson et al 2004 USA Children with late-onset autism stool Lau et al 2006 531 individuals representing healthy Amerindians from the Amazonas of Venezuela, Venezuela, residents of rural Malawian Yatsunenko, 2012 Anaerotruncus colihominis Malawi and USA communities, and inhabitants of USA metropolitan areas Faecal microbiota composition between Korea rheumatoid arthritis and osteoarthritis Lee JY et al 2019 patients Enterocloster aldenensis UK Blood cultures of 3 hospitalised patients Williams 2010 (previously known as Japan Patients Daimon et al 2008 Clostridium aldenens) Italy Faecal samples from healthy donors Masucci et al 2017

Intestinimonas Japan Milk samples Kano et al., 2018 butyriciproducens France Stool sample Hosny, 2016 Israel Blood culture Amir 2014 Eisenbergiella tayi Tissue and sterile body fluids (blood Canada Bernard 2017 cultures) Scotland Human faeces Duncan 2006 Roseburia hominis 127 ulcerative colitis patients and 87 age- Belgium Machiels et al 2014 matched and sex-matched controls 15 patients affected by Alopecia Spain Moreno-Arrones 2020 universalis and 15 controls 531 individuals representing healthy Amerindians from the Amazonas of Venezuela, Venezuela, residents of rural Malawian Yatsunenko, 2012 Malawi and USA communities, and inhabitants of USA Holdemania filiformis metropolitan areas Faecal specimens from melanoma USA Frankel et al 2017 patients Stool sample among individuals with ≥5 Canada years of continuous PPI use along with Clooney 2016 non‐PPI using controls Clostridium symbiosum South Korea Blood Huh 2010 Faecal materials collected from healthy Austria DSMZ, 2016 vegetarian humans Japan Patients Daimon et al 2008 531 individuals representing healthy Amerindians from the Amazonas of Venezuela, Venezuela, residents of rural Malawian Yatsunenko, 2012 Malawi and USA communities, and inhabitants of USA metropolitan areas Japan Faeces of a colon-cancer patient Kitahara et al., 2000 USA Faecal flora of humans Winter et al., 1989 Italy Faecal samples from healthy donors Masucci et al 2017 Clostridium scindens 531 individuals representing healthy Amerindians from the Amazonas of Venezuela, Venezuela, residents of rural Malawian Yatsunenko, 2012 Malawi and USA communities, and inhabitants of USA metropolitan areas France Faeces of a healthy patient Bessis et al, 2016 Faeces of wealthy woman >65 years with Florida (US) Dahl et al 2020 Emergencia timonensis body mass <30 Taiwan Human faeces Wu 2020 Croatia Sediment sample from effluent Gonzalez-Plaza et al 2018 France Stool sample Hosny, 2016 UK and Northern Human faeces DSMZ, 2014 Clostridium leptum Ireland Faecal microbiota composition between Korea rheumatoid arthritis and osteoarthritis Lee JY et al 2019 patients Canada People with intestinal blood Chenard 2020 Blautia obeum aka Gut bacteria adults (little difference of Ruminococcus obeum Korea gut microbiota between the Yoon et al 2019 cholecystectomy and control groups

Blautia wexlerae 30. Blautia wexlerae is very common in the USA (98% of the 199 subjects) and the EU (100% of the 34 subjects). It is also present in Australia (114 tool samples).

31. The species had also been isolated from infant faecal microbiotas in New Zealand and Indonesia (Lawley et al. 2019) as well as in Japanese human faeces (Touyama et al. 2015) and gut microbiotas of obese children in Spain (Benítez-Páez et al. 2020). Blautia obeum (aka Ruminococcus obeum)

32. Blautia obeum is very common in the USA (84% of the 199 subjects) and the EU (100% of the 34 subjects), as well as present in Australia (114 tool samples).

33. The species has also been isolated from human intestinal blood samples in Canada (Chénard et al. 2020) and adults gut bacteria in Korea (Yoon et al. 2019).

Eisenbergiella tayi 34. Eisenbergiella tayi is not well represented in the USA (12% of the 199 subjects) but is more frequent in the EU (35% of the 34 subjects). It is also found in Australia (114 tool samples).

35. The species was also isolated from human blood cultures in Israel (Amir et al. 2014) and tissue and sterile body fluids (blood cultures) in Canada (Bernard et al. 2017).

Roseburia hominis 36. Roseburia hominis is very common in the USA (75% of the 199 subjects) and the EU (97% of the 34 subjects), as well as present in Australia (114 tool samples).

37. The species was also isolated from human faeces in Scotland (Duncan et al. 2006) and ulcerative colitis patients, as well as age-matched and sex-matched controls, in Belgium (Machiels et al. 2014).

Enterocloster aldenensis (aka Clostridium aldenense) 38. Enterocloster aldenensis is not well represented in the USA (10% of the 199 subjects) and the EU (18% of the 34 subjects). It is present in Australia (114 tool samples).

39. The species was reported in blood cultures of patients in the UK (Williams et al. 2010) and Japan (Daimon et al. 2008), as well as in Italy from faecal samples of healthy donors (Masucci et al. 2017). Enterocloster bolteae (aka Clostridium bolteae)

40. Enterocloster bolteae is present in the USA (29% of the 199 subjects), the EU (41% of the 34 subjects), and Australia (114 tool samples).

41. The species was found in stool from American children with late-onset autism (Song et al. 2003) and in Japanese patients (Daimon et al. 2008). It was also isolated from healthy Amerindians from the Amazonas of Venezuela, residents of rural Malawian communities, and inhabitants of USA metropolitan areas (Yatsunenko et al. 2012).

Flavonifractor plautii 42. Flavonifractor plautii is very common in the USA (86% of the 199 subjects) and the EU (100% of the 34 subjects), and present in Australia (114 tool samples).

43. The species was found in human tool samples from India (Gupta et al. 2019) and France (Hosny et al. 2016). It was also isolated from patients aged 3-18 years with Crohn’s disease or ulcerative colitis in Canada (Armstrong et al. 2019).

Anaerotruncus colihominis 44. Anaerotruncus colihominis is more common in the EU (29% of the 34 subjects) than in the USA (17% of the 199 subjects) and is present in Australia (114 tool samples).

45. The species was isolated from the stool of children with late-onset autism (Lau et al. 2006) and human faeces (Lawson et al. 2004) in the USA, as well as from faecal microbiota composition between rheumatoid arthritis and osteoarthritis patients in Korea (Lee et al. 2019). It was also isolated from healthy Amerindians from the Amazonas of Venezuela, residents of rural Malawian communities, and inhabitants of USA metropolitan areas (Yatsunenko et al. 2012).

Clostridium symbiosum 46. Clostridium symbiosum is not well represented in the USA (14% of the 199 subjects) and the EU (26% of the 34 subjects), and present in Australia (114 tool samples). 47. However, the species is well distributed in human samples worldwide. The species was found in the blood of a Korean woman (Huh et al. 2010) and in patients of a local Japanese general hospital (Daimon et al. 2008). It was isolated from healthy Amerindians from the Amazonas of Venezuela, residents of rural Malawian communities, and inhabitants of USA metropolitan areas (Yatsunenko et al. 2012). The bacterium was also found in faecal materials collected from healthy vegetarians in Austria (DSMZ 2016).

Clostridium scindens 48. Clostridium scindens is not well represented in the USA (2% of the 199 subjects) but more frequent in the EU (38% of the 34 subjects), and present in Australia (114 tool samples).

49. The species was isolated from faecal samples of a colon-cancer patient (Kitahara et al. 2000) and healthy donors in Italy (Masucci et al. 2017). It was also isolated from healthy Amerindians from the Amazonas of Venezuela, residents of rural Malawian communities, and inhabitants of USA metropolitan areas (Yatsunenko et al. 2012).

Clostridium leptum 50. Clostridium leptum is very common in the USA (65% of the 199 subjects) and the EU (79% of the 34 subjects), and present in Australia (114 tool samples). 51. The species was found in the stool sample in France (Hosny et al. 2016) as well as from faecal microbiota composition between rheumatoid arthritis and osteoarthritis patients in Korea (Lee et al. 2019).

Clostridium innocuum 52. Clostridium innocuum is more common in the EU (79% of the 34 subjects) than in the USA (29% of the 199 subjects) and is present in Australia (114 tool samples).

53. The species was isolated from human empyema fluid and blood cultures in the USA (Gorbach & Thadepalli 1975) as well as from human stool samples in Taiwan (Chia et al. 2018), Japan (Hattori et al. 1985) and the UK (DSMZ ND).

Intestinimonas butyriciproducens 54. Intestinimonas butyriciproducens is common in the USA (49% of the 199 subjects) and the EU (53% of the 34 subjects) and is present in Australia (114 tool samples).

55. The species was also isolated from milk samples in Japan (Kano et al. 2018) and human stool samples in France (Hosny et al. 2016).

Holdemania filiformis 56. Holdemania filiformis is more common in the EU (68% of the 34 subjects), than in the USA (35% of the 199 subjects) and is present in Australia (114 tool samples).

57. The species was found in patients affected by alopecia universalis2 and healthy people from Spain (Moreno‐Arrones et al. 2020), as well as in faeces from melanoma patients in the USA (Frankel et al. 2017). Holdemania filiformis was also isolated from Canadian stool samples with more than five years of continuous Proton Pump Inhibitor (PPI) use along with non‐PPI using controls (Clooney et al. 2016). The bacterium was also isolated from healthy Amerindians from the Amazonas of Venezuela, residents of rural Malawian communities, and inhabitants of USA metropolitan areas (Yatsunenko et al. 2012).

Emergencia timonensis 58. Emergencia timonensis is not well represented in the USA (5% of the 199 subjects) but common in the EU (59% of the 34 subjects), and present in Australia (114 tool samples).

59. The species was isolated from healthy patients in France (Bessis et al. 2016), USA (Dahl et al. 2020), and Taiwan (Wu et al. 2020). It was also found in sediment samples from effluent in Croatia (González-Plaza et al. 2018).

ATCC PTA-126855, ATCC PTA-126856, and ATCC PTA-126857 60. There is no extra evidence for the three novel species as they have been newly identified and therefore cannot be found in the literature yet. However, like the other bacteria species in the application, they have been found in the USA, the EU and Australia. 61. ATCC PTA-126855 is well represented in the USA (66% of the 199 subjects) and the EU (100% of the 34 subjects). It is also found present in Australia (114 tool samples).

62. ATCC PTA-126856 is well represented in the USA (93% of the 199 subjects) and the EU (94% of the 34 subjects). It is also found present in Australia (114 tool samples).

63. ATCC PTA-126857 is well represented in the USA (83% of the 199 subjects) and the EU (82% of the 34 subjects). It is also found present in Australia (114 tool samples).

Conclusion

64. As summarised in Table 8, the 18 bacteria have been mainly isolated in the Americas (USA, Canada, Venezuela), Asia (South Korea, Taiwan, Japan, India, Indonesia, Israel), Africa (Malawi) and Europe (Spain, Italy, France, Scotland, Croatia). Furthermore, the types of habitats where these bacteria are known to grow (human guts, blood, and faeces) are present in New Zealand.

65. We noted that the majority of the evidence presented was found after the HSNO Act came into place (1998) as most of the 18 bacteria species have been identified after 1998. 66. Due to the global distribution of the 18 bacteria and the high number of visitors and immigrants from America, Europe and Asia, entering the country each year, we considered that the probability for these bacteria to have been present in New Zealand before 29 July 1998 is high.

Evaluation against legislative criteria

67. For an organism to be determined as “not new” under section 26 of the Act, the organism must be shown to lie outside the definition of a new organism as defined in section 2A(1) of the Act:

2 alopecia universalis is a medical condition involving the loss of all body hair.

68. A new organism is- a. an organism belonging to a species that was not present in New Zealand immediately before 29 July 1998: b. an organism belonging to a species, subspecies, infrasubspecies, variety, strain, or cultivar prescribed as a risk species, where that organism was not present in New Zealand at the time of promulgation of the relevant regulation: c. an organism for which a containment approval has been given under this Act: d. an organism for which a conditional release has been given: e. a qualifying organism approved for release with controls: f. a genetically modified organism: g. an organism that belongs to a species, subspecies, infrasubspecies, variety, strain, or cultivar that has been eradicated from New Zealand.

69. The decision pathway for a section 26 determination is outlined in Appendix 1. 70. Section 2A(1)(a) of the Act states that a new organism must belong to “a species that was not present in New Zealand immediately before 29 July 1998”. We have evaluated the information regarding the 18 bacteria against this criterion. 71. Regarding other criteria listed in section 2A of the Act, the 18 bacteria: o have not been prescribed as a risk species (section 2A(1)(b)); o have not been approved to be held in containment or released with controls (sections 2A(1)(c), (ca) and (cb)); o are not a genetically modified organisms (section 2A(1)(d)); and o have not been eradicated from New Zealand (section 2A(1)(e)).

Comments from Agencies

72. In accordance with section 58(1) of the Act, and the Methodology, the Department of Conservation (DOC) and the Ministry for Primary Industries (MPI) were notified and provided with the opportunity to provide further information on the application. 73. DOC considered it reasonable to assume that the ubiquity of these human gut bacteria organisms and therefore agree that they are not new organisms. DOC noted that the existing records for three of these organisms in New Zealand is not relevant as dates are not provided. 74. MPI considered that the information provided by the applicant adequately supports the contention that the 18 bacterial organisms were present in New Zealand immediately prior to 29 July 1998 and, therefore, concluded that they should not be considered to be new organisms.

Effect on New Zealand’s international obligations

75. EPA staff are not aware of any international obligations that may be affected by the determination of these 18 gut bacteria species.

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Liu C, Finegold SM, Song Y, Lawson PA 2008. Reclassification of Clostridium coccoides, Ruminococcus hansenii, Ruminococcus hydrogenotrophicus, Ruminococcus luti, Ruminococcus productus and Ruminococcus schinkii as Blautia coccoides gen. nov., comb. nov., Blautia hansenii comb. nov., Blautia hydrogenotrophica comb. nov., Blautia luti comb. nov., Blautia producta comb. nov., Blautia schinkii comb. nov. and description of Blautia wexlerae sp. nov., isolated from human faeces. International Journal of Systematic and Evolutionary Microbiology 58(8): 1896-1902. LPSN, ND. last https://lpsn.dsmz.de/species/metabacillus-indicus Machiels K, Joossens M, Sabino J, De Preter V, Arijs I, Eeckhaut V, Ballet V, Claes K, Van Immerseel F, Verbeke K 2014. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 63(8). Maczulak A 2011. "Clostridium", Encyclopedia of Microbiology, Facts on File. Masucci L, Quaranta G, Nagel D, Primus S, Romano L, Graffeo R, Ianiro G, Gasbarrini A, Cammarota G, Sanguinetti M 2017. Culturomics: bacterial species isolated in 3 healthy donors for faecal microbiota transplantation in Clostridium difficile infection. Microbiologia Medica 32(1). MOORE WC, Johnson J, Holdeman L 1976. Emendation of Bacteroidaceae and Butyrivibrio and descriptions of Desulfomonas gen. nov. and ten new species in the genera Desulfomonas, Butyrivibrio, Eubacterium, Clostridium, and Ruminococcus. International Journal of Systematic and Evolutionary Microbiology 26(2): 238-252. Moreno‐Arrones OM, Serrano‐Villar S, Perez‐Brocal V, Saceda‐Corralo D, Morales‐Raya C, Rodrigues‐ Barata R, Moya A, Jaen‐Olasolo P, Vano‐Galvan S 2020. Analysis of the gut microbiota in alopecia areata: identification of bacterial biomarkers. Journal of the European Academy of Dermatology and Venereology 34(2): 400-405. Ogita T, Yamamoto Y, Mikami A, Shigemori S, Sato T, Shimosato T 2020. Oral Administration of Flavonifractor plautii Strongly Suppresses Th2 Immune Responses in Mice. Frontiers in Immunology 11(379). Song Y, Liu C, Molitoris DR, Tomzynski TJ, Lawson PA, Collins MD, Finegold SM 2003. Clostridium bolteae sp. nov., isolated from human sources. Systematic and applied microbiology 26(1). Stebbings S, Munro K, Simon M, Tannock G, Highton J, Harmsen H, Welling G, Seksik P, Dore J, Grame G 2002. Comparison of the faecal microflora of patients with ankylosing spondylitis and controls using molecular methods of analysis. Rheumatology 41(12): 1395-1401. Touyama M, Jin J, Kibe R, Hayashi H, Benno Y 2015. Quantification of Blautia wexlerae and Blautia luti in human faeces by real-time PCR using specific primers. Beneficial Microbes 6(4): 583-590. Willems A 2015. Holdemania. Bergey's Manual of Systematics of Archaea and Bacteria: 1-5. Willems A, Moore W, Weiss N, Collins M 1997. Phenotypic and phylogenetic characterization of some Eubacterium-like isolates containing a novel type B wall murein from human feces: description of Holdemania filiformis gen. nov., sp. nov. International Journal of Systematic and Evolutionary Microbiology 47(4): 1201-1204. Williams OM, Brazier J, Peraino V, Goldstein EJ 2010. A review of three cases of Clostridium aldenense bacteremia. Anaerobe 16(5): 475-477. Wu W-K, Panyod S, Liu P-Y, Chen C-C, Kao H-L, Chuang H-L, Chen Y-H, Zou H-B, Kuo H-C, Kuo C-H 2020. Characterization of TMAO productivity from carnitine challenge facilitates personalized nutrition and microbiome signatures discovery. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP 2012. Human gut microbiome viewed across age and geography. nature 486(7402): 222-227. Yoon WJ, Kim H-N, Park E, Ryu S, Chang Y, Shin H, Kim H-L, Yi SY 2019. The impact of cholecystectomy on the gut microbiota: A case-control study. Journal of clinical medicine 8(1): 79.

Appendix 1: Revised s26 pathway

Figure 17: Decision pathway for applications under Section 26 for determination as to whether an organism is a new organism

Context This decision pathway describes the decision-making process for applications under Section 26 for determination as to whether an organism is a new organism.

Introduction The purpose of this decision pathway is to provide the HSNO decision maker3 with guidance so that all relevant matters in the Hazardous Substances and New Organisms Act (1996) (the Act) and the Hazardous Substances and New Organisms (Organisms Not Genetically Modified) Regulations (1998) (the Regulations) have been addressed. It does not attempt to direct the weighting that the HSNO decision maker may decide to make on individual aspects of an application.

The decision pathway has two parts –

 Flowchart (a logic diagram showing the process prescribed in the HSNO Act and the Methodology to be followed in making a decision), and  Explanatory notes (a discussion of each step of the process).

Of necessity the words in the boxes in the flowchart are brief, and key words are used to summarise the activity required. The explanatory notes provide a description of each of the numbered items in the flowchart, and describe the processes that should be followed.

For proper interpretation of the decision pathway it is important to work through the flowchart in conjunction with the explanatory notes.

3 The HSNO decision maker refers to either the EPA Board or any committee or persons with delegated authority from the Board.

Figure 17 Explanatory Notes

Section 26 pathway A

Review the content of the application and all relevant information I t Review the application, staff advice and any relevant information held by other Agencies, and advice from e experts. m 1

Is further information required? I t Review the information and determine whether or not there is sufficient information available to make a e decision. m 2

Seek additional information (Section 52 and Section 58) I t If the HSNO decision maker considers that further information is required, then this may be sought either e from the applicant (if there is an external applicant) or from other sources. m If the HSNO decision maker considers that the information may not be complete but that no additional 3 information is currently available, then the HSNO decision maker may proceed to make a determination.

If the application is not approved on the basis of lack of information (or if the organism is considered new) and further information becomes available at a later time, then the HSNO decision maker may choose to revisit this determination.

Is it an organism (i.e. fits the “organism” definition in Section 2)? I t An organism e (a) does not include a human being: m (ab) includes a human cell: 4 (b) includes a micro-organism: (c) includes a genetic structure, other than a human cell, that is capable of replicating itself, whether that structure comprises all or only part of an entity, and whether it comprises all or only part of the total genetic structure of an entity: (d) includes an entity (other than a human being) declared to be an organism for the purposes of the Biosecurity Act 1993: (e) includes a reproductive cell or developmental stage of an organism

If yes, go to item 5.

If no, as this is not an organism, it is not regulated under the new organism provisions of the HSNO Act.

Is the determination about a potential GMO (Section 2A(1)(d))? I t If the determination relates to whether an organism is a potential GMO, go to pathway B. e If the organism is not a GMO, go to item 6. m 5

Does the organism belong to a species that was known to be present in NZ immediately before 29 I July 1998 (Section 2A(1)(a))? t e Determine on the basis of the available information whether on balance of probabilities the organism is known to belong to a species that was present in New Zealand immediately prior to 29 July 1998. m 6

For the purposes of making a Section 26 determination an organism is considered to be present in New Zealand if it can be established that the organism was in New Zealand:

(a) immediately before 29 July 1998; and

(b) not in contravention of the Animals Act 1967 or the Plants Act 1970 (excluding rabbit haemorrhagic disease virus, or rabbit calicivirus).

If yes, go to item 7 to test the organism against the next criterion.

If no, go to item 12.

Is the organism prescribed as a risk species and was not present in New Zealand at the time of I promulgation of the relevant regulation (Section 2A(1)(b))? t e Determine whether the organism belongs to a species, subspecies, infrasubspecies, variety, strain, or cultivar that has been prescribed as a risk species by regulation established under Section 140(1)(h) of the Act. If the m organism is prescribed as a risk species, determine whether it was present in New Zealand when it was 7 prescribed. The organism is a new organism if it was not present in New Zealand at the time of the promulgation of the relevant regulation.

Note: at this point it may become apparent that the organism is an unwanted organism under the Biosecurity Act. If this is the case, then MPI and DOC may be advised (they may already have been consulted under items 1, 2 and 3).

If yes, go 12.

If no, go to item 8 to test the organism against the next criterion.

Has a containment approval been given for the organism under the Act (Section 2A(1)(c))? I t For the purposes of making a Section 26 determination, this will also include the following organisms which e are “deemed” to be new organisms with containment approvals under the HSNO Act: m (a) animals lawfully imported under the Animals Act 1967 before 29 July 1998 pursuant to Section 254 8 of the HSNO Act;

(b) animals lawfully present in New Zealand in a place that was registered as a zoo or circus under the Zoological Garden Regulations 1977 pursuant to Section 255 of the HSNO Act (except where other organisms of the same taxonomic classification were lawfully present outside of a zoo or circus – see section 2A(2)(c));

(c) hamsters lawfully imported under the Hamster Importation and Control Regulations 1972 pursuant to Section 256 of the HSNO Act; or

(d) plants lawfully imported under the Plants Act 1970 before 29 July 1998 pursuant to Section 258 of the HSNO Act.

If yes, go to item 12.

If no, go to item 9 to test the organism against the next criterion.

I Has a conditional release approval been given for the organism (Section 2A(1)(ca))? t If yes, go to item 12. e m If no, go to item 10 to test the organism against the next criterion. 9

Has a qualifying organism with controls approval been given for the organism (Section 2A(1)(cb))? I t A “qualifying organism” is an organism that is or is contained in a “qualifying medicine” or “qualifying e veterinary medicine”. These terms are defined in Section 2 of the HSNO Act. m If yes, go to item 12. 1 0 If no, go to item 11 to test the organism against the next criterion.

Is the organism known to have been previously eradicated (Section 2A(1)(e))? I t Determine whether the organism belongs to a species, subspecies, infrasubspecies, variety, strain, or cultivar e that is known to have been previously eradicated. m Eradication does not include extinction by natural means but is considered to be the result of a deliberate act. 1 1 If yes, go to item 12. If no, then the organism is not a new organism.

Has HSNO release approval without controls been given for an organism of the same taxonomic I classification under Sections 35, 38 or 38I of the Act or has an organism of the same taxonomic t classification been prescribed as a not new organism (Section 2A(2)(a))? e If a release approval has been given for an organism of the same taxonomic classification under Section 35 m or 38 of the Act then the organism is not a new organism. If a release approval has been given for an 1 organism of the same taxonomic classification under Section 38I of the Act without controls then the 2 organism is not a new organism, however, if this approval has been given with controls then it is a new organism.

If an organism of the same taxonomic classification has been prescribed by regulations as not a new organism4 then it is not a new organism.

If yes, the organism is not a new organism.If no, the organism is a new organism.

Section 26 pathway B

Have the genes or other genetic material been modified by in vitro techniques or inherited from genes I or other genetic material that has been modified by in vitro techniques? t e If yes, go to item 2. m If no, the organism is not a genetically modified organism. However, you must check whether it meets the 1 other new organism criteria so go to Pathway A item 6 onwards.

Does the organism result solely from selection or natural regeneration, hand pollination, or other I managed, controlled pollination (Regulation 3(1)(a) of the Regulations)? t e Is the organisms solely the result of selection or natural regeneration, hand pollination, or other managed, controlled pollination? m 2 If yes, the organism is not a GMO. However, you must check whether it meets the other new organism criteria so go to Pathway A item 6 onwards.

If no, go to item 3.

Is the organism regenerated from organs, tissues, or cell culture (Regulation 3(1)(b) of the I Regulations)? t e Is the organism regenerated from organs, tissues, or cell culture, using any of the following techniques: selection and propagation of somaclonal variants, embryo rescue, and cell fusion (including protoplast m fusion)? 3 If yes, the organism is not a GMO. However, you must check whether it meets the other new organism criteria so go to Pathway A item 6 onwards.

If no, go to item 4.

Is the organism a result of mutagenesis treatments in use on or before 29 July 1998 (Regulation I 3(1)(ba) of the Regulations)? t e Is the organisms the result of mutagenesis that uses a chemical or radiation treatment that was in use on or before 29 July 1998?

4 http://www.legislation.govt.nz/regulation/public/2009/0143/latest/whole.html#DLM2011201

m If yes, the organism is not a GMO. However, you must check whether it meets the other new organism 4 criteria so go to Pathway A item 6 onwards. If no, go to item 5.

Does the organism result solely from artificial insemination techniques (Regulation 3(1)(c) of the I Regulations)? t e Is the organism solely the result of artificial insemination, superovulation, embryo transfer, or embryo splitting? m 5 If yes, the organism is not a GMO. However, you must check whether it meets the other new organism criteria so go to Pathway A item 6 onwards.

If no, go to item 6.

Does the organism result from spontaneous deletions, rearrangements or amplifications (Regulation I 3(1)(e) of the Regulations)? t e Is the organism a result of spontaneous deletions, rearrangements, and amplifications within a single genome, including its extrachromosomal elements? m 6 If yes, the organism is not a GMO. However, you must check whether it meets the other new organism criteria so go to Pathway A item 6 onwards.

If no, go to item 7.

Is the organism modified solely by the movement of nucleic acids using physiological processes, I plasmid loss or spontaneous deletion (Regulation 3(1)(d) of the Regulations)? t e Is the organism modified solely by the movement of nucleic acids using physiological processes, including conjugation, transduction, and transformation, or by plasmid loss or spontaneous deletion? m 7 If yes, go to item 8.

If no, go to item 9.

Does the organism contain nucleic acid molecules produced using in vitro manipulation transferred I using physiological processes, plasmid loss or spontaneous deletion (Regulation 3(2) of the t Regulations)? e Are nucleic acid molecules produced using in vitro manipulation transferred using any of the techniques m referred to in item 7? 8 If yes, go to item 9.

If no, the organism is not a GMO. However, you must check whether it meets the other new organism criteria so go to Pathway A item 6 onwards.

Has HSNO release approval without controls been given or has an organism of the same taxonomic I classification with the same genetic modification been prescribed as a not new organism (Section t 2A(2)(b))? e If a release approval has been given for an organism of the same taxonomic classification with the same m genetic modification under Section 38 of the HSNO Act then the organism is not a new organism. If a release 9 approval has been given for an organism of the same taxonomic classification with the same genetic modification under section 38I of the HSNO Act without controls then the organism is not a new organism, however, if this approval has been given with controls then it is a new organism.

If an organism of the same taxonomic classification with the same genetic modification has been prescribed by regulations as not a new organism5 then it is not a new organism.

If yes, the organism is not a new organism.

If no, the organism is a new organism.

5 http://www.legislation.govt.nz/regulation/public/2009/0143/latest/whole.html#DLM2011201