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Classical Vaccine Development Suggests Pathogenic To Probiotic Conversion Of Bacteria Is Theoretically Possible

Classical vaccine development includes Attenuated vaccine, i.e., rendering a live pathogenic bacteria relatively harmless through the process of attenuation.

Starting in the late 19th century when scientists first succeeded in growing bacteria in culture, they attempted to generate live attenuated versions of a variety of pathogenic bacteria through their prolonged culture. A prominent success includes the live TB vaccine, BCG vaccine, from the pathogenic cow TB microbe, Mycobacterium bovis. Albert Calmette

and Camille Guérin (1)

heroically sub-cultured this bacterium every 3 weeks in their special glycerin-potato medium, adding ox bile to the mix when they noticed their bacterial cultures tended to clump, which fortuitously led to a reduction in virulence. Why heroically? Heroic because they continued their sub-cultures unabated through the German occupation of Lille, even through increasing scarcity of potato and ox bile! By 1919, after about 230 subcultures over 11 years, they had in their hands a tubercle bacillus that did not cause TB in guinea pigs, rabbits, cattle, or horses (2). Starting in 1921 and continuing to date, it’s estimated that more than 5 billion people got the BCG vaccine.

See figure below for examples of attenuated bacteria including Salmonella enterica serovar typhi and Vibrio cholerae, causative agents of typhoid and cholera, respectively (3).

Some Natural Examples Of Bacteria That Span The Spectrum From Probiotic To Pathogen

The WHO defines probiotic bacteria as ‘live microorganisms which when administered in adequate amounts confer a health benefit on the host‘ (4). Depending on the context, C. butyricum and H. pylori can be either beneficial or pathogenic.

Clostridium butyricum

Widely used in China, Japan, Korea, Clostridium butyricum, a strictly anaerobic, Gram-positive, sporulating bacillus, fits the definition of a probiotic (5, 6, 7). For e.g., the C. butyricum probiotic strain, CBM588, effectively treated and prevented antibiotic-associated diarrhea in children (8). It apparently worked by increasing anaerobes and by preventing the decrease of Bifidobacterium species in antibiotic-Rx children, i.e., by the well-known probiotic/beneficial mocrobe mechanism of Colonisation resistance.

However, C. butyricum is associated in the context of disease as well (9).

  • Other C. butyricum strains have been found in infant botulism in Italy (10), China, India, Ireland and the US (11).
  • Other C. butyricum strains have been found in NEC (Necrotizing enterocolitis), an extremely dangerous gastrointestinal disease that disproportionately affects preterm newborns (12, 13, 14).
  • A different C. butyricum strains was found in an elderly patient with antibiotic-associated diarrhea (15).

What gives? How could a microbe be safely consumed as a probiotic in some countries, as C. butyricum is in China, Japan and Korea and yet be associated with deadly diseases in other countries? Molecular analyses of pathogenic C. butyricum strains isolated from patients suggests acquisition of virulence factors such as enterotoxins and botulinum neurotoxin (see figure below from (9). However, the triggers that drive expression of beneficial or pathological traits are as yet completely unknown as culture of such strictly anaerobic bacterial strains continues to be extremely challenging.

Helicobacter pylori

Estimated to infect >50% of the global human population (16), the Gram-negative H. pylori also walks the spectrum all the way from pathogenicity to mutualism (see figures below from 17). H. pylori pathogenicity ensues from a complex interaction between microbial expression of virulence factors such as VacA and Cag A for e.g., and genetic predisposition among different ethnicities (18, 19).

Examples such as C. butyricum and H. pylori suggest that selection pressure imposed by human actions such as migration, dense populations and excessive antibiotic use contribute to the likelihood whether such highly prevalent microbes express pathogenic features or not.

Bibliography

1. Tirumalai Kamala’s answer to What (if anything) about tuberculosis makes producing a highly effective vaccine difficult?

2. Sakula, A. “BCG: who were Calmette and Guerin?.” Thorax 38.11 (1983): 806-812. http://www.ncbi.nlm.nih.gov/pmc/…

3. Plotkin, Stanley A., and Susan L. Plotkin. “The development of vaccines: how the past led to the future.” Nature Reviews Microbiology 9.12 (2011): 889-893.

4. Hotel, Amerian Córdoba Park. “Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria.” PREVENTION 5 (2001): 1. http://www.mesanders.com/probio_…

5. Chen, Zhao-Fei, et al. “Probiotics Clostridium butyricum and Bacillus subtilis ameliorate intestinal tumorigenesis.” Future microbiology 10.9 (2015): 1433-1445.

6. Zhang, Ling, et al. “Effects of dietary supplementation of probiotic, Clostridium butyricum, on growth performance, immune response, intestinal barrier function, and digestive enzyme activity in broiler chickens challenged with Escherichia coli K88.” Journal of animal science and biotechnology 7.1 (2016): 1. Journal of Animal Science and Biotechnology

7. Bader, J., A. Albin, and U. Stahl. “Spore-forming bacteria and their utilisation as probiotics.” Beneficial microbes 3.1 (2012): 67-75.

8. Seki, Hiromi, et al. “Prevention of antibiotic‐associated diarrhea in children by Clostridium butyricum MIYAIRI.” Pediatrics International 45.1 (2003): 86-90.

9. Cassir, Nadim, Samia Benamar, and Bernard La Scola. “Clostridium butyricum: from beneficial to a new emerging pathogen.” Clinical Microbiology and Infection 22.1 (2016): 37-45. https://www.researchgate.net/pro…

10. Fenicia, L., F. Anniballi, and P. Aureli. “Intestinal toxemia botulism in Italy, 1984–2005.” European Journal of Clinical Microbiology & Infectious Diseases 26.6 (2007): 385-394.

11. Dykes, Janet K., et al. “Laboratory Investigation of the First Case of Botulism Caused by Clostridium butyricum Type E Toxin in the United States.” Journal of Clinical Microbiology 53.10 (2015): 3363-3365. Laboratory Investigation of the First Case of Botulism Caused by Clostridium butyricum Type E Toxin in the United States

12. Howard, FrancesM, et al. “Outbreak of necrotising enterocolitis caused by Clostridium butyricum.” The Lancet 310.8048 (1977): 1099-1102.

13. Smith, Birgitte, et al. “Community analysis of bacteria colonizing intestinal tissue of neonates with necrotizing enterocolitis.” BMC microbiology 11.1 (2011): 1. BMC Microbiology

14. Cassir, Nadim, et al. “Clostridium butyricum strains and dysbiosis linked to necrotizing enterocolitis in preterm neonates.” Clinical Infectious Diseases 61.7 (2015): 1107-1115. Clostridium butyricum Strains and Dysbiosis Linked to Necrotizing Enterocolitis in Preterm Neonates

15. Kwok, Jamie SL, et al. “Draft genome sequence of Clostridium butyricum strain NOR 33234, isolated from an elderly patient with diarrhea.” Genome announcements 2.6 (2014): e01356-14. Draft Genome Sequence of Clostridium butyricum Strain NOR 33234, Isolated from an Elderly Patient with Diarrhea

16. Kauser, Farhana, et al. “The cag pathogenicity island of Helicobacter pylori is disrupted in the majority of patient isolates from different human populations.” Journal of clinical microbiology 42.11 (2004): 5302-5308. The cag Pathogenicity Island of Helicobacter pylori Is Disrupted in the Majority of Patient Isolates from Different Human Populations

17. Lin, Derek, and Britt Koskella. “Friend and foe: factors influencing the movement of the bacterium Helicobacter pylori along the parasitism–mutualism continuum.” Evolutionary applications 8.1 (2015): 9-22. http://onlinelibrary.wiley.com/d…

18. Datta, Simanti, et al. “Virulence genes and neutral DNA markers of Helicobacter pylori isolates from different ethnic communities of West Bengal, India.” Journal of clinical microbiology 41.8 (2003): 3737-3743. Virulence Genes and Neutral DNA Markers of Helicobacter pylori Isolates from Different Ethnic Communities of West Bengal, India

19. Tirumalai Kamala’s answer to Is there any strong research about the effects of increased exposure to pathogens from grouping children in settings like day care centers or schools?

https://www.quora.com/Can-we-convert-a-pathogenic-bacteria-to-a-probiotic/answer/Tirumalai-Kamala

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