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11 October 2018
Authors: Sonia Wróbel, Kaja Milanowska
Authors: Sonia Wróbel, Kaja Milanowska

Wind of change - review of two groundbreaking articles about microbiome and probiotics.

“I am prescribing you an antibiotic. You absolutely need a probiotic to protect your gut microflora!” How often have you heard such words from your doctor? What if I tell you that the latest research suggests that probiotics cannot help you at all and even slow down the healing process of the gut microbiome? Does it mean that we should stop taking probiotics? Check what this news means for the world of microbiome science, but also for the ordinary user of probiotic supplements.

Wind of change - review of two groundbreaking articles about microbiome and probiotics.

Caption: This illustration depicts a three-dimensional (3D) computer-generated image of a cluster of barrel-shaped Clostridium perfringens bacteria.  It is a normal component of the intestinal tract of humans, but can be also a cause of food poisoning. The artistic recreation was based upon scanning electron microscopic (SEM) images; Illustrator: Jennifer Oosthuizen; 2016, Content Providers(s): CDC/ James Archer [1]

“I am prescribing you an antibiotic. You absolutely need a probiotic to protect your gut microflora!”

How often have you heard such words from your doctor? What if I tell you that the latest research suggests that probiotics cannot help you at all and even slow down the healing process of the gut microbiome? Does it mean that we should stop taking probiotics? Check what this news means for the world of microbiome science, but also for the ordinary user of probiotic supplements.

The gastrointestinal system is the largest immune (or more precisely lymphoid) organ in the human body [2]. The digestive tract of an adult human occupies an area between 30 and 40 m2 [3] and it contains about 60-70% of all immunocompetent cells (gut-associated lymphoid tissue ‘GALT’) [4]. It is also a place inhabited by microorganisms called human gut microbiome (see Dictionary section). Studies confirmed that changes in microbiome interactions with the immune system are correlated with a wide array of illnesses, such as inflammatory bowel disease (IBD) [5-7] or even cancer [8]. In consequence, there is nothing surprising about that people try to care about their guts not only by healthy lifestyle and diet but also by taking probiotics. National Institute of Health (NIH) reported in National Health Interview Survey (NHIS) that in 2012, 3.9 million of U.S. adults used probiotics or prebiotics (see Dictionary section) [9]. Probably many of these people were concerned about the fact that at the beginning of September, the media flooded the Internet with alarming headlines:

One of the most recognizable and respected journal “Cell” has published two groundbreaking articles last month which were the reason for this confusion:

  1. “Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features” [10]
  2. “Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT” [11]

Caption: This illustration depicts a three-dimensional (3D), computer-generated image of a number of Salmonella serotype Typhi bacteria. Salmonella is a common cause of food poisoning. Probiotic products can antagonize Salmonella sp. infections, perhaps by inhibition of these inherent immune system evasion mechanisms [12]. The artistic recreation was based upon scanning electron microscopic (SEM) images; Illustrators: Alissa Eckert and Jennifer Oosthuizen; 2016; Content Providers(s): CDC/ James Archer [13]

Let’s take a closer look at the findings presented in the articles:

  • – Highlight 1: “The murine & human gut mucosal microbiome only partially correlates with stool”

Stool collection is fast, cheap and non-invasive, therefore it is widely used in research. For quite some time we know that stool samples do not fully reflect the entire composition of the digestive microbiome [14-15]. However, it cannot be said that such samples are completely uninformative. In some cases they prove to be completely sufficient to confirm the research or clinical theses [16-17].

  • – Highlight 2: ”Mice feature an indigenous-microbiome driven colonization resistance to probiotics”
  • – Highlight 3: ”Humans feature a person-specific gut mucosal colonization resistance to probiotics”
  • – Highlight 4: “Probiotic colonization is predictable by pre-treatment microbiome & host features”

This discovery confirms the scientific speculations that have been appearing in the journals for several years. First of all, every organism can react differently to probiotic therapy. It depends on many factors such as the initial state of the digestive and immune system of the host, the selection of probiotic strains, the diet used, stressors and generally understood hygiene of life (e.g. sleeping habits) [18]. In some cases, this will lead to a situation in which the host’s bacteria will inhibit the colonization of probiotic strains introduced into the organism. Secondly, we also had some evidence suggesting that probiotics do not necessarily colonize the intestines, but they modulate the immune system and change the dynamics of intestinal microbiota, providing favorable conditions for the development of commensal beneficial microorganisms [18]. Probiotics may also affect the expression of host genes [19].

  • – Highlight 5: “Murine gut mucosal probiotics colonization is only mildly enhanced by antibiotics”
  • – Highlight 6: “Human gut mucosal probiotic colonization is significantly enhanced by antibiotics”
  • – Highlight 7: “Post antibiotics, probiotics delay gut microbiome and transcriptome reconstitution”

It is a well-known fact that antibiotics disrupt the human bacterial ecosystem [20]. Microbiota can regenerate for years or never return to its original state, irreversibly changing the species and quantity characteristics [21-23]. Despite the commonly used practice of prescribing probiotics during and after antibiotic therapy, long-term effects of these interventions have not been studied until now. The discovery presented in the analyzed articles discusses the legitimacy of using probiotics after using antibiotics, indicating the possibility of slowing down the natural regeneration of microbiota. Certainly, more experiments are needed on larger groups of patients, but the medical community should start discussing the best clinical practice in this area.

  • – Highlight 8: ”In contrast, aFMT restores mucosal microbiome and gut transcriptome reconstitution”

The aFMT proved to be the most effective intervention, restoring the original composition of the faeces as early as the day after the transplant, showing great effectiveness in the regeneration of strains key for patient health (Alistipes shahii, Roseburia intestinalis, Coprococcus spp).

Conclusions for probiotics users

In conclusion, do not be afraid of taking probiotics. However, you must remember that taking care of the proper quality of the probiotic supplement is very important, because preparations of very different quality are available on the market. This is due to the fact that probiotics are dietary supplements and are not as thoroughly tested and controlled as drugs.

Ideal probiotic checklist:

  • – check if the quantity of bacteria is given on the packaging e.g “Each capsule contains approximately 10×109 (10 billion) colony forming units (CFU- colony forming units) of live bacteria. Probiotic contains a documented number of bacterial colonies – at least 10 milligrams of CFU per capsule throughout the declared shelf life.”
  • – check if the number of the strain appears on the packaging e.g Lactobacillus plantarum 299v
  • – check whether the package contains information on the origin of the strain
  • – check whether the package contains information about the indication for the use of the preparation – good quality probiotics are targeted supplements, used in specific disease entities e.g Lactobacillus plantarum 299v has an positive effect in irritable bowel syndrome (IBS)
  • – check if the probiotic strain contained in the supplement has clinical trials e. g Clinical trials for Lactobacillus plantarum 299v in irritable bowel syndrome (IBS) [24]
  • – check whether the probiotic producer has performed additional tests on the effectiveness and safety of its supplement
  • – check if any external center has done a quality control of the probiotic

It must be remembered that the best way to support our gut microflora will be the healthy lifestyle: a balanced diet, abundant with fresh, seasonal vegetables; adequate amount of physical exercise; stress reduction; regeneration; sleep hygiene [18].

Dictionary:

microbiome (genomes of) all microorganisms (bacteria, viruses, fungi, archaea) that can be found in a given multicellular plant or animal organism [25]

probiotic live microorganisms that when given in appropriate amounts bring a health benefit to the host [26]

prebioticnondigestible substances that act as food for the gut microbiota (stimulate growth or activity of certain healthy bacteria that live in human body) [27]

Bibliography

[1] “Public Health Image Library (PHIL).” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 20 Dec. 2017, phil.cdc.gov/Details.aspx?pid=21914.

[2] Ganusov, Vitaly V., and Rob J. De Boer. “Do Most Lymphocytes in Humans Really Reside in the Gut?” Trends in Immunology, vol. 28, no. 12, 2007, pp. 514–518., doi:10.1016/j.it.2007.08.009.

[3] Helander, Herbert F, and Lars Fändriks. “Surface Area of the Digestive Tract – Revisited.” Scandinavian Journal of Gastroenterology, vol. 49, no. 6, Feb. 2014, pp. 681–689., doi:10.3109/00365521.2014.89832

[4] Pabst, Reinhard, et al. “Tissue Distribution of Lymphocytes and Plasma Cells and the Role of the Gut.” Trends in Immunology, vol. 29, no. 5, 2008, pp. 206–208., doi:10.1016/j.it.2008.02.006.

[5] Frank, D. N., et al. “Molecular-Phylogenetic Characterization of Microbial Community Imbalances in Human Inflammatory Bowel Diseases.” Proceedings of the National Academy of Sciences, vol. 104, no. 34, 2007, pp. 13780–13785., doi:10.1073/pnas.0706625104.

[6] Gevers, Dirk, et al. “The Treatment-Naive Microbiome in New-Onset Crohn’s Disease.” Cell Host & Microbe, vol. 15, no. 3, 2014, pp. 382–392., doi:10.1016/j.chom.2014.02.005.

[7] Ni, Josephine, et al. “A Role for Bacterial Urease in Gut Dysbiosis and Crohn’s Disease.” Science Translational Medicine, vol. 9, no. 416, 2017, doi:10.1126/scitranslmed.aah6888.

[8] Kostic, Aleksandar D., et al. “Fusobacterium Nucleatum Potentiates Intestinal Tumorigenesis and Modulates the Tumor-Immune Microenvironment.” Cell Host & Microbe, vol. 14, no. 2, 2013, pp. 207–215., doi:10.1016/j.chom.2013.07.007.

[9] Zmora, Niv, et al. “Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.” Cell, vol. 174, no. 6, 2018, doi:10.1016/j.cell.2018.08.041.

[10] Zmora, Niv, et al. “Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.” Cell, vol. 174, no. 6, 2018, doi:10.1016/j.cell.2018.08.041.

[11] Suez, Jotham, et al. “Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT.” Cell, vol. 174, no. 6, 2018, doi:10.1016/j.cell.2018.08.047.

[12] Wagner, R. Doug, and Shemedia J. Johnson. “Probiotic Bacteria Prevent Salmonella – Induced Suppression of Lymphoproliferation in Mice by an Immunomodulatory Mechanism.” BMC Microbiology, vol. 17, no. 1, 2017, doi:10.1186/s12866-017-0990-x.

[13] “Public Health Image Library (PHIL).” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 20 Dec. 2017, phil.cdc.gov/Details.aspx?pid=21918

[14] Falony, Gwen, et al. “Population-Level Analysis of Gut Microbiome Variation.” Science, vol. 352, no. 6285, 2016, pp. 560–564., doi:10.1126/science.aad3503.

[15] Falony, Gwen, et al. “Richness and Ecosystem Development across Faecal Snapshots of the Gut Microbiota.” Nature Microbiology, vol. 3, no. 5, 2018, pp. 526–528., doi:10.1038/s41564-018-0143-5.

[16] Panek, Marina, et al. “Methodology Challenges in Studying Human Gut Microbiota – Effects of Collection, Storage, DNA Extraction and next Generation Sequencing Technologies.” Scientific Reports, vol. 8, no. 1, 2018, doi:10.1038/s41598-018-23296-4.

[17] Abrahamson, Melanie, et al. “Successful Collection of Stool Samples for Microbiome Analyses from a Large Community-Based Population of Elderly Men.” Contemporary Clinical Trials Communications, vol. 7, 2017, pp. 158–162., doi:10.1016/j.conctc.2017.07.002.

[18] Gilbert, Jack A, et al. “Current Understanding of the Human Microbiome.” Nature Medicine, vol. 24, no. 4, Oct. 2018, pp. 392–400., doi:10.1038/nm.4517.

[19] Plaza-Diaz, Julio. “Modulation of Immunity and Inflammatory Gene Expression in the Gut, in Inflammatory Diseases of the Gut and in the Liver by Probiotics.” World Journal of Gastroenterology, vol. 20, no. 42, 2014, p. 15632., doi:10.3748/wjg.v20.i42.15632

[20] Gunzburg, Jean De, et al. “Protection of the Human Gut Microbiome From Antibiotics.” The Journal of Infectious Diseases, vol. 217, no. 4, 2017, pp. 628–636., doi:10.1093/infdis/jix604.

[21] Reid, Gregor, et al. “Microbiota Restoration: Natural and Supplemented Recovery of Human Microbial Communities.” Nature Reviews Microbiology, vol. 9, no. 1, 2010, pp. 27–38., doi:10.1038/nrmicro2473.

[22] Dethlefsen, Les, et al. “The Pervasive Effects of an Antibiotic on the Human Gut Microbiota, as Revealed by Deep 16S RRNA Sequencing.” PLoS Biology, vol. 6, no. 11, 2008, doi:10.1371/journal.pbio.0060280.

[23] Dethlefsen, L., and D. A. Relman. “Incomplete Recovery and Individualized Responses of the Human Distal Gut Microbiota to Repeated Antibiotic Perturbation.” Proceedings of the National Academy of Sciences, vol. 108, no. Supplement_1, 2010, pp. 4554–4561., doi:10.1073/pnas.1000087107.

[24] “PubMed-NCBI.”,www.ncbi.nlm.nih.gov/pubmed/term=Lactobacillus+plantarum+299v+in+irritable+bowel+syndrome.

[25] “The Human Microbiome Project: Extending the Definition of What Constitutes a Human.” National Human Genome Research Institute (NHGRI), www.genome.gov/27549400/the-human-microbiome-project-extending-the-definition-of-what-constitutes-a-human/.

[26] Sanders, Mary Ellen. “Probiotics: Definition, Sources, Selection, and Uses.” Clinical Infectious Diseases, vol. 46, no. s2, 2008, doi:10.1086/523341.

[27]  Brennan, Michael D., and Verna Monson. “Professionalism: Good for Patients and Health Care Organizations.” Mayo Clinic Proceedings, vol. 89, no. 5, 2014, pp. 644–652., doi:10.1016/j.mayocp.2014.01.011.

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