Helicobacter pylori and gut microbiota in multiple sclerosis versus Alzheimer's disease: 10 pitfalls of microbiome studies

Abstract

Alteration of microbiota has been associated with intestinal, inflammatory, and neurological diseases. Abundance of “good bacteria” such as Bifidobacterium, or their products have been generally believed to be beneficial for any diseases, while “bad bacteria” such as pathogenic Helicobacter pylori are assumed to be always detrimental for hosts. However, this is not the case when we compare and contrast the association of the gut microbiota with two neurological diseases, multiple sclerosis (MS) and Alzheimer’s disease (AD). Following H. pylori infection, pro-inflammatory T helper (Th)1 and Th17 immune response are initially induced to eradicate bacteria. However, H. pylori evades the host immune response by inducing Th2 cells and regulatory T cells (Tregs) that produce anti-inflammatory interleukin (IL)-10. Suppression of anti-bacterial Th1/Th17 cells by Tregs may enhance gastric H. pylori propagation, followed by a cascade reaction involving vitamin B12 and folic acid malabsorption, plasma homocysteine elevation, and reactive oxygen species induction. This can damage the blood-brain barrier (BBB), leading to accumulation of amyloid-β in the brain, a hallmark of AD. On the other hand, this suppression of pro-inflammatory Th1/Th17 responses to H. pylori has protective effects on the hosts, since it prevents uncontrolled gastritis as well as suppresses the induction of encephalitogenic Th1/Th17 cells, which can mediate neuroinflammation in MS. The above scenario may explain why chronic H. pylori infection is positively associated with AD, while it is negatively associated with MS. Lastly, we list “10 pitfalls of microbiota studies”, which will be useful for evaluating and designing clinical and experimental microbiota studies.

Lymphatic system and gut microbiota affect immunopathology of neuroinflammatory diseases, including multiple sclerosis, neuromyelitis optica and Alzheimer's disease

“…Recently, however, the gut microbiota has been investigated in a variety of health and disease conditions, where there seems to be a myth that “good bacteria” are beneficial for everything from aging, obesity, and infections, to brain diseases, while “bad bacteria” are bad for anything. As reviewed by Dr. Park et al (6), this is likely not the case in MS and two “bad bacteria” Clostridium perfringens type A and Helicobacter pylori . While the former causes food poisoning and gas gangrene and the latter are associated with gastritis, gastric cancer and idiopathic thrombocytopenic purpura (ITP), the presence of both bacteria are lower in MS patients than controls.…”

“…Oversimplification and/or overestimation of the roles of the gut bacterial community (bacteriome) in microbiota studies can be explained by “10 pitfalls of microbiome studies” proposed by Dr. Park et al (6): 1) the presence of fungal (mycobiome) and viral communities (virome); 2) microbial taxonomy/classification; 3) fecal bacteria ratio underrepresentation; 4) “dysbiosis” as the outcome; 5) discrepancy with primary immunodeficiency diseases (PID); 6) age, gender, and country; 7) good bacteria is not always good; 8) antibiotics affect systemic microbiota and immunity, 9) fecal microbiome transplantation (FMT) methodology and safety, and 10) tailor-made therapy. The proposal is useful to plan and evaluate microbiota studies, clinically and experimentally.…”

Influx and Efflux of Immune Cells in the Central Nervous System

“…Although the lymphatic system and microbiota have been independently described in most medical textbooks of anatomy, immunology, and microbiology, their roles in CNS immunopathology had long been unclear. To elucidate this question, we are currently focusing on the involvement of the CNS lymphatics and gut microbiota [22].…”

Of ethnicity, environment, and microbiota

“…Recently, several 'pitfalls' of microbiome studies have been noted. 10 These include the omission of fungi, viruses, and parasites from microbiome studies, improper attention to microbial taxonomy, failure to quantify the total numbers of bacteria, not distinguishing the cause or outcome of microbial changes, discordance between experimental and clinical studies, lack of thorough understanding of the influence of environmental and other factors on gut microbiota, and uncertain benefits and safety of probiotics, prebiotics, antibiotics, and fecal microbial transfer for disease treatment. 10 Many other shortcomings that could contribute to discrepancies of results obtained in various studies deserve consideration and are briefly discussed below.…”

“…10 These include the omission of fungi, viruses, and parasites from microbiome studies, improper attention to microbial taxonomy, failure to quantify the total numbers of bacteria, not distinguishing the cause or outcome of microbial changes, discordance between experimental and clinical studies, lack of thorough understanding of the influence of environmental and other factors on gut microbiota, and uncertain benefits and safety of probiotics, prebiotics, antibiotics, and fecal microbial transfer for disease treatment. 10 Many other shortcomings that could contribute to discrepancies of results obtained in various studies deserve consideration and are briefly discussed below. Currently, direct comparison of microbiome data from various investigations is not possible due to a number of variations in experimental conditions including sample collection, storage prior to DNA extraction, use of different sequencing platforms, as well as the lack of standard data processing and analysis methods.…”