Sunday, 28 June 2015

Immune stability requires microbial diversity?

The gut microbiota regulates many aspects of host physiology, including immunity. This has long been emphasised by germ-free (i.e. microbiota-free) mice, which have a grossly underdeveloped immune system and enhanced susceptibility to infection, among other physiological deficits. More recent research is gradually showing how gut microbes influence every major immune cell type, from their birth in bone marrow (i.e. haematopoiesis), to the differentiation and functional activity/priming of immune cells throughout the body (e.g. gut, blood, spleen, nervous system, etc.).

I’m not aware of any comprehensive reviews on this stuff yet, but much of this research is hopefully illustrated by my table below (click for big).

Gut microbiota regulation of host immunity occurs via two main mechanisms:
  1. Microbes and their components (e.g. PAMPs) directly stimulate specific immune receptors (e.g. PRRs). This happens both within the gut mucosa and via the constant low-level translocation of PAMPs (e.g. LPS and peptidoglycan) from gut to bloodstream 7.
  2. Microbes release metabolites such as short-chain fatty acids (SCFAs) which also regulate the immune system. SCFAs (e.g. acetate, propionate and butyrate) are produced via bacterial metabolism of indigestible carbohydrates (i.e. resistant starch and fibre) and are absorbed into systemic circulation. SCFAs modulate energy metabolism, activate specific G-protein coupled receptors, and act as histone deacetylase inhibitors (HDIs) which modulate epigenetics 14,21.
Given the gut microbiota consists of trillions of microbes from hundreds of species, all of which can stimulate the immune system in specific ways, the diversity and balance of the gut microbiota is probably important for a balanced immune system! This may be emphasised by several basic observations. Firstly, as mentioned above, germ-free mice have profound immunodeficiencies. Similarly, mammalian newborns take several years to acquire an adult gut microbiota, and this is paralleled by initial immunodeficiency and reliance upon breast milk for passive immunity. Many animal studies have also shown that antibiotics deplete gut microbiota populations, induce inflammation, disrupt systemic immunity and increase vulnerability to allergy 12 and infection 5–7 (e.g. seasonal influenza 19,22).

When it comes to chronic diseases, varied microbial changes and lower diversity are often reported, which might skew the immune system in complex ways. This could result from many internal and environmental factors which shape the gut microbiota. Intriguingly, the increasing prevalence of many chronic diseases in developed countries is paralleled by practices which negatively impact the gut microbiota, such as C-section, formula feed, antibiotic use, extreme hygiene and processed foods 23,24. On the other hand, the gut microbiome of modern hunter-gatherer societies, largely untouched by modern practices, has greater microbial diversity (e.g. Hadza 25 and Yanomami 26). This suggests modernization may be gradually shrinking the core microbiome and altering our physiology 23. The new field of paleomicrobiology should gradually reveal the evolutionary significance of all this 24. So far it is clear that we have coevolved with our microbiota, it is deeply entwined within our physiology, and we depend upon it for health 24.

Could the gut microbiota influence the immunology and course of ME/CFS? Perhaps there are some initial clues. For instance, ME/CFS can be preceded by allergies/asthma 27 and triggered by many different infections; even in the course of the disease there is evidence for chronic infections and immunodeficiency 28. There is also increased translocation of LPS from gut bacteria 29,30, which correlates immune activation 31, autoimmunity 32 and even remission of CFS 33,34. Furthermore, a clinical trial with B. Infantis (a Treg-stimulating probiotic 18) lowered blood inflammatory markers in CFS 35.

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2.           Wang, G. Human antimicrobial peptides and proteins. Pharmaceuticals (Basel). 7, 545–94 (2014).
3.           Kosiewicz, M. M., Zirnheld, A. L. & Alard, P. Gut microbiota, immunity, and disease: a complex relationship. Front. Microbiol. 2, 180 (2011).
4.           Chung, H. et al. Gut immune maturation depends on colonization with a host-specific microbiota. Cell 149, 1578–93 (2012).
5.           Khosravi, A. et al. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 15, 374–81 (2014).
6.           Deshmukh, H. S. et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat. Med. 20, 524–30 (2014).
7.           Clarke, T. B. et al. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat. Med. 16, 228–31 (2010).
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11.        Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. (2015). doi:10.1038/nn.4030
12.        Hill, D. A. et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat. Med. 18, 538–46 (2012).
13.        Vulevic, J., Drakoularakou, A., Yaqoob, P., Tzortzis, G. & Gibson, G. R. Modulation of the fecal microflora profile and immune function by a novel trans-galactooligosaccharide mixture (B-GOS) in healthy elderly volunteers. Am. J. Clin. Nutr. 88, 1438–46 (2008).
14.        Kim, C. H., Park, J. & Kim, M. Gut microbiota-derived short-chain Fatty acids, T cells, and inflammation. Immune Netw. 14, 277–88 (2014).
15.        Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–98 (2009).
16.        Park, J.-H., Jeong, S.-Y., Choi, A.-J. & Kim, S.-J. Lipopolysaccharide directly stimulates Th17 differentiation in vitro modulating phosphorylation of RelB and NF-κB1. Immunol. Lett. 165, 10–9 (2015).
17.        Furusawa, Y., Obata, Y. & Hase, K. Commensal microbiota regulates T cell fate decision in the gut. Semin. Immunopathol. 37, 17–25 (2015).
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19.        Oh, J. Z. et al. TLR5-Mediated Sensing of Gut Microbiota Is Necessary for Antibody Responses to Seasonal Influenza Vaccination. Immunity 41, 478–92 (2014).
20.        Rosser, E. C. et al. Regulatory B cells are induced by gut microbiota–driven interleukin-1β and interleukin-6 production. Nat. Med. 20, 1334–9 (2014).
21.        Kasubuchi, M., Hasegawa, S., Hiramatsu, T., Ichimura, A. & Kimura, I. Dietary Gut Microbial Metabolites, Short-chain Fatty Acids, and Host Metabolic Regulation. Nutrients 7, 2839–2849 (2015).
22.        Ichinohe, T. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl. Acad. Sci. U. S. A. 108, 5354–9 (2011).
23.        Barzegari, A., Saeedi, N. & Saei, A. A. Shrinkage of the human core microbiome and a proposal for launching microbiome biobanks. Future Microbiol. 9, 639–56 (2014).
24.        Warinner, C., Speller, C., Collins, M. J. & Lewis, C. M. Ancient human microbiomes. J. Hum. Evol. 79, 125–36 (2015).
25.        Schnorr, S. L. et al. Gut microbiome of the Hadza hunter-gatherers. Nat. Commun. 5, 3654 (2014).
26.        Clemente, J. C. et al. The microbiome of uncontacted Amerindians. Sci. Adv. 1, e1500183–e1500183 (2015).
27.        Evans, M., Barry, M., Im, Y., Brown, A. & Jason, L. A. An Investigation of Symptoms Predating CFS Onset. J. Prev. Interv. Community 43, 54–61 (2015).
28.        Smith, A. P. & Thomas, M. A. Chronic fatigue syndrome and increased susceptibility to upper respiratory tract infections and illnesses. Fatigue Biomed. Heal. Behav. (2015).
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30.        Maes, M., Mihaylova, I. & Leunis, J.-C. Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J. Affect. Disord. 99, 237–40 (2007).
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32.        Maes, M. et al. In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation. J. Affect. Disord. 150, 223–30 (2013).
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35.        Groeger, D. et al. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes 4, 325–39 (2013).

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