The gut microbiota profoundly regulates many aspects of host physiology, including immunity. This has long been emphasised by germ-free (microbiota-free) mice, which have a grossly underdeveloped immune system and enhanced susceptibility to infection, amongst many 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 am not aware of any comprehensive reviews on this stuff yet, but most of this research is hopefully illustrated by my table below (click for big).
Gut microbiota regulation of host immunity occurs via two main mechanisms:
- Microbes and their components (PAMPs) directly stimulate specific immune receptors (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.
- 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 also act as histone deacetylase inhibitors (HDIs) which modulate epigenetics 14,21.
Given that 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 pretty important for a balanced immune system! This can be emphasised most bluntly by several observations. 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, a more diffuse loss of microbial balance and diversity is commonly seen, which might skew the immune system in complex ways. This could result from many internal and environmental factors which shape the gut microbiota. Importantly, 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 by far the greatest 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.
It seems likely the gut microbiota plays a role in the immunology of most chronic diseases. I think it is becoming pretty impossible to study immunology without considering the gut microbiota! So what about the immunological mess that is ME/CFS? I think there are some initial clues. For instance we know that 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. We also know there is increased translocation of LPS from gut bacteria, and this is linked to immune activation and autoimmunity in ME/CFS 29–34. Also a clinical trial showed that B. Infantis (a Treg-stimulating probiotic 18) can lower blood inflammatory markers in CFS 35. But most remarkable may be the ability of bacteriotherapy to induce profound symptom remission in people with CFS and comorbid IBS 36.
Unfortunately, despite all these interesting links, the show is let down by gut microbiota studies which seem a bit less convincing in ME/CFS 37,38. Perhaps studies which simply average all results, rather than stratify patients, are unlikely to pick up many changes in a varied condition like ME/CFS. I feel we need more symptom/subset-specific 30 and comprehensive gut microbiota/metabolome research in ME/CFS. This should help better define a ‘CFS/Gut’ subgroup at least.
1. Campbell, Y., Fantacone, M. L. & Gombart, A. F. Regulation of antimicrobial peptide gene expression by nutrients and by-products of microbial metabolism. Eur. J. Nutr. 51, 899–907 (2012).
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).
8. Rizzello, V., Bonaccorsi, I., Dongarrà, M. L., Fink, L. N. & Ferlazzo, G. Role of natural killer and dendritic cell crosstalk in immunomodulation by commensal bacteria probiotics. J. Biomed. Biotechnol. 2011, 473097 (2011).
9. Ochoa-Repáraz, J. et al. A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol. 3, 487–95 (2010).
10. Chang, P. V, Hao, L., Offermanns, S. & Medzhitov, R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc. Natl. Acad. Sci. U. S. A. 111, 2247–52 (2014).
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).
18. Konieczna, P., Akdis, C. A., Quigley, E. M. M., Shanahan, F. & O’Mahony, L. Portrait of an immunoregulatory Bifidobacterium. Gut Microbes 3, 261–6 (2012).
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. 2014, (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). at
29. 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).
30. Maes, M., Leunis, J.-C., Geffard, M. & Berk, M. Evidence for the existence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with and without abdominal discomfort (irritable bowel) syndrome. Neuro Endocrinol. Lett. 35, 445–453 (2014).
31. Maes, M. & Leunis, J.-C. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol. Lett. 29, 902–10 (2008).
32. Maes, M. et al. Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. J. Affect. Disord. 136, 909–17 (2012).
33. 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).
34. Maes, M., Coucke, F. & Leunis, J.-C. Normalization of the increased translocation of endotoxin from gram negative enterobacteria (leaky gut) is accompanied by a remission of chronic fatigue syndrome. Neuro Endocrinol. Lett. 28, 739–44 (2007).
35. Groeger, D. et al. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes 4, 325–39 (2013).
36. Borody, T. J., Nowak, A. & Finlayson, S. The GI microbiome and its role in Chronic Fatigue Syndrome: A summary of bacteriotherapy. J. Australas. Coll. Nutr. Environ. Med. 31, 3–8 (2012).
37. Frémont, M., Coomans, D., Massart, S. & De Meirleir, K. High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients. Anaerobe 22, 50–6 (2013).
38. Lakhan, S. E. & Kirchgessner, A. Gut inflammation in chronic fatigue syndrome. Nutr. Metab. (Lond). 7, 79 (2010).