- Open Access
We are not alone: a case for the human microbiome in extra intestinal diseases
Gut Pathogensvolume 9, Article number: 13 (2017)
“Dysbiosis” in the gut microbiome has been implicated in auto-immune diseases, in inflammatory diseases, in some cancers and mental disorders. The challenge is to unravel the cellular and molecular basis of dysbiosis so as to understand the disease manifestation.
Next generation sequencing and genome enabled technologies have led to the establishment of the composition of gut microbiomes and established that “dysbiosis” is the cause of several diseases. In a few cases the cellular and molecular changes accompanying dysbiosis have been investigated and correlated with the disease. Gut microbiome studies have indicated that Christensenella minuta controls obesity in mice, Faecalibacterium prausnitzii protects mice against intestinal inflammation and Akkermansia muciniphila reverses obesity and insulin resistance by secreting endocannabinoids. In mice polysaccharide antigen A on the surface of Bacteroides fragilis, reduces inflammation. Such experiments provide the link between the gut microbiome and human health but implicating dysbiosis with extra-intestinal diseases like arthritis, muscular dystrophy, vaginosis, fibromyalgia, some cancers and mental disorders appears to be more challenging. The relevance of gut microbiome to the eye appears to be very remote. But considering that the eye is the site of inflammatory diseases like uveitis, scleritis, Mooren’s corneal ulcer etc. it is possible that these diseases are also influenced by dysbiosis. In mice signals from the gut microbiota activate retina specific T cells that are involved in autoimmune uveitis. Such information would open up new strategies for therapy where the emphasis would be on restoring the diversity in the gut by antibiotic or specific drug use, specific microbe introduction, probiotic use and fecal transplant therapy. The ocular surface microbiome may also be responsible for eye diseases in man but such studies are lacking. Microbiome of the healthy cornea and conjunctiva have been identified. But whether the ocular microbiome exhibits dysbiosis with disease? Whether ocular microbiome is influenced by the gut microbiome? What mediates the cross-talk between the gut and ocular microbiomes? These are questions that need to be addressed to understand idiopathic infections of the eye.
Evaluating diseases remote from the gut would unfold the mysteries of the microbiome.
The only time we are alone is prior to birth. Then onwards we are colonized by innumerable number of bacteria acquired from the mother and the environment and by adulthood we have trillions of bacteria colonizing every surface of the body. In the adult gut the number increases to 1014 bacteria which weighs around 1.13 kg and is ten times more than the total number of cells in the human body (1013). Thus we are more bacteria than human. This enormous community of microorganisms was termed the “microbiome” by Lederberg and Mccray  and was defined as a multi-species community of microorganisms (bacteria, fungi and viruses) that differs from niche to niche in population density and community composition. For instance the microbiome of the gut is different from that on the skin, on the scalp, inside the nostrils, mouth, armpits, oesophagus, stomach, small intestine, vagina etc. [2,3,4]. What could be the reasons for the variation? How is it important? And what is the role of genes associated with the microbiome which according to conservative estimates is 200–300 times more than the total genes in the human body? These are few of the questions that need to be answered.
Dysbiosis and diseases
Till the 1990s, it has been a mystery as to whether the microbes/genes in the gut microbiome have any impact on human health other than the canonical role of the gut bacteria to break down food remnants, modulate the immune system, promote fat storage, biosynthesis of vitamins and amino acids, metabolism of drugs etc. But, with the advent of next generation sequencing and other genome enabled technologies including DNA based databases and metabolomics on human microbiome studies have become an eye-opener to hitherto unknown facts about the composition of gut microbiomes, their dynamics and their relevance to human welfare . At the phylum level Bacteroidetes and Firmicutes are the most dominant bacteria in the gut of normal individuals and together constitute 70–90% of the total bacterial community followed by Actinobacteria and Proteobacteria. This community is dynamic and known to vary in normal individuals with age, ethnicity, diet, exposure to chemicals and also host genetic variation [6,7,8,9]. Studies analyzing the gut microbiomes of twins established a link between human genotype and the composition of the gut microbiome . All these factors make the very definition of a normal core microbiome a great challenge. Aberrations from the normal core microbiome is referred to as “dysbiosis” (meaning imbalance in the microbiome) and has been implicated in auto-immune diseases like diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis and fibromyalgia, in inflammatory diseases like obesity, neonatal necrotizing enterocolitis, inflammatory bowel disease and vaginosis, in some cancers and mental disorders [10, 11]. Ability of the gut microbiome to modulate the immune system is considered as an important reason for the diseased state . The direct evidence that the microbiota are indeed the cause of the disease is strengthened by the pioneering studies on obesity in mice. Gut bacteria from fat mice when transplanted into genetically lean mice with no gut bacteria of their own, transform the lean mice into obese mice [13, 14]. Subsequent studies demonstrated that skinny germ free mice plump up on receiving a fecal transplant from a human donor implying that the bacteria help the recipient to digest and metabolise more efficiently [13,14,15]. But, if the fecal transplant of the human donor was supplemented with Christensenella minuta the recipient mice were thinner indicating that C. minuta controls obesity . Another example, emphasizing the role of gut bacteria is related to Clostridium difficile infection (CDI) patients who are cured of CDI when transplanted with fecal microbiota from normal individuals [16, 17]. This led to the concept that just as a pathogen could cause a disease a “good” microbe could prevent a disease? For instance Faecalibacterium prausnitzii could protect mice against experimentally induced intestinal inflammation since these gut bacteria were anti-inflammatory. Yet another example of a good microbe is Akkermansia muciniphila. Increase in abundance of A. muciniphila correlated with an improved metabolic profile and reversed obesity and decreased insulin resistance probably mediated by endocannabinoids secreted by A. muciniphila [18, 19].
Dysbiosis and extra-intestinal diseases
Linking food/gut related disease like obesity, inflammatory bowel disease, enterocolitis, diabetes etc. to dysbiosis appears to be obvious but implicating dysbiosis with extra-intestinal diseases like arthritis, muscular dystrophy, multiple sclerosis, vaginosis, fibromyalgia, some cancers and mental disorders appears to be more challenging. These studies indicate that the microbiome has an overarching influence on human health. For instance it was demonstrated that transplanting a specific combination of fecal bacteria into the gut of normal mice rendered them depressed due to changes in the “myelin” sheath that surrounds nerve fibers . Cresol, produced by certain gut bacteria and which reduces the amount of myelin produced by brain cells was higher in mice that became depressed after fecal transplants. It was also observed that in mice modeled on two inflammatory human diseases: colitis and multiple sclerosis, polysaccharide antigen A (PSA) on the surface of the gut microbe Bacteroides fragilis, regulates immunity and reduces inflammation . Experiments which produce such leads at the molecular level would help to understand the link between the gut and human health irrespective of the site of pathology and may thus provide leads for therapy.
Dysbiosis and ocular diseases
The relevance of gut microbiome to the eye appears to be very remote. But considering that the eye is the site of inflammatory diseases like uveitis, scleritis, Mooren’s corneal ulcer etc. which also occur due to autoimmune reaction, it is possible that under non-infectious conditions these diseases are influenced by dysbiosis in the gut. Last year it was demonstrated that in mice with experimentally induced autoimmune uveitis oral administration of antibiotics reduced the severity of uveitis . But, intraperitoneal administration of the same antibiotic did not have the desired effect thus highlighting the role of gut microbiota in affecting uveitis. Simultaneously, it was also observed that the gut microbiome was significantly altered following antibiotic administration. Thus implying that uveitogenic bacteria may exist, and some antibiotics may be able to alter the balance of microbiota in favour of protective bacteria and thus help to resolve uveitis. Such studies could form the basis for therapeutic modulation of diseases. In a recent study, in mice, it was demonstrated that signals from the gut microbiota activate retina specific T cells that are involved in autoimmune uveitis . Such information would open up new strategies for therapy were the emphasis would be on restoring the diversity in the gut by antibiotic or specific drug use, by specific microbe introduction, by probiotic use and by fecal transplant therapy.
Ocular surface microbiome may also be responsible for eye diseases in man. Dong et al.  studied the microbiome of the healthy cornea and conjunctiva of four individuals and identified a core microbiome of 12 genera which included commensal, environmental, and opportunistic pathogenic bacteria. Whether the ocular microbiome exhibits dysbiosis with disease? Whether ocular microbiome is influenced by the gut microbiome? What mediates the cross-talk between the gut and ocular microbiomes? These are questions that need to be addressed to understand idiopathic infections of the eye. Research directed on the above lines would help to establish whether the gut microbiome influences ocular surface disease directly or indirectly by altering the ocular microbiome and probably also help to identify the causative organism.
What seems to be amiss in these studies is an over emphasis on establishing core microbiomes rather than trying to ascertain the reasons for dysbiosis and methods to overcome dysbiosis. Further attempts to get at the relevance of dysbiosis by manipulating the microbiomes or by animals studies is also limiting. Above all, work on bacterial communities far outpaces that of viral and eukaryotic communities, although these agents are resident in the gut and could be the cause of several diseases. Finally evaluating diseases remote from the gut such as the eye, brain, kidney etc. would unfold the mysteries of the new organ the “microbiome”. It is only future studies that would either prove or disprove what Cho and Blaser  have said “—this (microbiome) is a frontier for human preventive medicine and for medical management of chronic diseases”.
Clostridium difficile infection
polysaccharide antigen A
Lederberg J, Mccray AT. ‘Ome sweet’omics—a genealogical treasury of words. Scientist. 2001;15(7):8–10.
Peterson J, Peterson S, Garges M, Giovanni P, McInnes L, Wang JA, et al. The NIH human microbiome project. Genome Res. 2009;19(12):2317–23. doi:10.1101/gr.096651.109.
Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59–65. doi:10.1038/nature08821.
Cho I, Blaser MJ. The human microbiome:at the interface of health and disease. Nat Rev Genet. 2012;13(4):260–70. doi:10.1038/nrg3182.
Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci. 2009;106(10):3698–703. doi:10.1073/pnas.0812874106.
Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med. 2009;1(6):6ra–14ra. doi:10.1126/scitranslmed.3000322.
Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, et al. Human genetics shape the gut microbiome. Cell. 2014;159(4):789–99. doi:10.1016/j.cell.2014.09.053.
Shetty SA, Marathe NP, Shouche YS. Opportunities and challenges for gut microbiome studies in the Indian population. Microbiome. 2013;1:24. doi:10.1186/2049-2618-1-24.
Hopkins MJ, Sharp R, Macfarlane GT. Age and disease related changes in intestinal bacterial populations assessed by cell culture, 16S rRNA abundance, and community cellular fatty acid profiles. Gut. 2001;48(2):198–205. doi:10.1136/gut.48.2.198.
Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis. 2003;36(5):580–5. doi:10.1086/367657.
Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SSK, McCulle SL, et al. Colloquium paper: vaginal microbiome of reproductive-age women. Proc Nat Acad Sci. 2011;108(1):4680–7. doi:10.1073/pnas.1002611107.
Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature. 2011;474(7351):327–36. doi:10.1038/nature10213.
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–31. doi:10.1038/nature05414.
Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Nat Acad Sci USA. 2005;102(31):11070–5. doi:10.1073/pnas.0504978102.
Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013;341(6150):1–10. doi:10.1126/science.1241214.
Burke KE, Lamont JT. Fecal transplantation for recurrent Clostridium difficile infection in older adults: a review. J Am Geriatr Soc. 2013;61(8):1394–8. doi:10.1111/jgs.12378.
Drekonja D, Reich J, Gezahegn S, Greer N, Shaukat A, MacDonald R, et al. Fecal microbiota transplantation for Clostridium difficile infection: a systematic review. Ann Intern Med. 2015;162(9):630–8. doi:10.7326/m14-2693.
Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016;65(3):426–36. doi:10.1136/gutjnl-2014-308778.
Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci. 2013;110(22):9066–71. doi:10.1073/pnas.1219451110.
Gacias M, Gaspari S, Santos PMG, Tamburini S, Andrade M, Zhang F, et al. Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. ELife. 2016;5:e13442. doi:10.7554/eLife.13442.
Dasgupta S, Deniz Erturk-Hasdemir D, Ochoa-Reparaz J, Reinecker H-C, Kasper DL. Plasmacytoid dendritic cells mediate anti-inflammatory responses to a gut commensal molecule via both innate and adaptive mechanisms. Cell Host Microbe. 2014;15(4):413–23. doi:10.1016/j.chom.2014.03.006.
Nakamura YK, Metea C, Karstens L, Asquith M, Grune H, Moscibrocki C, et al. Gut microbial alterations associated with protection from autoimmune uveitis. Invest Ophthalmol Vis Sci. 2016;57:3747–58. doi:10.1167/iovs.16-19733.
Horai R, Zárate-Bladés CR, Dillenburg-Pilla P, Chen J, Kielczewski JL, Silver PB, et al. Microbiota-dependent activation of an autoreactive T Cell receptor provokes autoimmunity in an immunologically privileged site. Immunity. 2015;43(2):343. doi:10.1016/j.immuni.2015.07.01.
Dong Q, Brulc JM, Lovieno A, Bates B, Garoutte A, Miller D, et al. Diversity of bacteria at healthy human conjunctiva. Invest Ophthalmol Vis Sci. 2011;52(8):5408–13. doi:10.1167/iovs10-6939.
LV Prasad Eye Institute, Hyderabad is acknowledged for the facilities provided.
The author declares that he has no competing interests.
I would also like to state that this project was not funded by any source.