Your gastrointestinal tract is home to complex microbial populations, which, collectively, are referred to as the microbiota. The relation between the microbiota and you – the host is meant to be symbiotic, with you providing a warm moist physical niche and suitable food to intestinal bacteria and then if all works well you in turn gain benefit from the enhancement of resistance to infection and the improved facilitation of the absorption of ingested food [1],[2]
Equally importantly is the impact the microbiota has on the mucosal immune system. It contributes to the development and differentiation of your immune system,[3] and aberrant changes in the microbiota have been linked to infections, atopy, inflammatory bowel disease, diabetes and arthritis.[4],[5],[6],[7],[8]
Recent and improved analysis of the over 70% of the GI based bacterial population unable to be cultured has revealed via parallel DNA sequencing platforms the complexity of bacterial populations inhabiting the gut, with thousands of different bacterial phylotypes belonging predominantly to the Firmicutes and Bacteroidetes phyla, and smaller populations belonging to the Proteobacteria, Actinobacteria, Verrucomicrobia or Fusobacteria phyla.[9]
As one might image due its position and size and primary function, the microbiota of the large intestine is more dense and diverse than the microbiota of the small intestine and the bacterial taxa in these two sites differ.[10] In addition other subtle but clinically relevant distinctions the bacterial populations associated with the mucus layer differ from those found in the intestinal lumen.[11]
Antibiotic administration perturbs the intestinal microbiota and affects immune defence against pathogens, moreover, recent studies have shown additional effects mediated by antibiotics on the gut microbiota, such as the stimulation of gene transfer among gut bacteria and the reduction of immune responses in peripheral organs.[12],[13]
Deep 16S rDNA sequencing following antibiotic treatment has revealed dramatic and long-term changes to the intestinal microbiota that have implications for immune defence.[14] For example the administration of ciprofloxacin to humans affected the majority of bacterial taxa in the gut, resulting in decreased richness (membership), diversity (membership and abundance), and evenness (numerical distribution of the members).[15]
It has been suggested by many papers that reducing microbial diversity and richness in the intestinal tract increases the susceptibility for enteric infections.[16] Plus this dysbiotic state facilitates the blooming of certain commensals that only by virtue of their increased abundance become pathobionts, which in turn contribute to altered homeostasis and inflammasome activation.[17] ,[18],[19]
Inflammasomes are protein scaffolds that play significant roles in the management of inflammation in the mucosal and other tissues, their activation through dysbiosis – loss of bacterial symbiosis has been linked to numerous chronic diseases and loss of functionality.[20],[21]
Inflammasomes are cytoplasmic protein complexes that induce innate immune responses and inflammation by responding to pathogen-derived molecules and also host-derived products released in response to a range of tissue perturbation.[22]
Intestinal commensal microbes influence the immune system and changes in the microbiota composition can affect immune responses. In modern societies, widespread antibiotic administration is probably a major factor contributing to changes in the mucosal microbiota. The chart below, extracted from reference 13.
|
Antibiotic |
Effect on the microbiota |
Effect on immunity |
References |
| Amoxicillin | Lactobacillus spp. depletion in SI ↓aerobic and anaerobic bacterial numbers in the colon |
↓ MHC I and MHC II expression in SI and LI ↓AMPs expression in SI ↑mast cell proteases expression in SI |
[[23]] |
| Metronidazole, neomycin and vancomycin | ↓ bacterial numbers in SI and LI Multiple effects on composition, including: ↓ Bacteroidetes ↑ Enterobacteriaceae |
↓ Reg3γ expression in SI | [2,10] |
| Metronidazole | Bacteroidales and Clostridium coccoides depletion ↑ Lactobacilli |
↑ Reg3γ and IL-25 expression in colon ↑ numbers of macrophages and NK cells in colon ↓ mucus |
[[24]] |
| Colistin | ND (Gram-negative spectrum) | ↓ numbers of ILFs | [[25]] |
| Ampicillin, neomycin, metronidazole, vancomycin | Microbiota depletion ↓ peptidoglycan levels in serum |
↓neutrophil-mediated killing of pathogenic bacteria ↓Reg3γ expression by γδ T cells ↓pro-IL1β, pro-IL18, NLRP3 |
[[26]] [[27]] [[28]] |
| Amoxicillin/clavulanate | ND | ↓ IgG serum levels | [[29]] |
| Ampicillin, gentamicin, metronidazole, neomycin, vancomycin | ↓ bacterial numbers in LI Multiple effects on composition, including: ↓ luminal Firmicutes in LI ↓ mucosal associate Lactobacillus in LI |
↓ IFNγ and IL-17 production by CD4+ T cells in SI ↑ IgE serum levels ↑ basophils in blood |
[5] [11] |
| Vancomycin | ↓ Gram-positive bacteria ↑ Enterobacteriaceae |
↓ Treg cells in colon ↓ Th17 in SI ↓ ILFs to a lesser extent than colistin |
[[30],[31],[32]] |
LI, large intestine; ND, not determined; SI, small intestine.
ND (Not determined but only Gram-negative bacteria are sensitive to colistin)
What to do about it.
Prevention is the preferred route to limit adverse commensal development post antibiotic therapy. The use of probiotics and S.Boulardii have been shown to be able to confer advantages both before, during and post antibiotic therapy.
Research into the potential application of probiotic lactobacilli to enhance aspects of immune defences, antagonise infectious agents including pathobionts, or counteract dysbiosis, has led to recommendations for clinical applications of probiotics aimed at preventing disease development and/or improving immune status.[33]
However, several studies and meta-analyses of randomised probiotic trials[34],[35]have reported that application of probiotics has safe but varying success rates. This is in part due to the application of different probiotic strains that can elicit strain-dependent effects on the host and the limited knowledge concerning the precise molecular mechanisms of action of specific probiotic strains. Moreover, differences among human individuals, including but not necessarily restricted to (epi-)genetic variation, lifestyle, diet and microbiota composition, may also influence the outcome of clinical trials. This poses the question: what is the best target group for a specific probiotic?[36]
The use of lactobacillus GG and Saccharomyces Boulardii have been extensively explored in linked articles, but Bifidobacteria and prebiotics as well as the use of butyrate also represent practical interventions to mediate altered immune and composition of bacterial communities.
References
[1] Hooper LV, Midtvedt T, Gordon JI. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr. 2002;22:283-307. View Abstract
[2] Vollaard EJ, Clasener HA. Colonization resistance. Antimicrob Agents Chemother. 1994 Mar;38(3):409-14 View Full Paper
[3] Cahenzli J, Balmer ML, McCoy KD. Microbial-immune cross-talk and regulation of the immune system. Immunology. 2013 Jan;138(1):12-22. View Abstract
[4] Brandl K, Plitas G, Mihu CN, Ubeda C, Jia T, Fleisher M, Schnabl B, DeMatteo RP, Pamer EG. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature. 2008 Oct 9;455(7214):804-7 View Full Paper
[5] Hill DA, Siracusa MC, Abt MC, Kim BS, Kobuley D, Kubo M, Kambayashi T, Larosa DF, Renner ED, Orange JS, Bushman FD, Artis D. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med. 2012 Mar 25;18(4):538-46 View Full Paper
[6] C. Abraham, J.H. Cho Inflammatory bowel disease. N. Engl. J. Med., 361 (2009), pp. 2066–2078 View Full Paper
[7] Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008 Oct 23;455(7216):1109-13 View Full Paper
[8] Wu HJ, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y, Littman DR, Benoist C, Mathis D. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity. 2010 Jun 25;32(6):815-27. View Full Paper
[9] P.B. Eckburg Diversity of the human intestinal microbial flora Science, 308 (2005), pp. 1635–1638 View Full Paper
[10] C. Ubeda et al. Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans J. Clin. Invest., 120 (2010), pp. 4332–4341 View Full Paper
[11] Hill DA, Hoffmann C, Abt MC, Du Y, Kobuley D, Kirn TJ, Bushman FD, Artis D. Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol. 2010 Mar;3(2):148-58 View Full Paper
[12] Looft T, Allen HK. Collateral effects of antibiotics on mammalian gut microbiomes. Gut Microbes. 2012 Sep-Oct;3(5):463-7. Epub 2012 Jul 24 View Full Paper
[13] Ubeda C, Pamer EG. Antibiotics, microbiota, and immune defense. Trends Immunol. 2012 Sep;33(9):459-66. View Abstract
[14] Dethlefsen L, Huse S, Sogin ML, Relman DA. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 2008 Nov 18;6(11):e280. View Full Paper
[15] Dethlefsen L, Huse S, Sogin ML, Relman DA. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 2008;6:e280. View Full Paper
[16] Bailey MT, Dowd SE, Parry NM, Galley JD, Schauer DB, Lyte M. Stressor exposure disrupts commensal microbial populations in the intestines and leads to increased colonization by Citrobacter rodentium. Infect Immun. 2010;78:1509–19. doi: 10.1128/IAI.00862-09. View Full Paper
[17] Stecher B, Maier L, Hardt WD.’Blooming’ in the gut: how dysbiosis might contribute to pathogen evolution. Nat Rev Microbiol. 2013 Apr;11(4):277-84. View Abstract
[18] Ayres JS, Trinidad NJ, Vance RE. Lethal inflammasome activation by a multidrug-resistant pathobiont upon antibiotic disruption of the microbiota. Nat Med. 2012 May;18(5):799-806. View Abstract
[19] Hoshi N, Medzhitov R. Germs gone wild. Nat Med. 2012 May 4;18(5):654-6. View Abstract
[20] Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012 Feb 1;482(7384): View Full Paper
[21] Stienstra R, van Diepen JA, Tack CJ, Zaki MH, van de Veerdonk FL, Perera D, Neale GA, Hooiveld GJ, Hijmans A, Vroegrijk I, van den Berg S, Romijn J, Rensen PC, Joosten LA, Netea MG, Kanneganti TD. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15324-9. View Full Paper
[22] T. Strowig et al. Inflammasomes in health and disease Nature, 481 (2012), pp. 278–286 View Abstract
[23] A. Schumann Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome Physiol. Genomics, 23 (2005), pp. 235–245 View Full Paper
[24] M. Wlodarska et al. Antibiotic treatment alters the colonic mucus layer and predisposes the host to exacerbated Citrobacter rodentium-induced colitis Infect. Immun., 79 (2011), pp. 1536–1545 View Full Paper
[25] D. Bouskra et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis Nature, 456 (2008), pp. 507–510 View Abstract
[26] T.B. Clarke et al. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat. Med., 16 (2010), pp. 228–231 View Abstract
[27] A.S. Ismail et al. Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc. Natl. Acad. Sci. U.S.A., 108 (2011), pp. 8743–8748 View Full Paper
[28] T. Ichinohe et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection Proc. Natl. Acad. Sci. U.S.A., 108 (2011), pp. 5354–5359. View Full Paper
[29] V. Dufour et al. Effects of a short-course of amoxicillin/clavulanic acid on systemic and mucosal immunity in healthy adult humans. Int. Immunopharmacol., 5 (2005), pp. 917–928 View Abstract
[30] D. Bouskra et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature, 456 (2008), pp. 507–510 View Abstract
[31] I.I. Ivanov et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe, 4 (2008), pp. 337–349 View Full Paper
[32] K. Atarashi et al. Induction of colonic regulatory T cells by indigenous Clostridium species Science, 331 (2011), pp. 337–341 View Abstract
[33] M.H. Floch et al. Recommendations for probiotic use-2011 update J. Clin. Gastroenterol., 45 (Suppl.) (2011), pp. S168–S171 View Abstract
[34] S. Sazawal et al. Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials Lancet Infect. Dis., 6 (2006), pp. 374–382 View Abstract
[35] M. Kalliomaki et al. Guidance for substantiating the evidence for beneficial effects of probiotics: prevention and management of allergic diseases by probiotics J. Nutr., 140 (2010), pp. 713S–721S View Full Paper
[36] van Baarlen P, Wells JM, Kleerebezem M. Regulation of intestinal homeostasis and immunity with probiotic lactobacilli. Trends Immunol. 2013 Feb 25. doi:pii: S1471-4906(13)00014-8. 10.1016/j.it.2013.01.005. [Epub ahead of print] View Abstract
