Antibiotics – Unintended Consequences; Microbiota and Immunity Suffer

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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


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[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

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