Antibiotics and Gut Flora

WHAT IS GOOD TO KNOW ABOUT THE EFFECT OF ANTIBIOTIC TREATMENT ON THE GASTROINTESTINAL MICROFLORA?

WHAT IS A MICROBIOME?
The aggregate of microorganisms normally inhabiting the human body is known as microflora, microbiota or microbiome. The human microbiome has been found to consist of approximately 100 trillion bacterial cells – 10 times more than the number of cells in the human body (Ursell 2018).
Microorganisms colonise or inhabit every surface of the human body, which has access to the environment, including the skin, the respiratory, urogenital and gastrointestinal tracts (Hoffmann 2015).
The colon is the most colonised part of the gastrointestinal tract, being inhabited by 1012 (1 trillion) microorganisms per gram faecal content, represented by hundreds of species (Donaldson 2016; Qin 2010).


WHAT ARE THE FUNCTIONS OF THE MICROBIOME IN THE HUMAN BODY?
“Friendly” bacteria perform important metabolic, protective and immunological functions for human health, such as (O’Hara 2006):

  • Improved digestion and absorption of nutrients that the human organism cannot absorb, which are accumulated in the ascending part of the colon as a result of the slow speed of the intestinal passage;
  • Synthesis of vitamins;
  • Inhibited growth of pathogenic (“bad”) bacteria;
  • Stimulation and regulation of the immune system.

The normal microflora is a stable ecosystem. Differences in the composition of the microflora exist between individuals in terms of species and microbial number, but the microflora remains a relatively constant value during the entire lifetime of an individual (Rodríguez 2015). Certain factors can contribute to impairing the balance in this ecosystem and the administration of antibiotics plays a leading role in this (Debelius 2016).


WHAT HAPPENS DURING ANTIBIOTIC TREATMENT?
The role of antibiotics for the treatment of bacterial infections is essential, but while fighting pathogenic bacteria, they can cause significant damage to the microflora. Thus, antibiotic treatment could have short-term or long-term negative impact on health (Francino 2015).

The complete recovery of the microbiome after antibiotic therapy takes a long time: from several months to several years. In some cases, individual strains (subtypes of a certain microorganism) are completely destroyed and the microbiome cannot recover to its initial number and diversity (Jernberg 2010). This has a negative effect on the regulation of many processes in the organism and can trigger pathologic conditions in the gastrointestinal tract or in other systems in the human body (Bull 2014).


SHORT-TERM CONSEQUENSES
Antibiotic treatment can kill some “good” bacteria in the guts, decreasing the resistance of the natural microflora against “bad” bacteria. This can cause various symptoms, most notably, diarrhea. In particular, antibiotics such as aminopenicillins, cephalosporins and clindamycin that act on anaerobes are most commonly associated with diarrhea. Studies in the general population indicate that the incidence of antibiotic associated diarrhea (AAD) ranges from 5 to 62%, and can start at any point: from initiation of therapy to two months after the end of treatment. The incidence of diarrhea in children receiving broad spectrum antibiotics has been reported in the range of 11 to 40% (Goldenberg 2015).

The overgrowth of many enteropathogens has been associated with antibiotic-induced diarrhea. Clostridium difficile (C. difficile) overgrowth is frequently associated with C. difficile diarrhea. C. difficile associated diarrhea (CDAD) is one of the most serious adverse effects of antibiotics, and is frequently seen in older, immunocompromised, hospitalized adults, but also in children (Elseviers 2015). Exposure to antibiotics within the previous three months is thought to be one of the most important risk factors for developing CDAD (Bartlett 2002).
​​​​​​​

LONG-TERM CONSEQUENSES
An increasing number of scientific publications demonstrate clear association between impaired gastrointestinal microflora and some diseases that affect organs and systems outside of the gastrointestinal tract. These pathologic conditions can have their clinical onset years after the antibiotic intake. 
​​​​​​​
When the gut microflora is altered early in life the result can be immune miscoordination making immune system overreactive to environmental substances.  This may lead to seasonal allergies in some and autoimmunity and/or chronic inflammatory conditions such as asthma in others (Benjamin 2014). Antibiotic use in the first year of life is associated with the development of transient wheezing and persistent asthma. A dose-response effect has been observed. When 5 or more antibiotic courses were received, the risk of persistent asthma doubled (Ong 2014).

Obesity is a complex syndrome that develops from a prolonged imbalance of energy intake and energy expenditure. Although lifestyle factors, diet and exercise contribute largely to the modern obesity epidemic, increasing number of scientific data demonstrate, that the microbial flora in the guts play significant role in the development of obesity (Bruder 2008). Dose–response meta-analysis of six studies (89 837 children) showed that there was a clear dose–dependent correlation between antibiotic exposure and childhood overweight. In fact, each additional course of antibiotic increased the risk for childhood overweight with 7% and the risk of childhood obesity with 6% (Xiaoqing Shao 2017).

A Population-Based Case-Control Study demonstrated dose-response relation between exposure to antibiotics and type 2 diabetes for all types of antibiotics, although the dose-response relationship was slightly stronger for narrow-spectrum and bactericidal antibiotics compared to broad-spectrum and bacteriostatic types, respectively (Mikkelsen 2015).

There is growing interest in a link between microbiota and cardiovascular disease based on data showing microbial metabolism of dietary phosphatidylcholine into the proatherosclerotic metabolite trimethylamine-N-oxide (Shreiner 2015).


ROLE OF PROBIOTICS IN ANTIBIOTIC THERAPY
Probiotics are increasingly used to neutralise the negative effect of antibiotic treatment on the microbiome (WGO Global Guideline Probiotics and prebiotics 2017).

Probiotics are living microorganisms which, administered in a sufficient concentration, have beneficial effects on the human organism (FAO/WHO, 2001). According to ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition) beneficial effects of probiotics in patients with acute diarrhoea depend on several conditions:  

  1. The dose of the probiotic is one of the most important factors for fast microbiome recovery. In patients with acute diarrhoea the effect of the probiotics is dose-dependent. An increase in the number of microorganisms in probiotics, for example from 10 to 100 billion CFU (colony-forming units of microorganisms), decreases the number of AAD (J Pediatr Gastroenterol Nutr 2008). Post hoc meta-analysis on dose showed a statistically significant association between CFU/day and AAD risk reduction. Higher number of CFUs taken per day is associated with greater AAD risk reduction (Johnston 2011).
  2. The selection of the strains in the probiotic formula is another important condition. The fast recovery of microbiome after antibiotic treatment depends on strains diversity, their resistance to different antibiotics and the speed of their replication. Probiotics containing mixture of different microorganisms have beneficial effects on clinically studied conditions, including irritable bowel syndrome, diarrhoea, atopic disease, immune function and respiratory tract infections, gut microbiota modulation, inflammatory bowel disease and treatment of Helicobacter pylori infection. 16 studies compared the effect of a mixture of multiple strains, with that of single microorganisms from the mixture. In 12 cases (75%), the mixture was more effective (Chapman 2011).
  3. The capacity of the strains to produce metabolites to feed the “good” microflora and bacteriocins, which inhibit the growth of “bad” bacteria, are another extremely important factor for the recovery process after antibiotic treatment (www.fao.org).


HIGHLIGHTS

  • The aggregate of microorganisms normally inhabiting the human body is known as microflora, microbiota or microbiome.
  • “Friendly” bacteria play important metabolic, protective and immunological functions for the human health.
  • The normal microflora is a stable ecosystem.
  • Certain factors can disrupt the balance in that ecosystem, and administration of antibiotics can be of great importance for that process.
  • This triggers disorders in the regulation of many processes in the organism, resulting in a range of short-term and long-term consequences.
  • The use of probiotics is increasing aiming at neutralisation of the negative effect of antibiotic treatment on the microbiome. 
  • Beneficial effects of probiotics on patients with acute diarrhoea depend on: dose (higher is better), strains selection (more is better), capacity of strains to produce metabolites and bacteriocins.


Reference

Bartlett JG. Antibiotic-associated diarrhea. NEnglJMed 2002; 346:334–339 (2008).
Benjamin J, Marsland and Eva S Gollwitzer, ‘Host–microorganism Interactions in Lung Diseases’. Nature Reviews Immunology, 14 (2014), 827.
Bruder, C. E. et al. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am. J. Hum. Genet. 82, 763–771 (2008)
Bull, Matthew J and Nigel T Plummer. “Part 1: The Human Gut Microbiome in Health and Disease” Integrative medicine (Encinitas, Calif.) vol. 13,6 (2014): 17-22.
Chapman C.M.C., Gibson G.R., Rowland I. Health benefits of probiotics: are mixtures more effective than single strains? European Journal of Nutrition, 2011, Volume 50, Number 1, Page 1 
Debelius et al, Tiny microbes, enormous impacts: what matters in gut microbiome studies?, Genome Biology (2016) 17:217 
Donaldson GP, Lee SM, Mazmanian SK. Gut biogeography of the bacterial microbiota. Nat Rev Microbiol. 2016;14(1):20-32. 
Elseviers, Monique M et al. “Prevalence and Management of Antibiotic Associated Diarrhea in General Hospitals.” BMC Infectious Diseases 15 (2015): 129. PMC. Web. 17 Aug. 2018.
Francino MP, “Antibiotics and the Human Gut Microbiome: Dysbioses and Accumulation of Resistances,” Frontiers in Microbiology, 2015.
Goldenberg  JZ, Lytvyn  L, Steurich  J, Parkin  P, Mahant  S, Johnston  BC. Probiotics for the prevention of pediatric antibiotic‐associated diarrhea. Cochrane Database of Systematic Reviews 2015, Issue 12. Art. No.: CD004827. 
Hoffmann A.R., et al. “The Microbiome: The Trillions of Microorganisms That Maintain Health and Cause Disease in Humans and Companion Animals.” Vet Pathol. 2015
http://www.fao.org/3/a-a0512e.pdf
J Pediatr Gastroenterol Nutr, Vol. 46, Suppl. 2, May 2008 European Society for Paediatric Gastroenterology, Hepatology,and Nutrition/European Society for Paediatric Infectious Diseases Evidence-based Guidelines for the Management of Acute  Gastroenteritis in Children in Europe
Jernberg C, Lofmark S, Edlund C, Jansson JK. Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology. 2010; 
Johnston BC,Goldenberg JZ, Vandvik PO, Sun X,GuyattGH. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database of Systematic Reviews 2011, Issue 11. Art. No.: CD004827. 
Mikkelsen KH, Knop FK, Frost M, Hallas J, Pottegård A. Use of Antibiotics and Risk of Type 2 Diabetes: A Population-Based Case-Control Study. The Journal of Clinical Endocrinology and Metabolism. 2015;100(10):3633-3640. 
O’Hara, Ann M, and Fergus Shanahan. “The Gut Flora as a Forgotten Organ.” EMBO Reports 7.7 (2006): 688–693
Ong M.S., D.T. Umetsu, K.D. Mandl, Consequences of antibiotics and infections in infancy: bugs, drugs, and wheezing, Ann. Allergy Asthma Immunol., 112 (2014), pp. 441–445
Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010)
Rodríguez, Juan Miguel et al. “The Composition of the Gut Microbiota throughout Life, with an Emphasis on Early Life.” Microbial Ecology in Health and Disease 26 (2015) 
Shreiner, Andrew B et al. “The gut microbiome in health and in disease” Current opinion in gastroenterology vol. 31,1 (2015): 69-75.
Ursell, Luke K et al. “Defining the Human Microbiome.” Nutrition reviews 70.Suppl 1 (2012): S38–S44. PMC. Web. 5 Oct. 2018.
WGO Global Guideline Probiotics and prebiotics, 2017, Evidence-based adult indications for probiotics, prebiotics, and synbiotics in gastroenterology.
Xiaoqing Shao and others, Frontiers in Endocrinology  , 2017, 170 ‘Antibiotic Exposure in Early Life Increases Risk of Childhood Obesity: A Systematic Review and Meta-Analysis 

THIS MATERIAL IS FOR CONSUMER INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

DISCLAIMER: NOTHING IN THIS WEBSITE IS INTENDED AS, OR SHOULD BE CONSTRUED AS, MEDICAL ADVICE. CONSUMERS SHOULD CONSULT WITH THEIR OWN HEALTH CARE PRACTITIONERS FOR INDIVIDUAL, MEDICAL RECOMMENDATIONS. THE INFORMATION IN THIS WEBSITE CONCERNS DIETARY SUPPLEMENTS, OVER-THE-COUNTER PRODUCTS THAT ARE NOT DRUGS. OUR DIETARY SUPPLEMENT PRODUCTS ARE NOT INTENDED FOR USE AS A MEANS TO CURE, TREAT, PREVENT, DIAGNOSE, OR MITIGATE ANY DISEASE OR OTHER MEDICAL OR ABNORMAL CONDITION.