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ANTIBIOTICS USE AND EFFECTS ON GUT FLORA

There is concern about the effects of irrational use of antibiotics. This is not only because of the issue of antimicrobial resistance but importantly about the effect of antibiotics on the gut microbiota. The digestive tract especially the large intestine is the habitat for millions of microbes living in concert with several functions of the body. Antibiotics have been very useful in treating and controlling infections with positive impact of standard of living.

However, our control over microbial disease is diminishing. Langdon et al. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutics modulation. Genome Medicine (2016). 8:39.

I will continue with an extract from the paper earlier referred to- human pathogens have repeatedly acquired the genetic capacity to survive antibiotic treatment due to heavy selective pressures from widespread antibiotic use. The incidence of antibiotic-resistant infections is rising sharply. Unfortunately, the rate of discovery of new antibiotics is slowing, in such a way that the number of withdrawals of antibiotics from healthcare exceeds the number of approvals by a factor of two. It appears biopharma do not find massive expenditures in discovering new antibiotic molecules rewarding. In 2015, antibiotic-resistant pathogens were estimated to cause over 50,000 deaths a year in Europe and the USA. The toll is projected to rise to 10 million deaths per year worldwide by 2050. These figures suggest we are reaching the end of the antibiotic era- the need therefore for rational use of what is available.

Apart from the development of resistance, the use of antibiotics heavily disrupts the ecology of the human microbiome (i.e., the collection of cells, genes, and metabolites from microorganisms, especially bacteria that inhabit the human body). A dysbiotic (imbalance) microbiome may not perform vital functions such as nutrient supply, vitamin production, and protection of these microbes. Dysbiosis of the microbiome has been associated with a large number of health problems and implicated in metabolic, immunological, developmental disorders, and susceptibility to development of infectious diseases. The wide variety of systems involved in these diseases provides ample cause for concern over the unintentional consequences of antibiotic use.

Critical developmental milestones for the microbiota (as well as for the child) occur, in particular, during infancy and early childhood, and both medical intervention and lack of such intervention during these periods can have lifelong consequences in the composition and function of the gut ecosystem. A child’s first contact with microbes is usually assumed to occur after the rupture of the sterile amniotic sac. However, the placenta and the first stool of infants have been found to contain a full complement of microbes. These findings indicate that the first human–microbial interaction occurs before birth. The microbes that first colonize a child after birth are known to have a fundamental influence on the development of the microbiome.

An infant’s mode of delivery is a critical determinant of the composition of their gut microbiota. During vaginal delivery, infants are colonized by the mothers’ vaginal microflora (s largely composed of Lactobacillus, Prevotella, and Sneathia species), whereas a Caesarean delivery omits transmission of vaginal microbes. Instead, the first microbes colonizing an infant delivered by Caesarean section are of environmental origin and generally associated with the skin (e.g. Staphylococcus, Corynebacterium, Propionibacterium species). Intestinal strains of Bifidobacterium specieshave been shown to be transmitted vertically with vaginal but not Caesarean delivery.

The effects of perinatal administration of antibiotics are likely to further distinguish the microbiota composition of infants delivered by Caesarian section from that of infants delivered vaginally. Postnatal antibiotics can also irreversibly disrupt the natural microbiome succession, as an infant is unlikely to be recolonized with a second dose of vaginal microbes. The composition of the gut microbiome of infants born by Caesarean section has been directly linked with increased susceptibility to, and frequency of infection by, methicillin-resistant Staph aureus (MRSA), which is a symptom of instability and low diversity in the gut ecosystem. Caesarean sections are also associated with a variety of long-term health problems, especially immunological disorders such as asthma and type 1 diabetes. There is on-going research on the relationships between these disorders and the composition of the gut microbiome and risks associated with antibiotic intervention in infants.

The effects of antibiotics on microbial succession, diversity, and resistance can last long past infancy. In the first two or three years of life, a healthy child’s microbiome increases in diversity to resemble an adult microbiome. During this period, microbes are continuously obtained from breast milk, other food, and the environment. When the developmental path of the microbiome is altered by modifying factors, the digestive function can be negatively affected, which can result in either undernutrition or obesity. The undesirable microbiome make-up associated with undernutrition and obesity are shaped via selection by diet (calorie restriction or a high-calorie, low-quality diet, respectively), by exposure to disease (high frequency of diarrhea or excessive hygiene), and by the use of medications such as antibacterial agents.

Severe calorie restriction during the first years of life has devastating long-term consequences, including damage to learning ability, physical stunting, and diminished economic productivity in the survivors. Undernutrition has a distinct microbial signature consistent with a delay in developmental progression of the microbiome.This immature microbiome state is associated with inefficient nutrient extraction from food and vulnerability to enteric infections, which perpetuate the malnourished state and often make nutritional therapy ineffective. Interestingly, a week-long course of  amoxicillin has been found to improve nutritional recovery and reduce mortality associated with severe acute malnutrition.

The combination of antibiotics and nutritional therapy has become standard of care in outpatient management of severe acute malnutrition. The growth response of malnourished patients to therapeutic-dose antibiotics parallels the phenomenon where increased growth is observed in animals given continuous, low-dose, broad-spectrum antibiotics- a major cause of antimicrobial resistance.

On the other hand, obesity has grown to epidemic proportions in developed countries. In 2015, over 30 % of adults and 17 % of children in the USA were estimated to have obesity. The gut microbes have been found to closely involved together with diet and lifestyle. A high-calorie diet shifts the microbial ecology toward Firmicutes at the expense of Bacteroidetes, thus increasing the energy harvesting capacity of the microbiota. Antibiotic exposure during infancy has been found to increase the risk of overweight in preadolescence for boys. The risk of developing type 2 diabetes increases with repeated use of penicillins, macrolides, cephalosporins, and quinolones.

The gut microbiota has strong role in the development of metabolic disease. Antibiotics upset the gut microbiota and therefore the need for rationale of antibiotics. Polyphenol-rich foods improve/restore gut health. Cocoa is the richest food source of polyphenols on weight basis.

DR. EDWARD O. AMPORFUL

CHIEF PHARMACIST

COCOA CLINIC

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