The ethicality of antibiotics is a “Four-edged sword”,3 the first two edges represent the benefit to the individual by treating the illness and benefit to the community by preventing the spread of diseases. The third is the cost to the community in the form of antibiotic resistance genes. When the infectious agent evolves, it becomes more resistant to the antibiotics. These resistant bugs are harder to kill and require more antibiotics which results in an antibiotic arms race. The fourth edge focuses on the cost to the individual due to the indiscriminate collateral damage to our microbiota, especially in infancy, where the microbiota is in crucial development. Antibiotic’s ubiquity could possibly be due to the perception that antibiotics are completely safe. The treatment of the individual trumps the potential impact on the community, thus, more children are experiencing delayed microbiota maturation. Single colonization species are also effected more than multiple colonization species. Decreased community diversity can restrict the immune system by limiting the experience it has in dealing with diseases, including its ability to recognize commensal bacteria which results in less healthy microbial communities. This can lead to obesity, asthma, diabetes, and even allergies.
Key words: Antibiotics, Microbiomes, Microbiome diversity, microbiota maturation, antibiotic resistance.
Microbiota in the infant GI track
Recently, antibiotics have been a massive help to medicine and have been distributed worldwide. Due to its indiscriminate destruction of bacteria, antibiotics can have profound effects on the development of microbiomes, especially in those of infants. Our relationships with our microbiota’s genes and their interactions between each other, is especially important during the early years of life because our microbiome is evolving2.This inhibition of the intestinal microbiota can lead to increased risk of obesity, diabetes, inflammatory bowel disease, asthma, and allergies. Antibiotic exposure has been shown to lead to increased adiposity in mice4.
Antibiotic use significantly diminishes phylogenic diversity immediately after birth1. This diversity is subsequently recovered during the first year when compared to the unexposed infants, but causes the microbiota maturation process to be delayed. In Figure 1A, you can see by the red curve that the antibiotic exposed microbiota had significantly more species with a single strain dominating. This is shown in B and C as well with the non-antibiotic exposed microbiota exhibiting more diversity in strains with the non-antibiotic diversity index being .55 compared to the antibiotic exposed microbiome’s .0003.
Figure 1. Diversity and strain similarities of the infant gut microbiota. (A) antibiotic exposed microbiome in red and unexposed green (B and C). (D) Partial phylogenic trees of Bacteroides fragilis and vulgatus (E) Distributions of mutation distance between fragilis (left) and vulgatus (right). (F) Distributions of mutation distances within individuals with antibiotics use colored red and non-antibiotic use colored green1.
Part D is showing the strain prominence within the Bacteroides fragilis and Bacteroides vulgatus. Bactreroids fragilis is a single colonization species, which means that a single strain colonized the gut. Vulgatus is a multi-colonization species which means that it is a species that is closely related to strains in other individuals. Bacteroides fragilis is much more abundant in the same child then it is in separate children as shown in part E. This means that Fragilis is more unique to the individual. Single colonization species are much more affected by repeated antibiotic treatments than their multi-colonization counterparts1. In part F, you can see that the antibiotic exposed microbiome is much less dense in the single colonization species.
The decrease in diversity of single colonization species occurs from birth until about a year, then it recovers as seen in figure 2A. The microbiota-by-age Z (MAZ) score of the exposed biome exceeds that of the unexposed biome after 12 months of life and then falls back in line with the unexposed trajectory. This causes a delay in microbiota maturation. Microbiota maturation is the rate at which a child’s microbiota develops. A mature microbiota contains certain taxa that are markers for that child’s age group whereas immature or delayed microbiota is more similar to that of a younger child. As in Figure 2B, the prominence of certain taxa is greater than other taxa when comparing the two. This means that the evolution of the microbiome in infants exposed to antibiotics will appear younger than those not exposed to antibiotics. The microbiome’s maturation is important because it effects the efficacy of the immune system. Ironically, the antibiotics are weakening the immune system of children rather than strengthening them due to its killing of commensal bacteria. The temporary decrease of microbiome diversity and the delaying of maturation could be to blame for the increased risk of diabetes, allegies, asthma, and obesity, but more testing would be necessary to prove causation.
Figure 2. Antibiotic exposure delays microbiota maturation during early life. (A) Microbiota-by-age Z (MAZ) scores at each month of life between antibiotic exposed (red) and unexposed (blue) infants. (B) Operational Taxonomic Units (OTU) heat map to illustrate abundance of age-dependent bacteria in the microbiome. Red text indicates OTUs that were most suppressed during the 6-12 month timeframe2.
Drug Resistant Bugs
Interestingly, after the course of antibiotics were completed, there was a sharp rise in drug resistant genes that fell after the withdrawal of the antibiotics. In Figure 3A, you can see that the chromosomally encoded genes such as LEN-2 Beta Lactamase (resistance gene) and ToIC, an antibiotic efflux gene, rose sharply, then fell. These genes are the genes that makeup the third edge of the antibiotic sword. They create a dilemma in which we must constantly create new antibiotics to stay one step ahead of the bacteria’s resistances.
Figure 3. Antibiotic gene profiles. (A) Chromosomally encoded resistance gene abundance in three children over time. (B) Bacteria abundance that correlates with the resistance gene profiles of A. (C) Examples of resistance genes that are present in the gut for much longer after antibiotic withdrawal. These are mainly episomally encoded genes1.
There was also a bacteria species that was strongly correlated in abundance in each test that likely harbored the resistance gene evident in Figure 3B. For episomally encoded genes, genes that replicate independently from the host, their resistance genes increased but did not decrease sharply like the chromosomally encoded genes as shown in Figure 3C. This might be due to the fact that episomally encoded genes are distributed across a broad spectrum of species1.This is significant because the creation of these antibiotic resistant genes can negatively affect the community by nullifying the efficacy of antibiotics and creating the need for novel antibiotics that are stronger to counteract the new resistant bugs.
Discussion and Summary
The increased usage of antibiotics has put us in a weird situation where our microbiomes are getting progressively less diverse. The gut microbiomes of infants are less diverse in the first year and suffer from delayed maturation as time goes on. The decline in microbiome diversity in infants could lead to increased instance of children that suffer from allergies, asthma, obesity, and diabetes which has profound effects on our healthcare system and ultimately means an unhealthy population. In the figure below, microbiome diversity is measured to show the direction in which our diversity is going.
Figure 4. Models of microbiota change in different societies. Populations with beginning modernization are yellow, countries with late modernization are red, and the US is blue. The y-axis is an arbitrary scale with the x axis representing years. The US’s diversity is markedly lower than the diversity of the other countries3.
If we fully assess the consequences of antibiotics, our microbiome diversity could restore itself in future generations. The risk of antibiotics is greatest for young children which is coincidentally when antibiotic usage is most intensive. Instead of carpet bombing bacteria in the gut, killing commensal bacteria, we could develop more precise treatments to uphold the diversity. Our increased sanitation as a society, such as hand sanitizers, chlorinated drinking water, and early antibiotic use is killing us. The average U.S. child receives about three courses of antibiotics by the age of 2 and 10 courses by the age of 10.5 The ubiquity of antibiotics is going to be a hard but necessary movement to combat. The third and fourth edges of the antibiotic sword – cost to the community in terms of bug resistance and to a person’s microbiome diversity – are both caused by the overuse of antibiotics3. Halting the use of antibiotics may not reverse the deterioration of our microbiome diversity that has already occurred, but it could potentially stabilize it to prevent the emergence of new problems resulting from a homogenous microbiome. Probiotics, used in tandem with antibiotics, could replace the vital species and strains that overlook crucial development pathways. The microbiome’s influence on an individual’s health will require more research.