Antibiotic Resistance and the Human Microbiome
Introduction
Imagine the following scenario: You wake up on a cold winter morning feeling lethargic and slightly feverish and notice a tingling in your throat. On your way to work, you decide to pop into an urgent care clinic where the doctor, after a 10-minute checkup, prescribes a course of antibiotics for a supposed throat infection. With no laboratory tests and trusting the doctor’s advice, you took the 6-day course of antibiotics. Might this be ultimately leading to the growing problem of antibiotic resistance?
This scenario has unfortunately become an almost routine procedure followed by thousands of healthcare professionals worldwide. In 2010, doctors, medical professionals, and other healthcare providers prescribed an estimated 258 million courses of antibiotics for people in the United States. That means we have roughly 833 antibiotic prescriptions for every 1,000 people. In some parts of the country, there was more than one prescription per person per year, with West Virginia having the highest rate at 1.237 prescriptions per person, followed by Kentucky at 1.232 and Tennessee at 1.199.
Perhaps even more worrisome is that 70 percent of all medically necessary antibiotics in the United States are destined for use in farm animals. In terms of weight, “medically important” antibiotics used in animals totaled 6 million kilograms (13.23 million pounds) in 2020.
As antibiotic and antimicrobial resistance has become much more pervasive, recent research shows how the human gut microbiome is essentially being “co-opted” by antibiotic-resistant pathogens to cause more severe illnesses and infections. A not-so-surprising outcome of this massive (mis)use and dependence on antibiotics has been a noticeable increase in antibiotic resistance. Below, we discuss the intersections between antibiotic resistance and the human gut microbiome. We also look at promising research into new treatment alternatives that might target the harmful bacteria without negatively affecting or changing the gut microbiome.
What Exactly is the Human Microbiome?
The human microbiome is composed of all the microorganisms, including bacteria, viruses, fungi, parasites, and other organisms that live in and on our bodies. Though further research is needed, some experts believe there may be up to ten times more microorganisms living in and on our bodies than human cells. Though the human microbiome contains viruses, protozoa, and fungi, bacteria are the most numerous members of the human microbiome. Some researchers estimate that the bacterial population of the human microbiome is between 75 trillion and 200 trillion individual organisms. This massive amount of microbial life suggests that the human body may be a “superorganism,” defined as a “collection of human and microbial cells and genes and thus a blend of human and microbial traits.”
Due to this vast number of different types of microorganisms that live in and on our bodies, scientists today are embarking on an ambitious project to understand the microbial components of the human genetic and metabolic landscape and how they contribute to normal physiology and predisposition to disease.
Microbiome research uses genetic sequencing technologies to identify the different types and quantities of microorganisms present. The collection of microbial genomes contributes to a human’s broader genetic portrait or metagenome, and as we stated above, plays a significant role in health and predisposition to disease.
Today, the Human Microbiome Project (HMP) continues to characterize the microbial communities in the human body and identify each microorganism’s role in health and disease. During the first couple of years, scientists and laboratory researchers discovered new species that made up part of the human microbiota. They were also able to characterize almost 200 different bacterial member species. Though this is a significant advance, most experts agree that the human microbiota consists of at least 1,000 other species of microorganisms.
Microbiota differs between individuals and between matching body parts, such as the right and left hands, of the same individual. The enormous diversity also means that each person will likely have a unique microbial composition. One exciting example from a 2015 study shows that a typical palm surface of the hand can have more than 150 different bacterial species. Of those species, however, only 17 percent are familiar to both hands of the same person, and other individuals share only 13 percent.
The gut is another part of the human body with an enormous degree of microbiome diversity and abundance, with one study finding 3.3 million microbial genes in the gut. Of this diversity, researchers found frequently occurring bacterial gut species, at least 160 of which were believed to inhabit each person’s gut (also known as common bacterial cores). Many of the species that make up the human microbiome help promote health. For example, in the human gut, some species of bacteria enter into a synergistic relationship with their environment. These bacteria obtain nutrients from ingested food. In return, they may help with the breakdown of food, the prevention of the colonization of the gut by harmful bacteria, or other beneficial “services.”
However, it is also important to note that microorganisms in the human microbiota are closely related to pathogenic (disease-causing) organisms. Other microorganisms in the human microbiome may become pathogenic given certain conditions occurring inside the human body. For example, the bacterial species of the genera Staphylococcus, Streptococcus, Enterococcus, Klebsiella, Enterobacter, and Neisseria are just a few pathogenic species that can cause disease.
The Growing Prevalence and Danger of Antibiotic Resistance
Unhealthy diets, processed foods, the ingestion of agrochemicals, and age are just a few of the factors that negatively affect the gut microbiome. However, the widespread use of antibiotics is another of the most troublesome aspects negatively affecting the human gut microbiome.
Antibiotic or antimicrobial resistance occurs when germs like bacteria and fungi develop the ability to defeat the drugs designed to kill them over time. When the germs or other pathogens are not killed by the antibiotic or antimicrobial medicine, the infection continues to grow and can become difficult, if not impossible, to treat.
According to the United States Center for Disease Control (CDC):
Antimicrobial resistance is an urgent global public health threat, killing at least 1.27 million people worldwide and associated with nearly 5 million deaths in 2019. In the U.S., more than 2.8 million antimicrobial-resistant infections occur each year. More than 35,000 people die as a result, according to CDC’s 2019 Antibiotic Resistance (AR) Threats Report. When Clostridioides difficile—a bacterium that is not typically resistant but can cause deadly diarrhea and is associated with antimicrobial use—is added to these, the U.S. toll of all the threats in the report exceeds 3 million infections and 48,000 deaths.
Furthermore, many leading scientists fear that a future pandemic caused by methicillin-resistant Staphylococcus aureus or other multi-drug resistance bacteria could be potentially more devastating than the COVID-19 pandemic.
What Effects do Antibiotics have on the microbiome?
Antibiotics are designed to kill enough pathogenic bacteria so that the human immune system has time and strength to help the body protect itself. Most antibiotics, unfortunately, are not sufficiently selective in targeting the specific bacteria they aim to eliminate. Even narrow-spectrum antibiotics kill beneficial bacteria and the damaging bacteria they are supposedly targeting. However, as stated in the introduction, many doctors and health professionals today routinely prescribe antibiotics for even the mildest infections that would likely resolve on their own.
Even in cases where antibiotic use may be an urgent part of a treatment plan (quick onset diarrhea in a young child, for example), using that antibiotic will also have adverse side effects. Antibiotics will temporarily damage an individual’s gut microbiome. These changes in the gut microbiota can lead to disease, with antibiotic-associated diarrhea being the most common. Furthermore, antibiotic use selects bacteria that are resistant to antibiotics.
One recent study states that:
Antibiotic‐induced changes in microbial composition can negatively impact host health, including reduced microbial diversity, changes in functional attributes of the microbiota, formation, and selection of antibiotic‐resistant strains, making hosts more susceptible to infection with pathogens such as Clostridioides difficile. Antibiotic resistance is a global crisis, and the increased use of antibiotics over time warrants investigation into its effects on microbiota and health.
Though researchers continue to discover the damage antibiotics have on the gut microbiome, clostridioides difficile infection is a practical example of demonstrating the unique relationship between the human microbiome and health and disease. Clostridioides difficile infection causes severe and recurrent diarrhea, abdominal cramping, and nausea. This infection most commonly occurs in people who have recently received a course of antibiotics while in a hospital. Though the course of antibiotics may have killed or stopped the reproduction of certain targeted pathogenic bacteria, they also may have caused extreme changes in ordinary human microbial communities.
After taking the antibiotic, previously established colonies of healthy and diverse gut microbiota may be surpassed by colonies of different and potentially pathogenic species, with Clostridioides difficile being one of the most common bacteria to take over after a course of antibiotics.
It is important to note that genetic mutation leading to antibiotic resistance doesn’t occur every time a person takes antibiotics. Every human being has millions of bacteria in their body. Thus, the probability of developing a resistance mechanism after a course of antibiotics is small, yet possible. However, this small probability on an individual level becomes significantly greater when millions of people regularly take antibiotics, especially for mild infections where antibiotic use is unnecessary.
The higher the use of antibiotics among the general population, the higher the possibility for antibiotic resistance to spread rapidly and across multiple species of bacteria. Furthermore, bacteria in the human body can also acquire antibiotic resistance through a process known as horizontal gene transfer, or the transfer of genetic material between organisms. Thus, bacteria in your gut may be able to obtain resistance to an antibiotic they’ve never been exposed to through this process.
Furthermore, the widespread use of antibiotics and the resulting resistance may also negatively affect the relationships between the reciprocal and health-enhancing relationship between the human microbiome and the host immune system. According to a 2018 study, these relationships:
Are shaped by past microbial encounters and prepare the host for future ones. Antibiotics and other antimicrobials leave their mark on both the microbiome and host immunity. Antimicrobials alter the structure of the microbiota, expand the host-specific pool of antimicrobial-resistance genes and organisms, degrade the protective effects of the microbiota against invasion by pathogens, and may impair vaccine efficacy. Through these effects on the microbiome, they may affect immune responses.
Other Alternatives Available to Combat Infection
As we have seen, the widespread use of antibiotics causes severe damage to the human microbiome. Antibiotic resistance is also an increasingly serious problem that could lead to even more severe health vulnerabilities. But what can be done to combat the pathogenic bacteria-causing disease in human beings where antibiotics have played an essential role in helping the human body fight off those infections?
Firstly, finding ways to reestablish a healthy and diverse microbial composition after administering a course of antibiotics has become an essential priority for health professionals.
A wide array of probiotics can play an important role in helping to regenerate your microbiome after being exposed to antibiotics.
A 2022 study titled “Impact of antibiotics on the human microbiome and consequences for host health” states that:
It is now well established that antibiotic use results in changes in microbial composition, the consequences of which can be detrimental for the host. Certain approaches can be used along with post-antibiotic therapy to restore the microbial composition faster. Probiotics are widely used for this purpose and have been shown to increase the abundance of beneficial microbes, stabilize the microbial community and thus alleviate the effects of antibiotics (Ki Cha et al., 2012; Korpela et al., 2018). Probiotics exert their effects by promoting antimicrobial peptide production, producing bacteriocins, suppressing the growth of non-commensals via competing for nutrients and receptors on the intestinal mucosa, enhancing barrier function in the gut, and modulating immunity (Bron et al., 2011; Cazorla et al., 2018; Collado et al., 2007; O’Shea et al., 2012; Xue et al., 2017), but the use of probiotics may not lead to complete restoration of the gut microbiota.
Furthermore, some research focuses on how vaccines can exert protective or therapeutic effects against bacterial pathogens. These vaccines may reduce the use of antimicrobial medicines, thus helping to slow the development and spread of antibiotic resistance and the harmful impacts of antibiotics on the microbiome. Other medical professionals are researching how harnessing phage—viruses that attack bacteria—might be able to attack bacteria directly or employ their ability to resist antibiotics.
However, continued research into the microbiome may yield alternatives to vaccines and antibiotics for combating infection. Strategies revolving around the purposeful manipulation of the microbiome may offer unique solutions for fighting off pathogens. Scientists and researchers are continuing to discover the potential beneficial combinations of organisms to promote health-enhancing outcomes. For example, gaining insight into how healthy and unhealthy varieties of microorganisms in the microbiome might be able to help against the invasion by disease-causing organisms could reduce dependence on antibiotics.
For example, researchers at the University of Michigan study how certain combinations of the bacteria in your nose and throat may help people avoid getting the flu (influenza). Though influenza is a virus (and antibiotics are ineffective against viral infections), similar research might show how bacterial combinations might help against bacterial respiratory diseases.
Also, continued research into the microbiome’s diversity may give doctors targeted strategies to attack harmful, disease-causing bacteria while limiting collateral damage to other parts of the microbiome. For example, some researchers are looking into how we can isolate particular molecules from microbial interactions that could help us fight some diseases.
As we continue to learn how the human microbiome works, we should continue to learn more about human physiology, particularly how human nutrition is affected by the gut microbiome. This information can allow us to create better nutritional paradigms for individuals that respond to their unique microbiome. Lastly, insight into the microbiome may allow us to keep our super organism healthier, thus reducing the need for antibiotics.
A Microbiome Signature is a unique identifier for a particular microbiome that can be used to track changes in the microbiome over time or compare different microbiomes. This microbiome signature could thus help better understand the health of an environment or system by pinpointing significant differences in microbial composition and diversity. Precise and detailed information about individual human microbiomes could also lead to the development of new diagnostic techniques and treatments for various human diseases.
Additionally, the data from a microbiome signature could be used to identify beneficial microbes and their potential functions within a larger host environment. Ultimately, these signatures are potent tools for better understanding our bodies’ ecosystems and will play an integral role in improving human health.
