Antibiotics and Immunity

How antibiotics could be destroying your good microbes.

Antibiotic resistance

The overuse of antibiotics, part 1

In 1980, Martin Blaser, an infectious disease expert at the Centers for Disease Control and Prevention (CDC) was infected with paratyphoid fever while on assignment in India. He had purchased a watermelon from a street vendor, which, he would later discover, had been injected with contaminated river water to increase its weight.

No one knew better than Blaser that were it not for the course of co-trimoxazole he was prescribed shortly after his return to Atlanta, he probably wouldn’t have survived the illness. But he also knew that antibiotics were not a panacea.

Our fixation with antibiotics is a perfect illustration of the adage, ‘too much of a good thing’. One indicator of our over-reliance on antibiotics is the tendency of doctors to use them as a first line of defense against upper respiratory tract infections (URIs).

Here’s the problem, though: only a fraction of URIs – between 5% and 20% – are caused by bacteria, and antibiotics have no effect on viruses. Most of the time, the attending doctor can’t tell whether an infection is caused by a bacterium or a virus using the diagnostic tools at his disposal.

The overuse of antibiotics, part 2

In the United States, health-care providers prescribed 258 million courses of antibiotics to their patients in 2010. The highest prescription rate – 1,365 courses per 1000 babies – was for children under the age of two.

If this seems odd, consider that young children are prone to developing ear infections and URIs. Then consider the tendency of pediatricians to be overly cautious of extremely rare but serious complications such as rheumatic fever, the looming threat of lawsuits in the event of misdiagnosis, pressure from anxious parents (who often do not have a good grasp of the way antibiotics actually work), and scheduling pressures, and you have the perfect storm of factors conspiring to push them towards an unnecessary antibiotic prescription.

Even more alarming is the tendency to prescribe broad-spectrum antibiotics on a ‘just in case’ basis, to cover their bases and increase the chances of wiping out the pathogen completely.

The overuse of antibiotics, part 3

In cases where the cause of an infection is not clear-cut, broad-spectrum antibiotics allow for a margin of error; they can also be developed more cheaply than narrow-spectrum antibiotics.

For Blaser, however, prescribing broad-spectrum antibiotics by default is excessive. He explains:

“[Here’s] the crux of this problem: there are always innocent bystanders, lots and lots of them. All mixed populations of bacteria include both susceptible and resistant bacteria. The antibiotic eliminates susceptible microbes all over the body along with the pathogen that usually is present in one place. It is like carpet bombing when a laserlike strike is needed.”

Broad-spectrum antibiotics are much more damaging to the gut microbiome than narrow-spectrum antibiotics and cause more collateral damage. Blaser also found that when prescribed at a critical stage in the child’s development (before the age of three), antibiotics can have a lasting impact on the child’s immunity.

Collateral damage: Antibiotic resistance

The overuse of antibiotics has been linked to a decrease in the diversity of our gut microbiome, and this can have serious consequences. Antibiotic resistance is one such consequence, where bacteria become resistant to certain types of antibiotics and no longer respond to treatment.

But why would a less diverse microbiome lead to antibiotic resistance?

The answer lies in a principle called Horizontal Gene Transfer (HGT), which is the movement of genetic material between different species of bacteria. In a less diverse microbiome, HGT occurs more frequently. This is because there are greater concentrations of particular species of bacteria, that will have the opportunity to transfer genes between themselves.

Thus, paradoxically, a less diverse microbiome will see accelerated evolution among its bacterial population. This allows bacteria to develop antibiotic resistance more quickly in dysbiotic gut envirovments.

Collateral damage: Increased susceptibility to infections

In addition to antibiotic resistance, one of the hidden costs of antibiotic use is increased susceptibility to new infections, which may be lethal. This may seem counterintuitive, but it’s a logical side-effect of a degraded ecosystem – when the good bacteria are obliterated along with the bad, the gut microbiome is compromised and vulnerable to attack.

Consider Salmonella, a common bacterial disease. Salmonella is contracted by consuming contaminated animal products (eggs, chicken, meat and fish). Despite the widespread practice of sanitation that successfully eliminated most water- and food-borne infectious diseases, cases of Salmonella in the developed world are on the rise.

This baffled the scientific community until it was discovered that the bacterium that causes it had developed an ability to evade antibiotic treatment. Studies also show exposure to antibiotics leaves people more susceptible to contracting Salmonella. As you can see, the two major drawbacks to antibiotics – resistance and increased susceptibility to infection – are related.

Solving the auto-immune puzzle, part 1

In 2000, Italian gastroenterologist, Dr. Alessia Fasano, was trying to develop a vaccine for cholera at the Massachusetts General Hospital for Children in Boston when he accidentally made an unexpected discovery of zonulin: a protein that increases the permeability of the intestinal wall, making it leaky. He realized that zonulin was the culprit behind the autoimmune condition, celiac disease.

An excess of zonulin was allowing gluten (a protein found in wheat, barley and rye) to seep through the gut walls of celiac patients. When gluten crosses the border in celiac patients, their bodies start to treat gluten as a foreign object rather than a food. This causes the immune cells to ‘go rogue’ and attack the cells of the patients’ guts instead of turning on intruders.

This rogue reaction to gluten triggered by zonulin is known as an autoimmune response. Somehow, zonulin was sending the immune system of celiac patients into a frenzy; causing the immune system to become overactive and instructing the immune cells to attack their tissues.

Solving the autoimmune puzzle, part 2

In addition to producing excess zonulin, two other factors make celiac sufferers susceptible to developing an autoimmune response: a genetic predisposition to gluten intolerance, and an altered gut microbiome, or dysbiosis.

The main driver behind dysbiosis is misuse of antibiotics. Dysbiosis triggers the release of zonulin, which increases the permeability of the intestinal wall. This, in turns, kicks off an inflammatory process by triggering the release of inflammatory messengers called cytokines. This is called a cytokine storm. The more permeable the intestinal wall, the more likely we are to develop a leaky gut.

But elevated zonulin levels aren’t exclusive to celiac patients. They’re also found in people living with type 1 diabetes, suggesting a causal link between leaky gut and other 21st century diseases. Some researchers believe that leaky gut syndrome is behind a number of autoimmune diseases, such as childhood asthma, rheumatoid arthritis and lupus.

Allergies and immune dysfunction

Since its discovery in 1982, Helicobacter pylori (or H. pylori) – the bacterium associated with stomach ulcers – has had a bad reputation. But Martin Blaser’s pioneering research has provided the infamous bacterium an opportunity to cast off its villain’s cloak, at least in some circumstances.

Blaser had noticed that asthma, hay fever and allergic rhinitis were becoming more common in children and set out to discover what was behind the alarming rise in allergies and their increasingly early age of onset. He found that among sufferers of childhood-onset asthma (i.e. asthma diagnosed before the age of 15), the presence of H. pylori was low or absent. This was consistent with his findings for hay fever and allergic rhinitis.

While it wreaks havoc in adults, Blaser argues that the presence of H. pylori in a child’s stomach might offer protection against these allergies, and that it appears to have “some general effect on immunity, on people’s ability to turn off an allergic response.” The reason behind the disappearance of H. pylori was – you guessed it – antibiotic use in early life.

Personal and societal impact

In *Missing Microbes*, Martin Blaser writes, “To reiterate my central idea, as our resident microbes succeed each other, we develop with them as an integrated circuit that includes our metabolism, immunity, and cognition. But we face unprecedented insults to our resident microbes.”

Eighty years after the mass roll-out of penicillin, Alexander Fleming’s warning upon acceptance of the Nobel Prize has come back to haunt us. Once touted as a wonder drug, antibiotics can provide a much-needed lifeline in situations where their use is warranted. However, a single dose of antibiotics can have a lasting impact on immunity, particularly in children under the age of three.

The common practice of prescribing broad-spectrum antibiotics for minor infections exacerbates the risk of resistance, presenting a major risk to human health.

Misusing antibiotics can also make us more susceptible to infection. This is because these drugs don’t discriminate between healthy and unhealthy bacteria and disrupt the fragile microbial ecosystem in our guts.

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