A new study found that pediatricians are over-prescribing broad spectrum antibiotics (which target both gram-negative and gram-positive bacteria, also known as most bacteria) at an increasing rate. 21% of all pediatric visits ended with a prescription for antibiotics, 50% of which were broad spectrum. For 23% of those visits ending in antibiotics (which accounted for over 10 million visits in total), they were prescribed for conditions that don’t even respond to antibiotics, like asthma, viral infections, flu, allergies, and bronchitis. The bulk of the antibiotics prescribed in these unwarranted situations were broad spectrum, and the bulk of the patients in these situations were younger than not.
Ugh. Antibiotics clearly have therapeutic merit – a statement some would debate, I’m sure – but I think everyone would agree that prescribing broad spectrum antibiotics for non-responsive conditions to young kids is unwise.
Anyway, last week we explored the negative ramifications of antibiotics overuse, particularly on a patient’s bodyweight. The disruption of gut flora composition and diversity by antibiotic therapy has been shown to affect metabolism and body weight in both animals and humans, and the relationship appears to be causal. Today, I’ll discuss a few other potential complications related to antibiotics. I want to stress that much of this research remains exploratory and quite young - many of the supporting studies are either in animals or in vitro situations (test tubes and such rather than live subjects) – but the hypotheses are plausible, and supporting epidemiology exists. Besides, given the chance that our gut flora may never fully recover from antibiotic therapy, it’s important to be aware of any potential fallout.
Direct and indirect effects on gut flora and host (that’s you).
A direct effect on gut flora by antibiotics is obvious: they are killed. But this can have numerous downstream effects, even on bacterial species that the antibiotics don’t target directly.
You know how I wrote that antibiotics alter makeup of bacteria in the gut last week? It turns out that even though the special ratios and diversity change, total biomass (total number of gut flora) often remains the same. So, if antibiotics eradicate one species from the gut, other species will quickly move to claim the vacancy and increase their population. Remember: even though these are microscopic organisms, they still occupy physical space, and space in the gut is limited. If one opportunistic species takes advantage of a vacancy and grows its sphere of influence (as C. diff often does following a round of antibiotics), that’s less room for another species.
Much is made of the symbiotic relationship between host and gut flora, but gut flora themselves often enjoy robust, vital relationships with other species of gut flora. One species may break down primary food components into secondary metabolites. A second species which cannot utilize primary food components must rely on the secondary metabolites from the first species. The secondary metabolites are broken down into waste products, which in turn are utilized for energy by other species. It’s a cycle, and if even one participant is missing (maybe from antibiotics), toxic metabolites can buildup and many of the flora that survived the initial onslaught will lack nutrients. Check out this cool visual of the cycle.
There’s even some (extremely limited thus far) evidence that antibiotics are linked to certain diseases and conditions, including some types of colitis, vaginal candidiasis, diarrhea, eczema, cholera, autism, and asthma.
Impaired immune function is another potential ramification. I’ve discussed the importance of the gut flora in maintaining proper immune function before, but here’s a table showing the effects of specific antibiotics courses on specific aspects of the immune system.
Loss of helpful gut bacterial metabolites.
Gut flora don’t really care about you. They’re just trying to survive, man, and survival requires sustenance. Nutrients. Food. Luckily for us, when bacteria break down some of the food we eat, they produce short chain fatty acids. Some species, like the gorilla with its cavernous gut and tendency to perpetually eat leafy fibrous things, rely almost entirely on the short chain fatty acids (SCFA) produced by gut flora. They chew and swallow ten pound Big Ass raw salads daily and derive most of their caloric energy from SCFA. Yep, those gorillas are ultimately on a high-fat diet. Anyway, we don’t house enough gut flora to live off of short chain fatty acids, but we can derive a lot of benefits from the SCFA our relatively meager flora produce.
I’ve written about prebiotics and butyric acid, or butyrate, one of the most important SCFAs. When certain types of gut flora consume certain prebiotic fibers (Melissa has a nice table detailing the butyrate production in response to various fibers), they make butyrate, which the colon uses for energy and which seems to inhibit colon tumors from forming (PDF). Additional benefits of butyrate include increased insulin sensitivity and mitochondrial function. Without the gut flora necessary to ferment fiber into butyrate, we’d be getting shortchanged (and being unable to break down the things we eat is no fun, either).
A common way to measure how many SCFAs an animal is producing is to look at the poop. If something is making a lot of SCFA, it’ll show up there. And sure enough, feces from mice given antibiotics contain fewer SCFA and related metabolites than feces from untreated mice. Oligosaccharides – what the flora ferment and turn into SCFA – appear more frequently in the feces of the treated mice, indicating that antibiotics disrupted carbohydrate fermentation (and, presumably, floral populations).
Interruption of gut bacteria signaling.
A fun thing about biology is that everything’s a multi-tasker. There are multiple levels to nearly every physiological process. For instance, reactive oxygen species are often thought of as wholly negative, but they also play important roles in signaling and maintaining cellular homeostasis. Same with the bacteria in our guts. They help digest food, they comprise the bulk of our immune systems, they produce helpful gut bacterial metabolites like butyric acid – all (relatively) well-known responsibilities – but they also act as important signaling agents in our body. More specifically, specific species of bacteria relay specific signals.
Here’s one example: a species called Saccharomyces boulardii (a common component of probiotic supplements) secretes a compound that blocks an inhibitor that normally causes a certain inflammatory cytokine to release; the result is lower inflammation. Luckily, S. boulardii isn’t targeted by antibiotics. But what happens if an important signaling bacterium is targeted by antibiotics?
Here’s an example of that: a single type of gut flora called segmented filamentous bacterium tells the body to start making CD4 T-helper cells, which in turn signal the creation of the inflammatory cytokines IL-17 and IL-22, which are crucial for certain immune responses. Those same segmented filamentous bacteria are fairly sensitive to antibiotics.
Sound confusing? It is. And those are just two examples of gut flora which act as signalers for very specific situations. One is resistant, one is not. There are undoubtedly hundreds more – most of which we can’t even culture, closely examine, nor fully understand – and they’re not all going to be resistant to antibiotics.
As you can see, the gut is complicated. We humans have evolved with the assumption that in return for hosting hundreds of species of gut flora, our guests would provide certain services. We’ve become accustomed to this arrangement. Indeed, the proper function of the human body depends on various strains of bacteria talking to each other, talking to the host cells, inducing inflammation when it’s needed, inhibiting inflammation when it’s not, (by)producing metabolites that other cells consume as energy, and helping regulate our immunity. The complexity means that a big blundering tool designed to take out a bunch of bacteria could be counterproductive – and there’s evidence that this is the case.
I’m not saying we swear off antibiotics. In fact, I’m not giving any medical advice at all. I’m just saying that caution should be exercised, that we need to weigh the known with the unforeseen and understand that there may be ramifications to antibiotics abuse, and perhaps even to normal use.
Tomorrow, I’ll discuss some possible solutions for the antibiotics problems. Stay tuned.
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