Hey! Today I’ll discuss two more factors that can debilitate the human immune system (allowing the microbiome to better cause disease). They are antibiotics (when used too frequently) and immunosuppressive drugs: two of the most common medical interventions of our time. Most of us are familiar with antibiotics. By immunosuppressive drugs I mean medications like Humira, Prednisone, Ritauximab, and Enbrel. These and similar drugs block or disable parts of the human immune response in an effort to temporarily palliate inflammatory symptoms.

It’s important to note that most antibiotics and immunosuppressive drugs were developed before mainstream science “discovered” the human microbiome around the year 2005. In other words, they were created/formulated during a period when the human body was assumed to be largely sterile. The antibiotic Penicillin was discovered by Scottish scientist Alexander Fleming in 1928. By the mid 1940s it was regarded as a wonder drug, especially during World War II when it saved countless soldiers from dying of infected wounds.

After World War II, antibiotics continued to be perceived as miracles, and it’s easy to understand why: diseases like pneumonia, scarlet fever, bacterial meningitis, gonorrhea and a range of ear, skin, urinary and throat infections could finally be treated! Life expectancy increased as antibiotics allowed patients to survive an ever-growing range of these specific bacterial infections. And since the human body was considered sterile, it was assumed that antibiotics only killed the single bacterial pathogen they were prescribed to treat. They were subsequently prescribed with increasing frequency, and for minor infections like colds or sore throats (especially in children).

Then, in the early 2000s, new molecular tools were developed that identify microbes by their DNA/RNA rather than their ability to grow in a laboratory Petri dish. When researchers turned these new tools on the human body, they discovered thousands of microbes in human tissue/blood that had been missed by previous techniques. With each new molecular analysis, mainstream science realized that the human body is the opposite of sterile! Instead, humans harbor vast ecosystems of bacteria, viruses, bacteriophages and other microorganisms. The human gut alone harbors trillions of microbes. These complex microbial communities were named the human microbiome – the “discovery” of which marks one of the most important turning points in the history of science.

Almost every facet of human health and biology must be re-evaluated to account for the human microbiome. When it comes to antibiotics we face a stark reality: Current antibiotics like penicillin have such a broad range of activity that they kill most bacteria in the human microbiome in addition to any single pathogen they are prescribed to treat. The situation could be compared to dropping an atomic bomb on an entire continent in an effort to target a group of rebels in one small city.

What are the implications of this? Research on the topic is still in early stages. But we know two things:

1. Health, diversity and balance of the human microbiome are key to prevention of human inflammatory disease
2. Microbiome populations decimated by antibiotics can recover, but sometimes not to their full, previous capacity

For example, in this Ted talk, researcher Rob Knight charts how an antibiotic prescribed to treat an infant’s ear infection impacted several of the child’s early microbiome communities. The antibiotic caused “a huge change in community structure” that “set back many months of (microbiome) development.” Interestingly, the infant’s microbiome eventually recovered to a place similar to that of untreated subjects. But as Knight suggests, it’s hard to imagine that there are no longer-term implications associated with the event (especially if the infant is administered even more antibiotics over time). And, as a society, are we taking more antibiotics? We sure are! From 2000-2015 approximately 65% more antibiotics have been sold globally (accounting for 34.8 billion doses in 2015). In the USA, 47 million of these antibiotics are prescribed annually for viral infections that don’t even respond to antibiotics.

With those numbers in mind, it’s no surprise that a second major antibiotic issue has also surfaced. Antibiotics have been prescribed with such frequency that many major pathogens have developed resistance against them. As discussed in previous podcasts, pathogens can easily change their gene expression to survive under difficult circumstances. Many human pathogens have done exactly that – they have acquired genes or mutated in ways that allow them to remain alive in the face of our most commonly used antibiotics. This has created a range of antibiotic-resistant pathogens often referred to as “superbugs.” Many of these “superbugs” are deadly (Acinetobacter baumannii, Pseudomonas aeruginosa, and MRSA for example). In fact, the CDC estimates that these and related “superbugs” kill at least 23,000 Americans a year (for comparison, about 38,000 Americans die every year in car crashes).

The situation is regarded as a global catastrophe. According to the CDC, the rate at which new strains of antibiotic-resistant bacteria have emerged in recent years “terrifies public health experts.” Many consider new “superbug” strains to be just as dangerous as emerging viruses like Zika or Ebola. Britain’s chief medical officer, Sally C. Davies, has described drug-resistant pathogens as a national security threat equivalent to terrorism. The problem is compounded by the fact that a large number of bacteria in the human body have yet to even be characterized and named. Who knows what our overly zealous use of antibiotics is doing to these understudied bacteria! It’s very possible that heavy antibiotic use may be pushing MOST bacteria in the human body into a more virulent, resistant state.

Add to this a third major antibiotic problem. Over the past decades, farmers started feeding antibiotics to many of the animals we consume as food (cows, chickens, pigs etc). Why? Antibiotics cause the animals to gain weight, increasing the amount of meat that can be sold to consumers. Again, few people paused to consider the long-term or chronic consequences of saturating our food supply with antibiotics. Instead, approximately 80% of antibiotics sold in the United States are used in meat and poultry production. This has created an amazing atmosphere for the development of virulent pathogens that may better resist antibiotics. In addition, genes conferring antibiotic resistance are regularly transferred from farm animals into the human food supply. If ingested, these antibiotic resistance genes can theoretically be transferred and “taken up” by almost any bacterial species in the human body.

To make matters worse, antibiotics were added to the food supply during the first time in history where the average 1st world inhabitant started eating meat imported from around the world. For example, the USA imported 3.01 billion pounds of beef in 2016, from 22 countries across the globe (from Europe, to South America, to China and Thailand). Consumers are subsequently exposed to meat-associated pathogens from around the world – basically a potential cocktail of global pathogens. For example, a study by researchers in Germany found high levels of S.aureus and E.coli in pork/poultry imported into the EU, with other pathogens like Salmonella and Enterobacteriaceae present in lower amounts.

The above questions the interpretation of studies that tie meat consumption to chronic inflammatory conditions like heart disease. If a negative association between the two is identified, is the meat itself to blame? Or are pathogens in the meat to blame? (or a combination of both and/or other variables). The relatively unexplored possibility that pathogens in meat may promote chronic disease is supported by the fact that heart disease is increasingly tied to infection and microbiome dysbiosis. A recent study even found that lipids or fat molecules in arterial plaque can be created by persistent bacteria. Also, to be fair, the possible impact of food-borne pathogens on chronic disease applies to most foods – for example, what do the range of pesticides and chemicals sprayed on plants across the globe do to the microbes that live in/on the produce we consume?

Now I’ll take the topic one step further, by posing a rarely asked but extremely important question: “Where has the human immune system been during the modern era of antibiotics (1940-today)? Because, as I’ve argued in previous blogs/papers, the healthy, activated human immune system has incredible defense strategies for keeping antibiotic resistant bacteria or “superbugs” in check.

After the turn of the century, a range of chronic conditions were linked to persistent inflammation. This chronic inflammation generally results when the immune system attempts to target pathogens. However at that time (as mentioned) the human body was incorrectly assumed to be sterile. Researchers subsequently developed the “theory of autoimmunity” – the belief that in diseases like Crohn’s, Multiple Sclerosis and arthritis, the immune system “loses tolerance” and attacks its own tissues.

By the 1960s-80s the theory of autoimmunity had gained incredible traction. Over 80 different conditions were deemed “autoimmune” in origin. The result? Pharmaceutical companies created drugs specifically designed to shut down key parts of the human immune system. These drugs, which temporarily palliate symptoms, have been prescribed so aggressively that today they are the top-selling medications in the world. For example, the potent immunosuppressive drug Humira is literally the top-selling drug in the world: generating more than 18.4 billion dollars in revenue in 2017.

This means we have been using antibiotics at the same time that we have deliberately compromised the immune systems of a growing chunk of the human population. In fact, it’s no coincidence that most “superbugs”  form or are identified in elderly, sick and/or hospitalized patients; patients much more likely to be on cocktails of immunosuppressive drugs/steroids. This trend escalates when severely immunocompromised patients are gathered in one place: a recent analysis found that pipes under NIH’s ICU rooms tested positive for bacterial plasmids that confer resistance to carbapenem antibiotics. The pipes were described as a “seething hookup zone for antibiotic-resistant bacteria.” Another report found that many veterans of the Iraq War suffered from antibiotic-resistant A. Baumannii infections. But the “superbug” was almost always identified in wounded veterans with complex injuries. Indeed, the report clarifies that,  “A. Baumannii  is not particularly virulent. If you’re in good health and (it) were to get into a wound it might not be a problem. It’s a problem for people who are the weakest of the weak.”

The most common treatments for “non-autoimmune” conditions are also immunosuppressive to various degrees. Opioids, antidepressants and antipsychotics dampen the immune response (especially when administered over long periods of time). Certain forms of birth control have been shown to lower immunity. Cancer chemotherapies substantially weaken the immune system. Indeed, childhood cancer survivors are prone to a wide range of health problems later in life including organ damage, cognitive deficits and high blood pressure. These long-term health issues are similar to those observed in patients administered “classical” immunosuppressive drugs. Even in animals given antibiotics for weight gain – do the overcrowded/unsanitary conditions at many farms favor “superbugs” by lowering animal immunity?

All in all, we are living in an era of mass immunosuppression. This has created a field day for antibiotic resistant and virulent pathogens! Such pathogens can easily thwart the human immune system because our drugs are “knocking it down” for them. We are greatly assisting the enemy.

Most concerning is that the “theory of autoimmunity” no longer holds up in the era of the microbiome. A growing body of research suggests that “autoantibodies” are created in response to microbiome pathogens rather than “self.” In addition, “autoimmune” conditions are increasingly linked to microbiome dysbiosis and not a defective immune response. So we are using immunosuppressive drugs to treat patients based on a failing and outdated paradigm. For more on this topic please read this paper.

To combat antibiotic resistance we must subsequently re-evaluate the “theory of autoimmunity” and the immunosuppressive drugs that have stemmed from its promotion. And we must do so NOW. We cannot afford to wait the decades it usually takes for an outdated theory to be replaced by a new, improved paradigm (Thomas-Kuhn style). Too many lives and the health of the entire public are at stake.

How else can we fix the situation? At least in the short-term, antibiotics and immunosuppressive drugs should be considered last resort treatment options. Patients should exhaust all other treatment options BEFORE being prescribed these medications. We must prioritize diet/lifestyle changes that the average doctor does not yet include in treatment plans. Although this may sound simple, it’s easier said than done when drug companies spend millions of dollars a year marketing immunosuppressive medications directly to physicians.

In the longer-term we should replace immunosuppressive therapies with new treatments that support the immune system and encourage balance + diversity of the human microbiome. This would require another major paradigm shift that I describe more here.

This last paradigm shift is essential because we NEED some antibiotics. When administered in a careful, responsible fashion antibiotics still save countless lives. Antibiotics are also a valuable tool for treating chronic inflammatory conditions that are increasingly tied to infection. For example, this article describes how a young boy with crippling OCD used antibiotics to treat a chronic strep infection. His OCD symptoms diminished to the point where he is able to function in society again.

I have several suggestions for how to best move forward:

1. Antibiotics should be re-branded as complex, immunomodulatory drugs: Few people realize that antibiotics have profound effects on the immune system in addition to their antimicrobial properties. For example, many commonly used antibiotics (rifampin, cephradine, tetracycline, clindamycin, and penicillin among others) can bind directly into the human PXR nuclear receptor: a receptor that controls how the body detoxifies foreign substances. The PXR in turn modulates CYP3A4 – an enzyme key to controlling the human immune response. These and related interactions may explain why antibiotics like minocycline are regularly used as “anti-inflammatory” or “immunomodulatory” drugs in patients with arthritis and other rheumatic conditions. 

So imagine if every time an antibiotic was prescribed doctors were required to say: “I’m giving you a powerful medication that will impact your entire microbiome and immune system in profound ways still not fully understood by science.” This would give people pause before prescribing and/or popping an antibiotic for the common cold.
2. We should keep this complexity in mind when developing new antibiotics: The superbug crisis has set off a wave of research aimed at creating new antibiotics. Many research teams working in this vein are trying to develop antibiotics that would target specific bacterial pathogens in lieu of the entire bacterial microbiome. This makes sense, but part of the trend involves taking parts of the human immune system and trying to make them into new antimicrobial drugs.

For example, researchers at Vanderbilt University recently made a fascinating discovery: human milk oligosaccharides (HMOs) in breast milk possess strong antimicrobial and antibiofilm activity against several superbugs (Eg: A. baumannii and MRSA). Several research teams responded to the finding by suggesting that these HMOs should be made into new antibiotics. While this makes sense in theory it also runs a large risk – any pathogen that develops resistance against these HMOs will have developed resistance against a key component of the human immune system itself.

What makes the above scenario likely to occur is that the human body constantly adapts its antimicrobial defenses to keep up with the changing nature (evolution) of virulent pathogens. For example, in this interview, Harvard researcher Robert Moir describes how the human immune system regularly changes the structure of the human antimicrobial peptide cathelicidin in response to different pathogen threats (each different form of cathelicidin is called an oligomer). The flexible nature of these oligomers means that when a pathogen mutates to survive in the face of the peptide, the peptide can change its own structure/function to “fight back.”

Human drugs based on only a single form of a human antimicrobial peptide/molecule would lack this flexibility, making resistance against them much more likely.

Ok that’s it for today. I’ll leave with the following message. Let’s not get so worried about current “superbugs” that we rush into making new antibiotics without fully considering long-term consequences. We’ve already done that once right? As the saying goes, “Fool me once, shame on you; fool me twice, shame on me!” The same goes for phage therapy – another proposed alternative to antibiotics. In this interview, Texas A&M researcher Ry Young does a great job explaining how we can move forward with phage therapy in the most proactive and responsible fashion.

Also, not everyone is surprised by the recent surge in antibiotic resistance and superbugs. Certain communities of researchers have been warning about the possibility since the 1960s. I will also do another podcast that talks about these researchers and several of their key findings – findings that should still be taken into consideration today.