Antibiotics attack the body, not just the germs, new study shows
Results from a new study may revolutionize the way in which we view antibiotics and also provide hope for millions of sufferers from Inflammatory Bowel Disease (IBD), a condition which is believed to affect as many as 1 percent of the world’s population.
Antibiotics have become virtually ubiquitous and even those who avoid using them are often exposed to antibiotics in a variety of ways regardless. Until recently, it was believed that antibiotics only affected bacteria, indirectly causing an imbalance in the body. This new study has revealed that antibiotics can also have a direct and damaging impact on the body’s cells, a finding which the head of the research team called “blasphemous” as it overturns conventional medical belief.
Good germs, bad germs, and ugly results
The study, conducted by Dr. Shai Bel, of Bar Ilan University in Israel, and his research team, focused on the impact of antibiotics on the development of IBD, given that it is already known that antibiotics disrupt the microbiome, the mix of bacteria in the intestines. In healthy intestines, that doesn’t usually matter too much, given that a layer of mucus lines the intestinal walls, protecting the body from infection and inflammation caused by substances passing through, as Dr. Bel describes:
The colonic mucus layer separates the host from the trillions of microbes that inhabit the gut lumen.
Furthermore, many believe that any damage caused by antibiotics can be reversed by fixing the imbalance they cause in the microbiome (by taking probiotics, etc.).
The hypothesis of Dr. Bel's study, however, was that antibiotics directly affect the integrity of the mucus barrier, thereby enabling bacteria to penetrate the intestinal walls and leading to inflammation and pain. Although rectifying the microbiome could help some people with IBD, the occurence of direct damage to the mucus barrier could explain why such measures do not help for others.
The research team investigated this hypothesis by transferring the microbiota (the microbes in the intestines) from mice that had been treated with antibiotics to germ-free mice which had not received antibiotics. While the treated mice had experienced damage to the mucus layer, the mice with the imported microbiome did not seem to suffer any harmful consequences:
To our surprise, transferring the microbiota after abx [antibiotic] treatment to germ-free mice did not transfer this penetration phenotype. This implied that perhaps the abx might be affecting the mouse directly.
Antibiotics affect your genes
The research also revealed that two of the antibiotics studied, neomycin and vancomycin, induced what is called an Endoplasmic reticulum (ER) stress response in the colon. ER stress limits the amount of mucus produced by goblet cells in the intestines. The study found,
1266 genes that were differently expressed in the same manner ... in response to vancomycin treatment ... We found mice treated systemically with vancomycin lacked a clear mucus in most areas of the colonic epithelial circumference.
The testing “demonstrated that the deleterious effect of vancomycin on mucus secretion is microbiota independent.” That said, the researchers stressed that their findings did not rule out damage caused to the mucus barrier by changes in the microbiome itself.
They concluded that,
We have discovered that antibiotic use actually damages the protective mucus layer that separates the immune system in the gut from the microbiome...
This antibiotic-induced mucus secretion flaw leads to penetration of bacteria into the colonic mucus layer, translocation of microbial antigens into circulation, and exacerbation of ulcerations in a mouse model of IBD. Thus, antibiotic use might predispose to intestinal inflammation by impeding mucus production...
This finding shatters the paradigm that antibiotics harmonly bacteria and not our own cells.
A week to cure your infection, minutes to mess up your guts...
Earlier studies have already shown that there are “long-term impacts of repeated antibiotic use on intestinal mucus function.” In this new study, the aim was to mimic a short-term course of antibiotics in humans, by administering antibiotics to mice twice a day for just three days. Four different antibiotics, each from a different class, were tested.
The researchers found that all of the four antibiotic types damaged the mucus barrier, allowing bacteria in the intestines to penetrate the intestinal wall:
We found that all four antibiotics tested led to breakdownof the mucus barrier ... short-term oral antibiotic treatment was sufficient toimpair the separation between host and microbiota in the colon ... [enabling]encroachment of bacteria upon the colonic epithelium.
In fact, the effect of antibiotics was so immediate that within a few minutes of introducing one of the antibiotics, vancomycin, the ability of certain intestinal cells to produce mucus was already impaired:
Unexpectedly, this effect of vancomycin on the ability of goblet cells to secrete mucus was immediate, as a few minutes following vancomycin infusion into the ex vivo chamber, we observed a stark reduction in mucus secretion rates.
... and months to fix them
Dr. Bel and his team also investigated whether the damage caused by antibiotics could be reversed and, if so, how long it would take to see improvements. They found that a certain bile acid had beneficial properties:
Next, we wanted to test whether we could reverse the mucus secretion defect caused by vancomycin treatment in vivo. We have previously found that the bile acid tauroursodeoxycholic acid (TUDCA) can increase mucus secretion rates by reducing ER stress in colonic goblet cells. As vancomycin treatment induces ER stress in the colon, we attempted to restore proper mucus secretion by alleviating this ER stress using TUDCA.
We found that TUDCA treatment reversed the mucus secretion defect caused by vancomycin treatment, restoring a proper mucus barrier.
However, while damage was caused within moments of introducing antibiotics, recovery took weeks to months:
... it takes approx. 6 to 8 weeks after microbial colonization of germ-free mice until their penetrable mucus layer becomes impenetrable and reaches the thickness of conventionally raised mice.
Benefits, risks, and blasphemous conclusions
The study concluded that more research is needed to conclusively show that antibiotics “play a causative role in the development of IBD,” and, if so, how, with the researchers noting that, “this question will be hard to answer in humans ... [as] animal models only partially reflect IBD pathology and development.”
Dr. Bel also stressed that his team was interested in looking at ways to minimize the necessity for antibiotics, given the drawbacks, while recognizing their important contribution:
Antibiotics are a broad family of drugs that disrupt multiple crucial processes in microbes. Since their discovery, antibiotics have become life-saving therapeutics used to treat microbial infections. The prolific use of antibiotics in both medicine and agriculture has resulted in the rise of antibiotic-resistant microbes, which pose a major challenge to modern health care.
This extensive use of antibiotics is based on the assumption that, other than toxicity issues when used in large doses, antibiotics disrupt biological processes in microbes and not the host.
In fact, antibiotics are today known to cause many different kinds of harm in those who use them, and the drugs have been linked to many modern-day afflictions such as obesity and type-2 diabetes:
... recent epidemiological studies have shown a strong and dose-dependent link between these diseases and antibiotic use.
Although antibiotics are not believed to be effective against viruses, Dr. Bel notes that research has shown that “antibiotic drugs can activate an antiviral response,” and also “affect tolerance to infection and influence host metabolism.”
How antibiotics exert this effect on host cells is not completely clear, yet it is thought that they can interfere with mitochondrial function, DNA replication, and various other cellular processes. Even the use of antibiotics to protect cultured cells from infection, a staple of cellular and molecular biology, has come into question because of their effect on these cells.
Impaired mucus function itself has also been linked to various diseases such as metabolic disease and also cancer in mice. While antibiotics reduce mucus production, other factors do as well, such as a low-fiber Western-style diet, and studies have shown that within just 3 to 7 days of adopting such a diet (from a previously high-fiber one), the mucus growth rate drops.
Summing up the implications of his findings, Dr. Bel writes on his X account (where he is known as Mucus_Man):
This is of course blasphemy, as it's known to all that antibiotics target microbes and not mammals. Turns out that's not true...
