Of Two Minds: Antibiotics And The Gut-Brain Axis
Scientists have known for several decades that the gut and the brain communicate bi-directionally. And newer evidence suggests that the gut microbiota — all the microorganisms that live in the human digestive tract, with the greatest concentration in the colon — play a part in this communication through different mechanisms.
The knowledge that bugs may influence the gut-brain axis raises important questions: for one, does it mean that whatever modulates the gut microbiota could potentially change the brain?
Antibiotics constitute an interesting case: on the one hand, they are highly effective at eliminating bacterial intruders that are trying to take over the gut ecosystem (or that are threatening other parts of the body, via the gut or otherwise). But on the other hand, they perturb the gut ecosystem — sometimes allowing pathogens to gain a foothold and cause severe illness or even death, as in the case of Clostridium difficile infection. Antibiotics have been documented to decrease gut microbiota diversity, perhaps even changing the microbial ecosystem permanently (1), and seem to have especially pronounced effects when taken early in childhood. So what could be the implications of these drugs, positive or negative, for brain function?
Take rifaximin, for example. This antibiotic acts on a wide array of bacteria in the human gut, since for the most part it can’t get past the intestinal wall to enter into circulation; it has 1% resorption. Thus, it’s the only locally-acting broad-spectrum antibiotic — and being confined to the gut, at first glance, it’s the least likely to effect changes in the brain.
Rifaximin interrupts how pathogenic bacteria reproduce by blocking their RNA transcription and preventing protein synthesis; and it does the same thing for some commensal (friendly) bacteria, but since they are in different stages of replication, the drug does not completely eliminate them. The most prevalent ones (lactobacilli and bifidobacteria) may even take over the ecological niches and prosper. Several trials, including a 2016 study from Acosta, et al. (2), show how rifaximin — quite unsurprisingly — changes the gut microbiota (for example, causing a decrease in overall richness).
Positive effects on the brain
Antibiotics are a go-to treatment in cases where a bacterial infection implicates the brain: say, in meningitis. But it may be the case that the ‘eubiotic’ actions of rifaximin relate to different brain-related conditions. Take irritable bowel syndrome (IBS), for instance (3): Rifaximin can help people with IBS (4), but it’s not yet certain whether the observed clinical benefits derive from how rifaximin eliminates unwanted bacteria or from how it fosters the growth of beneficial bacteria.
A new study (5) also showed a somewhat unexpected effect of rifaximin in healthy individuals. Using magnetoencephalography (MEG) in a human pilot study, led by Dr. Paul Enck of University Hospital Tübingen (Germany) found that rifaximin modified aspects of brain functioning in healthy people in the context of social stress. It came as a surprise that the antibiotics had a positive effect on mood — similar to effects previously shown for specific probiotics.
Negative effects on the brain
Reports of psychosis induced by systemic antibiotics (not rifaximin) have existed for several decades: that is, some individuals who take antibiotics to address a bacterial infection experience an episode in which thought and emotions are disconnected with external reality. This phenomenon, which was once considered a rare side effect of antibiotic use, acquires new significance in light of the microbiota-gut-brain axis. Could it be evidence that microbiota are directly affecting aspects of mental functioning?
The true prevalence of antibiotic-induced psychosis is, unfortunately, difficult to estimate. For example, urinary tract infections in hospitalized elderly adults is often associated with delirium, dementia, and other neuropsychiatric disorders (6) — and in infections such as these, when antibiotics are truly required, any effects related to the central nervous system are often attributed to the primary disease, and not to the treatment of it.
Recurrent antibiotic exposure, meanwhile, is associated with an increased risk for depression and anxiety (7) — an intriguing finding, especially as probiotics have shown promise as an adjunctive treatment for depression (8), though not for anxiety (9).
Where are we now?
Martin Blaser (10) laid out the conflicting activities of antibiotics with regard to the gut microbiota: the drugs: (a) treat individual infections, and (b) prevent the spread of the pathogenic bacteria; but on the other hand, they (c) create antibiotic resistance, and (d) may exert negative effects on health via collateral damage on the microbiota. To the last point, research is ongoing about what these health effects might be — but they at least theoretically could pertain to brain health.
Incidentally, another recent finding shows it might not just be antibiotics having these good, bad, and ugly effects on the gut microbiota: researchers recently showed that up to 25% of other drugs — including painkillers, blood pressure lowering drugs, or cancer medicines — potentially alter the gut microbiota (11), and indirectly contribute to antibiotic resistance (12). While the effects on health need to be investigated in more detail, it may eventually link back to our mental well-being.
But medically, we’re left where we started: antibiotics are excellent for treating bacterial infections that affect the brain and other organs. And the other interesting data support the conjecture that a microbiota-gut-brain axis exists in humans as we know it does in mice.
The task ahead: to better characterize the effects of different antibiotics on the gut ecosystem and attempt to understand the mechanisms of how they could affect brain function, either positively or negatively. This might enable the development of psychobiotics that would zero in on brain function with positive effects, either in health or disease, while avoiding the collateral damage that antibiotics inflict on the rest of the gut ecosystem.
This is part 2 of a series covering “microbiota” provided by Paul Enck from the Tübingen University Hospital and science writer Kristina Campbell. Continuous updates on microbiota research can be found at www.gutmicrobiotaforhealth.com.
- Dethlefsen L, Huse S, Sogin ML, Relman DA. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 2008;6(11):e280.
- Acosta A, Camilleri M, Shin A, Linker Nord S, O’Neill J, Gray AV, Lueke AJ, Donato LJ, Burton DD, Szarka LA, Zinsmeister AR, Golden PL, Fodor A. Effects of Rifaximin on Transit, Permeability, Fecal Microbiome, and Organic Acid Excretion in Irritable Bowel Syndrome. Clin Transl Gastroenterol. 2016; 7(5): e173.
- De Palma G, Collins SM, Bercik P. The microbiota-gut-brain axis in functional gastrointestinal disorders. Gut Microbes. 2014; 5(3):419-429.
- Menees SB, Maneerattannaporn M, Kim HM, Chey WD. The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol. 2012;107(1):28-35;
- Wang H, Braun C, Enck, P. Effects of Rifaximin on Central Responses to Social Stress—a Pilot Experiment. Neurotherapeutics. 2018. doi: 10.1007/s13311-018-0627-2. [Epub ahead of print]
- Chae JHJ & Miller BJ. Beyond Urinary Tract Infections (UTIs) and Delirium: A Systematic Review of UTIs and Neuropsychiatric Disorders. Journal of Psychiatric Practice. 2015; 21(6):402–411.
- Lurie I, Yang Y-X, Haynes K, Mamtani R, Boursi B. Antibiotic Exposure and the Risk for Depression, Anxiety, or Psychosis: A Nested Case-Control Study. J Clin Psychiatry. 2015; 76(11):1522–1528.
- Wallace CJK & Milev R. The effects of probiotics on depressive symptoms in humans: a systematic review. Ann Gen Psychiatry. 2017; 16:14.
- Reis DJ, Ilardi SS, Punt SEW. The anxiolytic effect of probiotics: A systematic review and meta-analysis of the clinical and preclinical literature. PLOSOne. 2018;13:e0199041.
- Blaser MJ. Antibiotic use and its consequences for the normal microbiome. Science. 2016; 352(6285):544-545.
- Le Bastard Q, Al-Ghalith GA, Grégoire M, Chapelet G, Javaudin F, Dailly E, Batard E, Knights D, Montassier E. Systematic review: human gut dysbiosis induced by non-antibiotic prescription medications. Alimentary Pharmacology and Therapeutics. 2018; 47(3):332-345.
- Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, Brochado AR, Fernandez KC, Dose H, Mori H, Patil KR, Bork P & Typas A. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018; 555:623–628.