Clinical Context

Healthcare professionals have experience in describing the potential negative consequences of inappropriate antibiotic use, including adverse events and a higher risk for incident resistant bacteria. However, many clinicians do not consider the potential long-term health effects of antibiotic prescriptions, which might be related to changes in the microbiome. A previous study by Petrelli and colleagues provides a systematic review of the relationship between antibiotic use and incident cancer. Their results were published in the August 2019 issue of Cancers.^[1]

The researchers found 25 observational studies of the risk for cancer after antibiotic prescriptions, which included a total of nearly 8 million people. Overall, the odds ratio (OR) for incident cancer in comparing individuals who received antibiotics vs those who did not was 1.18 (95% confidence interval [CI], 1.12-1.24). The researchers found that antibiotic use was associated with higher risks for lung cancer, lymphomas, pancreatic cancer, renal cell carcinoma, and multiple myeloma. Beta lactams, cephalosporins, macrolides, and quinolones were all associated with a higher risk for cancer.

Previous research has found a link between antibiotic use and the risk for neuropsychiatric illness, but data on antibiotic use and cognitive decline are lacking. The current study addresses this issue.

Study Synopsis and Perspective

A new study, published online March 23 in PLOS ONE, suggests that prolonged use of antibiotics in midlife is related to cognitive decline several years down the road.^[2]

For the study, scientists paired self-reported antibiotic use of more than 14,000 middle-aged nurses with outcomes on neuropsychological tests conducted 7 years later. The results revealed that those nurses who received antibiotics for at least 2 months during a period of 4 years had lower scores on tasks involving memory, learning, attention, and psychomotor speed. Overall, the negative effects of antibiotics on cognition were comparable to those caused by 3 to 4 years of aging.

Although Andrew Chan, MD, MPH, a gastroenterologist at Harvard Medical School who co-led the study, does not preclude the possibility that the antibiotics might have acted directly on the brain, he told Medscape Medical News that his leading hypothesis is that the drugs had disruptive effects on the gut microbiota. Indeed, research on mice shows that antibiotics such as ampicillin, although undetectable in the brain, are linked to gut dysbiosis and cognitive impairment.^[3]

A previous study on humans showed that those afflicted with Alzheimer's dementia had altered gut microbiome compared with healthy volunteers.^[4] They had, for instance, more bacteria from the genus Bacteroides and less of those from the genus Bifidobacterium. Other research has revealed changes in diversity and decreased richness of gut microbes in several other conditions, from Crohn's disease and autism spectrum disorder to multiple sclerosis and Parkinson's disease.

"Numerous animal studies, and some human studies as well, have shown that gut dysbiosis is linked to cognitive impairment as well as brain alterations," Viktoriya Nikolova, MRes, MSc, a PhD student and researcher at King's College London, told Medscape Medical News when asked for independent comment. Antibiotics can cause changes in the microbiome that may last months or even years.^[5,6]

There are many ways in which the trillions of microbes that reside in the human gut may affect the mind. They can hack into the vagus nerve, release neurotransmitters into the blood that crosses into the brain and interact with immune cells.

According to Dr Chan, "antibiotics and the disruption of the gut microbiome may trigger a chronic state of inflammation that predisposes people to develop cognitive decline." Such inflammation could be caused, for instance, by bacterial endotoxins, which are potentially toxic compounds released by gram-negative bacteria, such as Bacteroides, which are found in abundance in the guts of patients with Alzheimer's disease.

Experiments show that injecting mice with endotoxins can lead to greater formation of amyloid plaques, which are insoluble clumps of misfolded proteins that form between nerve cells in the brain, potentially blocking cell-to-cell signaling.^[7] Rodent research suggests that antibiotics can indeed affect the formation of amyloid plaques.^[8]

Although the new study in PLOS ONE adds to our knowledge of the potential negative effects of antibiotics on brain health, Dr Chan believes that it is too early to make any recommendations about whether people should avoid antibiotics specifically out of concern regarding dementia.

He does believe, however, that the study "does provide some additional rationale for being careful about how one uses antibiotics." Considering that the Centers for Disease Control and Prevention estimates that at least 30% of outpatient antibiotic prescriptions in the US are unnecessary, that is certainly a cause for concern.^[9]

The study was independently supported. Dr Chan and Dr Nikolova have disclosed no relevant financial relationships.

PLoS One. Published online March 23, 2022.

Clinical Implications

• In a previous systematic review of observational studies, antibiotic use was associated with a significant 18% increase in the risk for subsequent cancer, including lymphoma, lung cancer, pancreatic cancer, and multiple myeloma. Multiple classes of antibiotics were associated with a higher risk for cancer.
• The current study suggests that antibiotic use during middle age among women can advance the rate of cognitive decline by the equivalent of 3 to 4 years of age.
• Implications for the healthcare team: Antibiotic use may be associated with significant negative long-term health outcomes, including cognitive decline among women. Members of the healthcare team should use antibiotic stewardship to ensure unnecessary antibiotic prescribing.

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