Antibiotics Can Reshape Host Immunity and Circadian Rhythms Without Any Microbes (Oct 2026, mice) Disentangling microbiota-dependent and -independent impacts of antibiotics on host physiology Antibiotics

[Michael Harrop]

https://bioengineer.org/antibiotics-can-reshape-host-immunity-and-circadian-rhythms-without-any-microbes/
https://www.nature.com/articles/s41564-026-02453-w

Using a combination of germ-free mice, metagenomic sequencing, transcriptomics and a purpose-built computational tool called CompoRes, the researchers demonstrate that vancomycin, one of the most widely used antibiotics in clinical practice, directly rewires host physiology in ways that persist even when no microbes are present at all.

The central challenge the team confronted is one that has long frustrated microbiome researchers. When an antibiotic treatment changes both the composition of the gut microbiota and the expression of host genes, it is extraordinarily difficult to determine which host changes are caused by the microbial shifts and which are caused by the drug acting directly on host cells

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They treated specific pathogen-free mice with four commonly used antibiotics—vancomycin, ampicillin, metronidazole and neomycin—either individually or in combination, and delivered them through three different routes: oral gavage, intraperitoneal injection and intravenous injection. Mice were treated twice daily for three and a half days, mimicking the shorter antibiotic regimens now favoured in clinical practice. Stool samples were collected before and after treatment to profile the microbiota using 16S rRNA amplicon sequencing, while colonic tissue was harvested for RNA sequencing to capture the host transcriptional response.

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One of the most surprising findings concerned vancomycin itself. This is a large, hydrophilic molecule that should cross the gut mucosa poorly, which is precisely why it is given orally to treat intestinal infections like Clostridioides difficile. Yet when the researchers administered vancomycin systemically by intraperitoneal injection, mass spectrometry confirmed that detectable amounts of the drug reached the small intestinal and colonic lumen.

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This indicates that IV antibiotics are still harmful to gut bacteria.

clinically relevant pairs such as vancomycin plus metronidazole produced non-additive effects on the host that could not be predicted from the single-drug responses

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This preservation of the vancomycin response across evolutionarily distant organisms suggests that the antibiotic taps into an ancient cellular stress pathway, one that links metabolism, circadian biology and immunity through mechanisms that operate independently of any microbe.

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Abstract​

Antibiotics are believed to affect host physiology by altering the gut microbiota. However, it remains unclear which effects of antibiotics are microbiota dependent and which are microbiota independent. Here we present a resource encompassing host and microbiota responses to antibiotic treatment and a computational tool with which to analyse them.

Metagenomic and transcriptomic analyses of conventional and germ-free mice revealed that antibiotic administration routes and their combinations affect host and microbiota responses. We developed CompoRes—a computational tool that distinguishes the microbiota-independent impact of antibiotic-induced perturbations, revealing that antibiotics directly impact host physiology.

We found that diurnal expression of major histocompatibility complex class II in the mouse colon is controlled by glucose via feeding. This pattern was lost during antibiotic treatment as vancomycin altered feeding behaviour in a microbiota-independent and evolutionarily conserved manner.

Together, our study establishes a direct, non-microbial pathway by which antibiotics reshape host immunity and circadian physiology.

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