Gut microbiota #23

Gut microbiota regulates insomnia-like behaviors via gut-brain axis

While sleep is known to be in bidirectional connection with the gut microbiota, the underlying mechanisms have been largely unknown. However, it seems that gut-derived metabolites can affect some behaviors in the host, such as anxiety-like behavior. Additionally, some clinical studies have reported alterations in the gut microbiota in individuals with chronic insomnia.

Wang et al. sought to clarify how the gut microbiota could shape sleep behavior. For this purpose, they studied sleepwake behavior in specific pathogen-free (SPF) and germ-free (GF) mice. GF mice are free of all microorganisms, including those that are typically found
in the gut, while SPF mice are free of a specific list of pathogens by routine testing The recording of 24-h ambulatory electroencephalogram (EEG)-electromyogram (EMG) showed that GF mice had decreased time of wakefulness and REM sleep compared to SPF mice. To identify specific metabolites that are involved in gut microbiota-mediated sleep-related behavioral changes, the authors studied feces and hypothalamus tissue samples using targeted metabolomics. It was found that gut microbiota-derived short chain fatty acid, butyrate was the most significant modulator of sleep behavior. Further, oral administration of tributyrin, a precursor of butyrate administration led to a significant 39.50% reduction of wakefulness and 77.99% increase in REM sleep. The underlying mechanism seems to be that tributyrin inhibits lateral hypothalamus orexin neuron activity.

By studying humans, the authors also observed a decrease in 39 butyrate producers in insomnia patients compared with controls. Ultimately, the authors also showed that GF mice that received microbiota from insomnia patients exhibited sleep disturbances, which were recovered by butyrate supplementation. To conclude, the study highlights the potential of butyrate as a therapeutic agent to mitigate sleep disorders.

^{Wang Z, Wang Z, Lu T, et al. Gut microbiota regulate insomnia-like behaviors via gut-brain metabolic axis. Mol Psychiatry 2025; 30: 2597-611.}

Campylobacter jejuni-derived cytolethal distending toxin promotes colorectal cancer metastasis

Several pro-tumorigenic bacteria, such as genotoxic Escherichia coli (E. coli), and enterotoxigenic Bacteroides fragilis (B. fragilis), have been associated with the promotion of cancer metastasis. In addition, cytolethal distending toxin (CDT)-producing Campylobacter have been found to be enriched in tumor tissues compared to normal adjacent tissues. However, the connection between genotoxin-producing bacteria and cancer metastasis is poorly understood. The authors of this study obtained primary colorectal cancer (CRC) tissues from 34 chemotherapy-naive patients (TNM stage I and IIA) with distant metastasis within 3 years (metastasis group) and 37 patients who remained metastasis-free (non-metastasis group) during 3 years’ follow-up. They found a significant enrichment of Campylobacter in the metastasis group, and that the patients with intratumor Campylobacter had significantly poorer prognosis. They also confirmed their findings using a validation cohort and a publicly available database. CDT is the major virulence factor responsible for Campylobacter-mediated pathogenesis, and in the host cells it induces DNA damage and cell-cycle arrest. The metastasis group expressed more bioactive CDT subunit cdtB and Campylobacter invasion antigen B (ciaB), a virulence factor specific to C. jejuni. In vitro, C. jejuni significantly increased cell migration and invasion ability of various CRC cell lines. In one mice model, administration of C. jejuni increased migration and invasion ability as compared with controls, and in another it significantly increased liver metastasis. Altogether, these findings prove that intestinal C. jejuni promotes CRC metastasis. Interestingly, the pro-metastasis ability was attenuated in the absence of CdtB. Mechanistically, it seems that CDT activated JAK-STAT signaling pathway leading to expression of MMP genes and tumor metastasis.

^{He Z, Yu J, Gong J, et al. Campylobacter jejuniderived cytolethal distending toxin promotes colorectal cancer metastasis. Cell Host Microbe 2024; 32: 2080-91.}

Quiescent Crohn’s disease, sulfidogenic microbes and sulfur metabolic pathways: the functional consequences

In the quiescent inflammatory bowel disease, there is no active inflammation. However, the patients report persistent symptoms, especially with Crohn’s disease (CD). The microbiome is shown to be altered in quiescent CD patients with persistent symptoms (qCD + S). Specifically, the patients with qCD + S have been shown to have more sulfidogenic microbes and microbial gene pathways of sulfur metabolism. Nevertheless, the functional significance of these changes has remained unknown. In this multicenter observational study,
metagenomic shotgun sequencing and metabolomics profiling of the qCD + S patients’ feces were performed. Additionally, patient with active Crohn’s Disease (aCD), with quiescent Crohn’s disease without persistent GI symptoms (qCD-S) and with diarrhea predominant irritable bowel syndrome (IBS-D) were included and compared with qCD + S.

The authors report that fecal metabolites within cysteine/methionine, bile acid, and fatty acid pathways were among the most differentially abundant in qCD + S patients relative to other groups. The differences persisted even when inflammation, i.e., calprotectin levels were lower. Glycine, serine, and threonine; glutathione; and cysteine and methionine were the most enriched pathways in
qCD + S, and these are important sulfur metabolic pathways in the human gut. In addition to metabolites, many bacterial sulfur metabolic genes were dysregulated in qCD + S. By integrating the metagenomic and metabolomic datasets, the authors further found that taurine and hypotaurine; nicotinate and nicotinamide; cysteine and methionine; and glycine, serine, and threonine were the top metabolic pathways associated with the enriched microbes in qCD + S. AS elevated H2S concentrations inhibit mitochondrial
functions of the host, the results suggest links between microbial-derived metabolites and host mitochondrial function in patients with qCD + S. Altogether, the results of this study suggest that strategies to decrease sulfidogenic microbes and associated sulfur metabolic pathways could represent a novel strategy to improve quality of life in quiescent Crohn’s disease with persistent symptoms.

^{Golob J, Rao K, Berinstein JA, et al. Why Symptoms Linger in Quiescent Crohn’s Disease: Investigating the Impact of Sulfidogenic Microbes and Sulfur Metabolic Pathways. Inflamm Bowel Dis 2025; 31: 763-76.}