Nature Microbiology最新文献

Intestinal crypts harbour a specific microbiota but whether and how these bacteria regulate intestinal stem cells (ISCs) or influence colorectal cancer (CRC) development is unclear. Here we screened crypt-resident bacteria in organoids and found that indole acetic acid (IAA) secreted by Acinetobacter radioresistens inhibits ISC turnover. A. radioresistens inhibited cellular proliferation in tumour slices from CRC patients and inhibited intestinal tumorigenesis and spheroid initiation in APC^Min/+ mice. Targeted clearance of A. radioresistens from colonic crypts using bacteriophage increased EphB2 expression and consequently promoted cellular proliferation, ISC turnover and tumorigenesis in mouse models of CRC. The protective effects of A. radioresistens were abrogated upon deletion of trpC to prevent IAA production, or upon intestine-specific aryl hydrocarbon receptor (AhR) knockout, identifying an IAA-AhR-Wnt-β-catenin signalling axis that promotes ISC homeostasis. Our findings reveal a protective role for an intestinal crypt-resident microbiota member in tumorigenesis.

Correction to: Nature Microbiology https://doi.org/10.1038/s41564-024-01820-9, published online 22 October 2024.

Host immunity and commensal bacteria synergistically maintain intestinal homeostasis and mediate colonization resistance against pathogens. However, the molecular and cellular mechanisms remain unclear. Here, with a mouse infection model of Citrobacter rodentium, a natural mouse intestinal pathogen that mimics human enteropathogenic Escherichia coli and enterohaemorrhagic Escherichia coli, we find that group 3 innate lymphoid cells (ILC3s) can protect the host from infection by regulating gut microbiota. Mechanistically, ILC3s can control gut dysbiosis through IL-22-dependent regulation of intestinal galactosylation in mice. ILC3 deficiency led to an increase in intestinal galactosylation and the expansion of commensal Akkermansia muciniphila in colonic mucus. The increased A. muciniphila and A. muciniphila-derived metabolic product succinate further promoted the expression of pathogen virulence factors tir and ler, resulting in increased susceptibility to C. rodentium infection. Together, our data reveal a mechanism for ILC3s in protecting against pathogen infection through the regulation of intestinal glycosylation and gut microbiota metabolism.

Mpox is a zoonotic disease endemic to Central and West Africa. Since 2022, two human-adapted monkeypox virus (MPXV) strains have caused large outbreaks outside these regions. Tecovirimat is the most widely used drug to treat mpox. It blocks viral egress by targeting the viral phospholipase F13; however, the structural details are unknown, and mutations in the F13 gene can result in resistance against tecovirimat, raising public health concerns. Here we report the structure of an F13 homodimer using X-ray crystallography, both alone (2.1 Å) and in complex with tecovirimat (2.6 Å). Combined with molecular dynamics simulations and dimerization assays, we show that tecovirimat acts as a molecular glue that promotes dimerization of the phospholipase. Tecovirimat resistance mutations identified in clinical MPXV isolates map to the F13 dimer interface and prevent drug-induced dimerization in solution and in cells. These findings explain how tecovirimat works, allow for better monitoring of resistant MPXV strains and pave the way for developing more potent and resilient therapeutics.

Correction to: Nature Microbiology https://doi.org/10.1038/s41564-024-01914-4, published online 3 February 2025.

More effective treatments are needed for impaired fasting glucose or glucose intolerance, known as prediabetes. Sulforaphane is an isothiocyanate that reduces hepatic gluconeogenesis in individuals with type 2 diabetes and is well tolerated when provided as a broccoli sprout extract (BSE). Here we report a randomized, double-blind, placebo-controlled trial in which drug-naive individuals with prediabetes were treated with BSE (n = 35) or placebo (n = 39) once daily for 12 weeks. The primary outcome was a 0.3 mmol l⁻¹ reduction in fasting blood glucose compared with placebo from baseline to week 12. Gastro-intestinal side effects but no severe adverse events were observed in response to treatment. BSE did not meet the prespecified primary outcome, and the overall effect in individuals with prediabetes was a 0.2 mmol l⁻¹ reduction in fasting blood glucose (95% confidence interval −0.44 to −0.01; P = 0.04). Exploratory analyses to identify subgroups revealed that individuals with mild obesity, low insulin resistance and reduced insulin secretion had a pronounced response (0.4 mmol l⁻¹ reduction) and were consequently referred to as responders. Gut microbiota analysis further revealed an association between baseline gut microbiota and pathophysiology and that responders had a different gut microbiota composition. Genomic analyses confirmed that responders had a higher abundance of a Bacteroides-encoded transcriptional regulator required for the conversion of the inactive precursor to bioactive sulforaphane. The abundance of this gene operon correlated with sulforaphane serum concentration. These findings suggest a combined influence of host pathophysiology and gut microbiota on metabolic treatment response, and exploratory analyses need to be confirmed in future trials. ClinicalTrials.gov registration: NCT03763240.

Aliphatic polyamides, or nylons, are widely used in the textile and automotive industry due to their high durability and tensile strength, but recycling rates are below 5%. Chemical recycling of polyamides is possible but typically yields mixtures of monomers and oligomers which hinders downstream purification. Here, Pseudomonas putida KT2440 was engineered to metabolize C₆-polyamide monomers such as 6-aminohexanoic acid, ε-caprolactam and 1,6-hexamethylenediamine, guided by adaptive laboratory evolution. Heterologous expression of nylonases also enabled P. putida to metabolize linear and cyclic nylon oligomers derived from chemical polyamide hydrolysis. RNA sequencing and reverse engineering revealed the metabolic pathways for these non-natural substrates. To demonstrate microbial upcycling, the phaCAB operon from Cupriavidus necator was heterologously expressed to enable production of polyhydroxybutyrate (PHB) from PA6 hydrolysates. This study presents a microbial host for the biological conversion, in combination with chemical hydrolysis, of polyamide monomers and mixed polyamids hydrolysates to a value-added product.

Urinary tract infections (UTIs) are compounded by antimicrobial resistance, which increases the risk of UTI recurrence and antibiotic treatment failure. This also intensifies the burden of disease upon healthcare systems worldwide, and of morbidity and mortality. Uropathogen adhesion is a critical step in the pathogenic process, as has been mainly shown for Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus agalactiae, Proteus, Enterococcus and Staphylococcus species. Although many bacterial adhesion molecules from these uropathogens have been described, our understanding of their contributions to UTIs is limited. Here we explore knowledge gaps in the UTI field, as we discuss the broader repertoire of uropathogen adhesins, including their role beyond initial attachment and the counter-responses of the host immune system. Finally, we describe the development of therapeutic approaches that target uropathogenic adhesion strategies and provide potential alternatives to antibiotics.

Enveloped viruses such as influenza A virus (IAV) often produce a mixture of virion shapes, ranging from 100 nm spheres to micron-long filaments. Spherical virions use fewer resources, while filamentous virions resist cell-entry pressures such as antibodies. While shape changes are believed to require genetic adaptation, the mechanisms of how viral mutations alter shape remain unclear. Here we find that IAV dynamically adjusts its shape distribution in response to environmental pressures. We developed a quantitative flow virometry assay to measure the shape of viral particles under various infection conditions (such as multiplicity, replication inhibition and antibody treatment) while using different combinations of IAV strains and cell lines. We show that IAV rapidly tunes its shape distribution towards spheres under optimal conditions but favours filaments under attenuation. Our work demonstrates that this phenotypic flexibility allows IAV to rapidly respond to environmental pressures in a way that provides dynamic adaptation potential in changing surroundings.

The gut microbiome modulates immunotherapy treatment responses, and this may explain why immune checkpoint inhibitors, such as anti-PD-1, are only effective in some patients. Previous studies correlated lipopolysaccharide (LPS)-producing gut microbes with poorer prognosis; however, LPS from diverse bacterial species can range from immunostimulatory to inhibitory. Here, by functionally analysing faecal metagenomes from 112 patients with melanoma, we found that a subset of LPS-producing bacteria encoding immunostimulatory hexa-acylated LPS was enriched in microbiomes of clinical responders. In an implanted tumour mouse model of anti-PD-1 treatment, microbiota-derived hexa-acylated LPS was required for effective anti-tumour immune responses, and LPS-binding antibiotics and a small-molecule TLR4 antagonist abolished anti-PD-1 efficacy. Conversely, oral administration of hexa-acylated LPS to mice significantly augmented anti-PD-1-mediated anti-tumour immunity. Penta-acylated LPS did not improve anti-PD-1 efficacy in vivo and inhibited hexa-acylated LPS-induced immune activation in vitro. Microbiome hexa-acylated LPS therefore represents an accessible predictor and potential enhancer of immunotherapy responses.