Objective The significance of the liver-microbiome axis has been increasingly recognised as a major modulator of autoimmunity. The aim of this study was to take advantage of a large well-defined corticosteroids treatment-naïve group of patients with autoimmune hepatitis (AIH) to rigorously characterise gut dysbiosis compared with healthy controls. Design We performed a cross-sectional study of individuals with AIH (n=91) and matched healthy controls (n=98) by 16S rRNA gene sequencing. An independent cohort of 28 patients and 34 controls was analysed to validate the results. All the patients were collected before corticosteroids therapy. Results The gut microbiome of steroid treatment-naïve AIH was characterised with lower alpha-diversity (Shannon and observed operational taxonomic units, both p<0.01) and distinct overall microbial composition compared with healthy controls (p=0.002). Depletion of obligate anaerobes and expansion of potential pathobionts including Veillonella were associated with disease status. Of note, Veillonella dispar , the most strongly disease-associated taxa (p=8.85E–8), positively correlated with serum level of aspartate aminotransferase and liver inflammation. Furthermore, the combination of four patients with AIH-associated genera distinguished AIH from controls with an area under curves of approximately 0.8 in both exploration and validation cohorts. In addition, multiple predicted functional modules were altered in the AIH gut microbiome, including lipopolysaccharide biosynthesis as well as metabolism of amino acids that can be processed by bacteria to produce immunomodulatory metabolites. Conclusion Our study establishes compositional and functional alterations of gut microbiome in AIH and suggests the potential for using gut microbiota as non-invasive biomarkers to assess disease activity.
We present the measurements of all-particle energy spectrum and mean logarithmic mass of cosmic rays in the energy range of 0.3-30 PeV using data collected from LHAASO-KM2A between September 2021 and December 2022, which is based on a nearly composition-independent energy reconstruction method, achieving unprecedented accuracy. Our analysis reveals the position of the knee at 3.67±0.05±0.15 PeV. Below the knee, the spectral index is found to be -2.7413±0.0004±0.0050, while above the knee, it is -3.128±0.005±0.027, with the sharpness of the transition measured with a statistical error of 2%. The mean logarithmic mass of cosmic rays is almost heavier than helium in the whole measured energy range. It decreases from 1.7 at 0.3 PeV to 1.3 at 3 PeV, representing a 24% decline following a power law with an index of -0.1200±0.0003±0.0341. This is equivalent to an increase in abundance of light components. Above the knee, the mean logarithmic mass exhibits a power law trend towards heavier components, which is reversal to the behavior observed in the all-particle energy spectrum. Additionally, the knee position and the change in power-law index are approximately the same. These findings suggest that the knee observed in the all-particle spectrum corresponds to the knee of the light component, rather than the medium-heavy components.
The ultra-high-energy (UHE) gamma-ray source 1LHAASO J0007+7303u is positionally associated with the composite SNR CTA1 that is located at high Galactic Latitude $b\approx 10.5^\circ$. This provides a rare opportunity to spatially resolve the component of the pulsar wind nebula (PWN) and supernova remnant (SNR) at UHE. This paper conducted a dedicated data analysis of 1LHAASO J0007+7303u using the data collected from December 2019 to July 2023. This source is well detected with significances of 21$\sigma$ and 17$\sigma$ at 8$-$100 TeV and $>$100 TeV, respectively. The corresponding extensions are determined to be 0.23$^{\circ}\pm$0.03$^{\circ}$ and 0.17$^{\circ}\pm$0.03$^{\circ}$. The emission is proposed to originate from the relativistic electrons and positrons accelerated within the PWN of PSR J0007+7303. The energy spectrum is well described by a power-law with an exponential cutoff function $dN/dE = (42.4\pm4.1)(\frac{E}{20\rm\ TeV})^{-2.31\pm0.11}\exp(-\frac{E}{110\pm25\rm\ TeV})$ $\rm\ TeV^{-1}\ cm^{-2}\ s^{-1}$in the energy range from 8 TeV to 300 TeV, implying a steady-state parent electron spectrum $dN_e/dE_e\propto (\frac{E_e}{100\rm\ TeV})^{-3.13\pm0.16}\exp[(\frac{-E_e}{373\pm70\rm\ TeV})^2]$ at energies above $\approx 50 \rm\ TeV$. The cutoff energy of the electron spectrum is roughly equal to the expected current maximum energy of particles accelerated at the PWN terminal shock. Combining the X-ray and gamma-ray emission, the current space-averaged magnetic field can be limited to $\approx 4.5\rm\ \mu G$. To satisfy the multi-wavelength spectrum and the $\gamma$-ray extensions, the transport of relativistic particles within the PWN is likely dominated by the advection process under the free-expansion phase assumption.
Multiple clinical similarities exist between IgG4-related sclerosing cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC), and while gut dysbiosis has been extensively studied in PSC, the role of the gut microbiota in IgG4-SC remains unknown. Herein, we aimed to evaluate alterations of the gut microbiome and metabolome in IgG4-SC and PSC.We performed 16S rRNA gene amplicon sequencing of faecal samples from 135 subjects with IgG4-SC (n=34), PSC (n=37) and healthy controls (n=64). A subset of the samples (31 IgG4-SC, 37 PSC and 45 controls) also underwent untargeted metabolomic profiling.Compared with controls, reduced alpha-diversity and shifted microbial community were observed in IgG4-SC and PSC. These changes were accompanied by differences in stool metabolomes. Importantly, despite some common variations in the microbiota composition and metabolic activity, integrative analyses identified distinct host-microbe associations in IgG4-SC and PSC. The disease-associated genera and metabolites tended to associate with the transaminases in IgG4-SC. Notable depletion of Blautia and elevated succinic acid may underlie hepatic inflammation in IgG4-SC. In comparison, potential links between the microbial or metabolic signatures and cholestatic parameters were detected in PSC. Particularly, concordant decrease of Eubacterium and microbiota-derived metabolites, including secondary bile acids, implicated novel host-microbial metabolic pathways involving cholestasis of PSC. Interestingly, the predictive models based on metabolites were more effective in discriminating disease status than those based on microbes.Our data reveal that IgG4-SC and PSC possess divergent host-microbe interplays that may be involved in disease pathogenesis. These data emphasise the uniqueness of IgG4-SC.
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