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Background: The aim of this study was to identify the differences in diversity, composition, and function of the gut microbiota between tuberculosis (TB) patients and healthy controls (HCs)., Methods: A cross-sectional study was conducted in three cities of China. Stool samples from 94 treatment-naive TB patients and 62 HCs were analyzed by 16S rRNA gene sequencing. TB patients were further divided into antibiotic-free and antibiotic-exposure according to their use of non-specific antibiotics before the TB diagnosis., Results: Compared with HCs, antibiotic-free TB patients presented a different gut microbial community (P < 0.005) and decreased Shannon diversity (P < 0.005). Among TB patients, the relative abundances of short-chain fatty acid (SCFA)-producing genera such as Lachnospiraceae ND3007 group (log2(FC) = -2.74) were lower, while several conditional pathogen-related genera such as Enterococcus (log2(FC) = 12.05) and Rothia (log2(FC) = 6.322) were at higher levels. In addition, 41% of patients received antibiotics before TB diagnosis. Antibiotic exposure was correlated with an additional reduction in α diversity and depletion of SCFA-producing bacteria. Microbial functional analysis revealed that the biosynthesis capacity of amino acids and fatty acids was lower among TB patients compared to HCs., Conclusions: Significant alterations in gut microbiota composition and metabolic pathways of TB patients were observed. Antibiotic exposure could alter the gut microbiota of TB patients, which should be considered in anti-TB treatment., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The gastrointestinal microenvironment, dominated by dietary compounds and the commensal bacteria, is a major driver of intestinal CD4 + T helper (Th) cell differentiation. Dietary compounds can be sensed by nuclear receptors (NRs) that consequently exert pleiotropic effects including immune modulation. Here, we found that under homeostatic conditions the NR Liver X receptor (LXR), a sensor of cholesterol metabolites, regulates RORγt + CD4 T cells in the intestine draining mesenteric lymph node (MLN). While LXR activation led to a decrease, LXR-deficiency resulted in an increase in MLN Th17 and RORγt + Tregs. Mechanistically, LXR signaling in CD11c + myeloid cells was required to control RORγt + Treg. By contrast, modulation of MLN Th17 was independent of LXR signaling in either immune or epithelial cells. Of note, horizontal transfer of microbiota between LXRα -/- and WT mice was sufficient to only partially increase MLN Th17 in WT mice. Despite LXRα deficiency resulted in an increased abundance of Ruminococcaceae and Lachnospiraceae bacterial families compared to littermate controls, microbiota ablation (including SFB) was not sufficient to dampen LXRα-mediated expansion of MLN Th17. Altogether, our results suggest that LXR modulates RORγt + Treg and Th17 cells in the MLN through distinct mechanisms.