Excess fermentation and lactic acidosis as detrimental functions of the gut microbes in treatment-naive TB patients.

Introduction: The link between gut microbiota and host immunity motivated numerous studies of the gut microbiome in tuberculosis (TB) patients. However, these studies did not explore the metabolic capacity of the gut community, which is a key axis of impact on the host's immunity. Methods: We used deep sequencing of fecal samples from 23 treatment-naive TB patients and 48 healthy donors to reconstruct the gut microbiome's metabolic capacity and strain/species-level content. Results: We show that the systematic depletion of the commensal flora of the large intestine, Bacteroidetes, and an increase in Actinobacteria, Firmicutes, and Proteobacteria such as Streptococcaceae, Erysipelotrichaceae, Lachnospiraceae, and Enterobacteriaceae explains the strong taxonomic divergence of the gut community in TB patients. The cumulative expansion of diverse disease-associated pathobionts in patients reached 1/4 of the total gut microbiota, suggesting a heavy toll on host immunity along with MTB infection. Reconstruction of metabolic pathways showed that the microbial community in patients shifted toward rapid growth using glycolysis and excess fermentation to produce acetate and lactate. Higher glucose availability in the intestine likely drives fermentation to lactate and growth, causing acidosis and endotoxemia. Discussion: Excessive fermentation and lactic acidosis likely characterize TB patients' disturbed gut microbiomes. Since lactic acidosis strongly suppresses the normal gut flora, directly interferes with macrophage function, and is linked to mortality in TB patients, our findings highlight gut lactate acidosis as a novel research focus. If confirmed, gut acidosis may be a novel potential host-directed treatment target to augment traditional TB treatment.

Treatment efficacy of drug-resistant tuberculosis in Bashkortostan, Russia: A retrospective cohort study.

BACKGROUND: Russia, together with other former Soviet Union countries, is characterized by one of the highest burdens of drug-resistant tuberculosis. Published data on the drug-resistant tuberculosis for these countries are limited, and it is not clear whether current treatment regimens remain effective against constantly evolving drug-resistant strains. OBJECTIVES: The aim of the study was to evaluate treatment efficacy of patients with multidrug-resistant (MDR), extensively drug-resistant (XDR) and drug-susceptible (DSTB) tuberculosis in the most populous region of Russia (Bashkortostan) that borders with Central Asia. METHODS: A retrospective cohort study was performed on 436 patients with pulmonary tuberculosis who were enrolled between January 1, 2016, and February 28, 2018, and received treatment according to WHO recommendations. Altogether, 369 patients completed the full course of chemotherapy. Clinical characteristics and treatment outcomes of DSTB, MDR, and XDR-TB patients were analyzed. RESULTS: Of 436 patients, 169 (39%) had XDR-TB, 94 (22%) had MDR-TB and 173 (40%) had DSTB. Half of the MDR-TB patients (44%) and 82% of XDR-TB patients failed treatment. Patients with DSTB had unexpectedly poor treatment efficacy: only 67% had treatment success. We found that most of the MDR isolates from our patients were resistant to all first-line drugs, and a majority of the XDR isolates were resistant to more than 6-7 anti-TB drugs. While this can explain poor treatment efficacy in drug-resistant cases, causes of poor treatment efficacy in DSTB patients remain unclear. Finally, a considerable fraction (46%) of newly diagnosed patients had MDR-TB (27%) and XDR-TB (19%), suggesting that drug-resistant Mtb is being transmitted in the general population. To our best knowledge, this study is the first one to report XDR-TB prevalence in Russia in recent years (2016-2018). CONCLUSIONS: MDR and XDR-TB became more common in recent years and treatment efficacy is declining at the face of more extensive drug resistance. There is evidence for the transmission of resistant strains in the general population, which calls for urgent changes not only in clinical practice but also in measures to prevent spread in the general population.

Psoriasis patients demonstrate HLA-Cw*06:02 allele dosage-dependent T cell proliferation when treated with hair follicle-derived keratin 17 protein.

It is broadly accepted that psoriasis is an immune-mediated disease with a heritable component, but it is not clear what causes inflammation in the skin. Previous research suggests that fragments of the keratin 17 (K17) protein, which are constitutively expressed in hair follicles, could act as autoantigens. In this study, we synthesized the K17 protein from mRNA derived from hair follicles and tested whether it elicited T cell responses depending on the patient genotype at the major susceptibility locus HLA-Cw*06:02. We treated peripheral blood-derived cells with the K17 protein and its short fragments to assess the T cell proliferation response using flow cytometry. Our analyses show a significantly stronger increase in cell proliferation among patients but not in healthy controls. We then examined whether the variation in T cell proliferation correlated with the patient HLA-Cw*06:02 risk genotype. Considering the affected status and patient genotype as two independent predictors, we fitted a linear model and showed that the HLA-Cw*06:02 allele dosage strongly predicted the T cell response. Our study findings suggest that the K17 protein likely acts as an autoantigen in psoriasis and that patients' risk genotype is strongly correlated with the magnitude of the response to this putative autoantigen.