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18 páginas, 11 figuras, 3 tablas. Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2019.02464/full#supplementary-material, The administration of a high fat content diet is an accelerating factor for metabolic syndrome, impaired glucose tolerance, and early type 2 diabetes. The present study aims to assess the impact of a high fat diet on tuberculosis progression and microbiota composition in an experimental animal model using a C3HeB/FeJ mouse strain submitted to single or multiple consecutive aerosol infections. These models allowed us to study the protection induced by Bacillus Calmette-Guérin vaccination as well as by the natural immunity induced by chemotherapy after a low dose Mycobacterium tuberculosis infection. Our results show that a high fat diet is able to trigger a pro-inflammatory response, which results in a faster progression toward active tuberculosis and an impaired protective effect of BCG vaccination, which is not the case for natural immunity. This may be related to dysbiosis and a reduction in the Firmicutes/Bacteroidetes ratio in the gut microbiota caused by a decrease in the abundance of the Porphyromonadaceae family and, in particular, the Barnesiella genus. It should also be noted that a high fat diet is also related to an increase in the genera Alistipes, Parasuterella, Mucispirillum, and Akkermansia, which have previously been related to dysbiotic processes. As diabetes mellitus type 2 is a risk factor for developing tuberculosis, these findings may prove useful in the search for new prophylactic strategies for this population subset., This work was supported by the European Commission Horizon 2020 research and innovation program under grant agreement TBVAC2020 No. 643381, European Research Council research grant 638553-TB-ACCELERATE and Ministerio de Economía y Competitividad (Spanish government) research grant SAF2017-92345- EXP (to IC). CV has a project Servet II contract funded by the Instituto de Salud Carlos III (ISCIII, CPII 18/00031). LA received an Improvement and Mobility Program grant from the Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES). GG contract was funded by Ministerio de Economia y Competitividad (Spanish Government) (BES-2014-071066). PC contract was funded by the Instituto de Salud Carlos III (IFI14/00015). The Experimental Tuberculosis Unit is accredited by the Catalan Agency for Management of University and Research Grants with code 2017 SGR500 and the IGTP is a member of the CERCA network of institutes. The funders played no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

An excessive, non-productive host-immune response is detrimental in active, chronic tuberculosis (TB) disease as it typically leads to tissue damage. Given their anti-inflammatory effect, non-steroidal anti-inflammatory drugs can potentially attenuate excessive inflammation in active TB disease. As such, we investigated the prophylactic and therapeutic effect of low-dose aspirin (LDA) (3 mg/ kg/ day), either alone or in combination with common anti-TB treatment or BCG vaccination, on disease outcome in an experimental murine model of active TB. Survival rate, bacillary load (BL) in lungs, and lung pathology were measured. The possible mechanism of action of LDA on the host's immune response was also evaluated by measuring levels of CD5L/AIM, selected cytokines/ chemokines and other inflammatory markers in serum and lung tissue. LDA increased survival, had anti-inflammatory effects, reduced lung pathology, and decreased bacillary load in late-stage TB disease. Moreover, in combination with common anti-TB treatment, LDA enhanced survival and reduced lung pathology. Results from the immunological studies suggest the anti-inflammatory action of LDA at both a local and a systemic level. Our results showed a systemic decrease in neutrophilic recruitment, decreased levels of acute-phase reaction cytokines (IL-6, IL-1 beta, and TNF-alpha) at late stage and a delay in the decrease in T cell response (in terms of IFN-gamma, IL-2, and IL-10 serum levels) that occurs during the course of Mycobacterium tuberculosis infection. An antiinflammatory milieu was detected in the lung, with less neutrophil recruitment and lower levels of tissue factor. In conclusion, LDA may be beneficial as an adjunct to standard anti-TB treatment in the later stage of active TB by reducing excess, non-productive inflammation, while enhancing Th1-cell responses for elimination of the bacilli.