Anaerobic Bacterial Fermentation Products Increase Tuberculosis Risk in Antiretroviral-Drug-Treated HIV Patients

Abstract

Despite the immune-reconstitution with antiretroviral therapy (ART), HIV-infected individuals remain highly susceptible to tuberculosis (TB) and have an enrichment of oral anaerobes in the lung. Products of bacterial anaerobic metabolism, like butyrate and other short chain fatty acids (SCFAs), induce regulatory T cells (Tregs). We tested if SCFAs contribute to poor TB control in a longitudinal cohort of ART treated HIV-infected South Africans. Increase in serum SCFAs was associated with increased TB susceptibility. SCFAs inhibited IFN-γ and IL-17A production in peripheral blood mononuclear cells from HIV-infected ART-treated individuals in response to M. tuberculosis antigen stimulation. Pulmonary SCFAs correlated with increased oral anaerobes such as Prevotella in the lung and with M tuberculosis antigen-induced Tregs. Metabolites from anaerobic bacterial fermentation may therefore increase TB susceptibility by suppressing IFN-γ and IL-17A production during the cellular immune response to M. tuberculosis.

Friends and foes of tuberculosis: modulation of protective immunity

“…Assessment of microbiota in BAL from TB patients revealed specific differences, with Cupriavidus as dominant genus, in lower respiratory tracts . The microbiome of individuals with detectable proprionate levels in BAL had a relative abundance of anaerobic bacteria , which is in line with the hypothesis that SCFA are produced locally in the lung. Together, these data indicate that the microbiome locally in the airways is disturbed during active TB disease; however, the differences in study populations (adults vs children, different ethnic origins including differences in diet), clinical samples (nasopharynx, sputum, BAL) and analysis methods make it impossible to draw any major conclusions on the alterations in microbiota composition during TB disease.…”

“…In contrast, controls had more beneficial, commensal organisms of the Bacteroidetes phylum [194]. Furthermore, increased serum concentrations of SCFA, the products of the commensal bacteria, were associated with increased TB susceptibility in HIVinfected individuals [191]. Butyrate inhibited IFN-c and IL-17 production in response to Mtb-antigen stimulation of PBMCs [191], in a HDAC-dependent manner [195].…”

The role of the lung microbiota and the gut-lung axis in respiratory infectious diseases

“…Two recent studies have shown that the short chain fatty acid (SCFA) butyrate modulates the production of M. tuberculosis-induced pro-and anti-inflammatory cytokines in the lungs, associated with an increased susceptibility to M. tuberculosis (Lachmandas et al, 2016;Segal et al, 2017). Two recent studies have shown that the short chain fatty acid (SCFA) butyrate modulates the production of M. tuberculosis-induced pro-and anti-inflammatory cytokines in the lungs, associated with an increased susceptibility to M. tuberculosis (Lachmandas et al, 2016;Segal et al, 2017).…”

Systemic proinflammation after Mycobacterium tuberculosis infection was correlated to the gut microbiome in HIV‐uninfected humans

“…Previous investigation showed systemic inflammation may be due to alterations in gut commensal microorganisms by a high-fat, high-caloric, low-fibre diet; this led to a high Firmicutes to Bacteroidetes (F/B) ratio in the gut microbiota, with further degradation of the gut epithelial barrier and leakage of lipopolysaccharide-positive (LPS+) bacteria. 3 To date, most studies on TB have focused on the interaction between respiratory microbiota and clinical outcomes, 4 whereas only a few have described the interaction between the host and microbiome with regard to short-chain fatty acids (SCFAs) and Treg activation. 4 Patients with active TB sometimes had concurrently increasedin both pro-and anti-inflammatory cytokines, such as IL-6, TNF, IFN-γ and IL-10, and leucocytosis in peripheral blood.…”

“…3 To date, most studies on TB have focused on the interaction between respiratory microbiota and clinical outcomes, 4 whereas only a few have described the interaction between the host and microbiome with regard to short-chain fatty acids (SCFAs) and Treg activation. 4 Patients with active TB sometimes had concurrently increasedin both pro-and anti-inflammatory cytokines, such as IL-6, TNF, IFN-γ and IL-10, and leucocytosis in peripheral blood. Some investigations showed that the Bifidobacteriaceae family may downregulate the inflammatory response after MTB infection, resulting in fewer constitutional symptoms.…”