The Relevance of Host Gut Microbiome Signature Alterations on de novo Fatty Acids Synthesis in Patients with Multi-Drug Resistant Tuberculosis

Abstract

Background Tuberculosis (TB) is still the single pathogen infectious disease with the largest number of deaths worldwide. The relationship that intestinal microbiota disorder and de novo fatty acid synthesis metabolism have with disease progression in multi-drug resistant TB (MDR-TB) has not yet been fully studied. Objective To investigate the effects of long periods of MDR-TB, pre-extensively drug-resistant TB (pre-XDR-TB), or rifampicin-resistant TB (RR-TB) on gut microbiome dysbiosis and advanced disease. Methods The sample was chosen between March 2019 and September 2019 in Wenzhou Central Hospital and comprised 11 patients with pre-XDR-TB, 23 patients with RR-TB, and 28 patients with MDR-TB. Healthy individuals were chosen as the control group (CK group). An overnight fast blood sample was drawn via venipuncture into tubes without anticoagulant. For analysis, 300 mg of faeces from patients from the same group was mixed and analysed using DNA extraction, NGS sequencing, and bioinformatics. A QIAamp Fecal DNA Mini Kit was used to isolate the DNA. The extracted DNA was stored at −20°C. Results Advanced TB was concurrent with an elevated level of the proportions of acetyl-CoA carboxylase (ACC1) to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and fatty acid synthase (FASN) to GAPDH in de novo fatty acids synthesis, and Eubacterium, Faecalibacterium, Roseburia , and Ruminococcus were increased significantly in RR-TB patients compared to healthy individuals, whereas their abundance in the pre-XDR-TB and MDR-TB groups showed little change in comparison with the control group. Proteobacteria levels were greatly increased in the RR-TB and MDR-TB patient groups but not in the patients with pre-XDR-TB or the healthy subjects. The pre-XDR-TB group exhibited alterations of the intestinal microbiome: coliform flora showed the highest abundance of Verrucomicrobiales, Enterobacteriales, Bifidobacteriales and Lactobacillales . De novo fatty acids synthesis was enhanced in patients and was associated with the gut microbiome dysbiosis induced by the antimicrobials, with Bacteroidetes, Bacteroidales , and Bacteroidaceae displaying the most important correlations on a phylum, order, and family level, respectively. Conclusion The progression to advanced TB was observed to be a result of the interaction between multiple interrelated pathways, with gut–lung crosstalk potentially playing a role in patients with drug-resistant TB.

The microbiome and the gut-lung axis in tuberculosis: interplay in the course of disease and treatment

“…Moreover, members of the Bacteroidetes phylum were only found in healthy individuals. Gut-derived metabolites, such as SCFAs, tryptophan and secondary bile acids, decreased from MDR to Pre-XDR and RR to healthy participants, underscoring a complex interaction between the microbiota and immune system (Shi et al, 2022). Studies of monotherapies, although not in TB patients, particularly cycloserine treatment, a group B drug, reduces Bifidobacterium species and other butyrate producers in the gut microbiota (Minichino et al, 2021).…”

“…Alterations in the gut microbiota of DR-TB-treated patients have been reported in terms of overall decrease in alpha diversity that can last for years after treatment completion (Wang et al, 2020;Shi et al, 2021). In particular, an increase of Enterobacteriaceae is seen from healthy to RR and MDR, along with a decrease in members of the phylum Actinobacteria and Firmicutes in MDR patients (Wang et al, 2020;Shi et al, 2022). Furthermore, phylum Verrucomicrobia was found as a predominant component in Pre-XDR-TB, whereas it is almost undetectable in healthy, RR or MDR individuals (Shi et al, 2022).…”

“…In particular, an increase of Enterobacteriaceae is seen from healthy to RR and MDR, along with a decrease in members of the phylum Actinobacteria and Firmicutes in MDR patients (Wang et al, 2020;Shi et al, 2022). Furthermore, phylum Verrucomicrobia was found as a predominant component in Pre-XDR-TB, whereas it is almost undetectable in healthy, RR or MDR individuals (Shi et al, 2022). On the other hand, studies on the macaque model have shown an increase in Proteobacteria in RR and MDR but not in Pre-XDR-TB or healthy controls (Namasivayam et al, 2019).…”