Balancing TB Treatment and Microbiome Health: A Delicate Act

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the world's leading infectious disease killers. Standard treatment is a long course of multidrug antibiotic treatment, which is essential to cure the infection. But more and more, there is concern that this life-saving treatment carries an unheralded cost—dysruption of the respiratory microbiome.

The Forgotten Side Effect: Microbiome Disruption

The respiratory microbiome is a dynamic and complex assemblage of microbes that live within the airways. Far from being passive observers, these microbes regulate inflammation homeostasis, confer mucosal integrity, and condition the immune system. They comprise health-promoting genera like Streptococcus, Prevotella, Veillonella, and Haemophilus, which are all integral to respiratory well-being.

Unfortunately, anti-TB antibiotics—particularly broad-spectrum ones such as rifampicin and moxifloxacin—do not differentiate between pathogenic bacteria and beneficial commensals. Our recent study comparing seven regimens of anti-TB therapy reported that soon after starting treatment, the microbiome lost a substantial amount of abundance and diversity.

One involving moxifloxacin and 20mg/kg rifampicin showed transient depression of the microbiome but reassuringly normalization of pretreatment levels at three months. In contrast, when rifampicin dose was increased to 35mg/kg, recovery took longer and was less than full at follow-up. This suggests that higher doses, while potentially improving TB clearance, are potentially more toxic to the microbial community sustaining overall recovery.

Why Microbiome Disruption Matters

A disordered respiratory microbiome—dysbiosis—has serious consequences:

• Compromised immunity: Without commensals to assist with signaling the immune system, the body won't be able to keep infections at bay or heal from inflammation.
• Opportunistic infections: Reduced microbial diversity creates space for opportunistic pathogens like Pseudomonas and Staphylococcus to dominate.
• Chronic inflammation: A healthy microbiome helps provide balance of immune responses. When that's lost, inflammation is likely to become chronic, leading to tissue damage and preventing healing.

In high TB burden countries where co-infection with HIV or the flu is common, the stakes are even higher. There are also some study proposals that the microbiome might influence the body's sensitivity to Mtb itself or even influence the efficacy of vaccines.

To minimize collateral damage to the microbiome without sacrificing effective TB treatment, we must reconsider antibiotic dosing and delivery. These are a few promising directions:

1. Precision Dosing & Therapeutic Drug Monitoring (TDM)

People absorb and metabolize TB drugs differently. Uniform dosing could lead to overexposure in some, harming the microbiome unnecessarily. TDM allows for individualized dosing to hit therapeutics with precision, without excess.

2. Shorter Regimens

Recent experiments have shown that four-month regimens of moxifloxacin or rifapentine are equally effective as conventional six-month regimens in some individuals. While this reduces exposure to antibiotics overall, it's noteworthy that the shorter regimens could be coupled with increased drug doses, which in turn can still have a spectacular impact on the microbiome. More research is needed.

3. Targeted Therapies

Future treatment might move towards narrow-spectrum or host-directed therapy that avoids the beneficial microbes. Targeted delivery and inhaled formulations may reduce systemic exposure and leave microbial communities intact elsewhere in the body.

4. Probiotics and Microbiome Support

Probiotics and prebiotics offer some promise in preserving microbial balance in the application of antibiotics in other contexts. While we did not utilize probiotics in our experimental design, we did experience some rebound of the microbiome, though its quality is an area to continue investigating. Targeted phage therapy is also a pathway to pursue in the future, with pathogen-specific killing but not commensal harm.

Toward a New Treatment Paradigm

TB treatment is an act of balance: destroying the pathogen while not undermining the host's long-term well-being. Toxification or prolonged antibiotic treatments risk upsetting the balance in the direction of harm, especially if they decimate the microbiome. Under-treatment risk drug resistance and relapse.

In order to balance this delicate act, we must adopt a more nuanced, precision-based approach to treatment—one where the microbiome is not an innocent bystander, but a willing participant in recovery.

As our understanding of the microbiome's role in immunity and disease expands, the time has come to make microbiome health a central determinant of TB drug development and clinical trials. Then we can really optimize treatment strategies—not just for pathogen eradication, but for holistic recovery and best possible wellness.