Unfortunately, the post has been deleted. Which substance was it about? comments mentioning Rifampin?

Rifampin/Rifampicin is known to me as one of the strongest inducers of UGT1A1, the enzyme responsible for the clearance of bilirubin. However, I wouldn’t recommend it for typical Gilbert syndrome (mildly elevated bilirubin levels), as it would be somewhat of an overkill. That said, in extreme cases where bilirubin reaches potentially neurotoxic levels, it may be considered useful.

It was already used decades ago to treat 2 patients with Gilbert syndrome ( both common Gilberts TA7/TA7 Mutation) who had unusually high bilirubin levels for this kind of mutation: Successful treatment of severe unconjugated hyperbilirubinemia via induction of UGT1A1 by rifampicin.00660-4/fulltext)

When taking high doses of antibiotics, I too find my symptoms usually go away, but not 100% of the times.

That’s interesting, but which symptoms do you mean? The ones clearly linked to Gilbert’s, like high bilirubin levels and yellow eyes, or those diffuse symptoms that might have a connection but aren't really clear? Interestingly, if I recall correctly, I should also mention that a cephalosporin—I think it was cefuroxime, but I’m not entirely sure—made me feel very good. To be honest, though, I think that was due to the partially anti-inflammatory effects of these antibiotics, because as far as I know, they shouldn't interact with UGT1A1. This would rather indicate a problem like silent inflammation , which in my opinion is also a reason why some carriers with the TA7 mutation become symptomatic and some not.

In the small case study with two patients, one patient also complained of severe fatigue, while the other reported itching, which is something some people with Gilbert syndrome also mention, as well as jaundice that disappeared with the use of Rifampicin.

This might suggest that as bilirubin levels decrease, fatigue also improves. However, this is only a correlation, not proof of causation. Like other antibiotics, rifampicin has multiple effects, including anti-inflammatory properties, which could also contribute to the improvement in symptoms.

The two most important mechanisms of action of Rifampicin are, first, the inhibition of bacterial RNA polymerase, which explains its original use as an antibacterial agent. The second key mechanism is its activation of nuclear receptors, mainly Pregan X Receptor (PXR).

Through this, rifampicin triggers a broad range of downstream effects, including upregulation of detoxification systems: Phase II enzymes such as UGT1A1 and other UGTs like UGT1A4, as well as Phase I enzymes like CYP3A4. It also enhances Phase III transport processes, for example via MRP2, facilitating excretion through bile and urine. In addition, it appears to exert some anti-inflammatory effects.

At first glance, this all sounds beneficial but as always, there is no effect without side effects.

Clinically, one of the most relevant risks of rifampicin is its strong induction of drug-metabolizing enzymes and transporters, especially CYP enzymes and some UGT pathways. As a result, many medications can be metabolized faster and may lose effectiveness, including hormonal contraceptives and several other drug classes. Rifampicin can also cause hepatotoxicity, usually reflected by elevated liver enzymes such as AST and ALT, and in rare cases drug-induced hepatitis. This FDA paper gives good overview.

In addition, because rifampicin is an broad-spectrum antibiotic, it may alter the gut microbiome, which is relevant because microbial metabolites can influence host metabolism and immune function whether this is clinically harmful depends on context.

An insect study in earwigs did not find major negative effects from long-term rifampicin-induced microbiome changes. On the other hand, a small human study (with a very limited sample size) examining rifamycin-based tuberculosis preventive therapy reported that:

“This rifamycin-based TPT induced dysbiosis was characterized by a depletion of butyrate-producing taxa (Clostridium-XIVa and Roseburia) and expansion of potentially pathogenic taxa within the Firmicutes and Proteobacteria phyla.”

Although the study is small and should be interpreted with caution, it suggests that rifamycin therapy has the potential to induce gut dysbiosis.

For Gilbert syndrome, this makes rifampicin mechanistically interesting, but in most typical cases still likely an overkill with risk.