Short-Chain Fatty Acid Sodium Butyrate Suppresses Protective Humoral Immunity by Inhibiting Follicular T Helper Cell Differentiation 2025 Gupta et al

[Andy]

ABSTRACT

The gut microbiome and its metabolites are critical regulators of intestinal homeostasis, with emerging evidence highlighting their influence on humoral immune responses and vaccine efficacy. The development of effective humoral immunity depends on the magnitude and quality of germinal centers (GCs), which are driven by follicular T helper (Tfh) cells.

Here, we investigate the role of short-chain fatty acids (SCFAs) in shaping humoral immunity, with a particular focus on Tfh cells. In ex vivo assays, we found that sodium butyrate, not sodium acetate or sodium propionate, directly suppresses Tfh cells differentiation and helper functions. Using antigen-specific and influenza virus infection models, we further demonstrate that sodium butyrate impairs Tfh cell differentiation, leading to diminished GC B cell responses and compromised humoral immunity during systemic infection. Notably, mice treated with sodium butyrate succumbed to virus infection, underscoring its effect on impairing protective immunity.

Mechanistically, our findings reveal that sodium butyrate mediates these suppressive effects on Tfh cells via histone deacetylase (HDAC) inhibition. Together, our findings establish sodium butyrate as a negative regulator of humoral immunity by directly suppressing the Tfh-cell differentiation and Tfh-derived GC responses. These insights provide a mechanistic link between gut microbiome-derived metabolites and humoral immunity, with potential implications for vaccine efficacy and therapeutic interventions.

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[BrightCandle]

This is quite interesting because its been proposed as a potential therapeutic and something that is low in ME/CFS patients in a number of (too small) studies. If some part of the condition involves an infection in the gut then sodium butyrate might be quite counterproductive. It might make us feel a bit better temporarily by dampening the immune response but at the same time allow increased damage.

 

[Creekside]

For every one discovery about a negative effect of something, how many health magazine articles focus on a single good effect and claim that we should boost whatever that is? We're too complex for simplistic "x is good for you!" claims. We need more researchers making the effort to find these negative effects. Negative findings aren't as prestigious as positive ones, but can be equally valuable.

 

[Wanted! Alive]

I think this could confuse the issue between the benefits of butyrate v sodium butyrate.
Sodium butyrate is a stable form of butyrate that is commonly used in supplements, but I’m not aware there is any evidence that production of butyrate by the microbiome is in this sodium form? Butyrate provides something like 70% of the fuel source for colonocytes, helps tamp down inflammation in the colon, among other benefits.

Maybe then, newer forms of butyrate supplements like Tributyrin are better.

 

[Jonathan Edwards]

Sodium butyrate is a stable form of butyrate that is commonly used in supplements, but I’m not aware there is any evidence that production of butyrate by the microbiome is in this sodium form?

In a biological context I am pretty sure the sodium will always be dissociated from the butyrate as a hydrated ion so there will be no difference. And the local sodium level will rapidly become that of the biological fluid - plasma or tissue fluid or whatever.

 

[Wanted! Alive]

In a biological context I am pretty sure the sodium will always be dissociated from the butyrate as a hydrated ion so there will be no difference. And the local sodium level will rapidly become that of the biological fluid - plasma or tissue fluid or whatever.

Yes, I’m sure you are most likely correct, butyrate without sodium is a known HDAC inhibitor. So in the context of this study, it’s probable the butyrate has dissociated from its original form.

It could simply be that too much butyrate is overly suppressive…no doubt they substantially overdosed the mice!

 

[Creekside]

Does it make a difference where their ex-vivio sample was taken? The intestinal tract varies a lot in function and production and absorption of butyrate and possible cofactors. Butyrate might have different effects on immune cells in different locations. I think this is one of those "opens up a new field of study" discoveries: too little information for immediate medical use, but the beginnings of deeper understanding.