Managing Die-Off Symptoms
The Jarisch Herxheimer reaction was first described in the late 1800s. Herxheimer reactions are typically described as transient symptoms associated with antibiotic therapy for treatment of spirochetes, like Lyme and syphilis, typically occurring within the first 24 hours of treatment.1 Symptoms included fever, chills, nausea and vomiting, headache, tachycardia, hypotension, hyperventilation, flushing, and muscle pain. Since the late 1800s, these reactions have been noted in the treatment of other bacterial, fungal, and protozoan infections. In integrative medicine, Herxhemier or die-off reactions have been noted when modulating the microbiome, whether with antibiotics or other antimicrobial substances.
What causes die-off reactions?
The exact mechanism of die-off reactions is unclear. It is thought that the killing of the microbe causes release of microbial toxins that stimulate an immune reaction. In classic Herxheimer reactions, the research has found an increase in inflammatory cytokines such as interleukin-6, interleukin-8, and tumor necrosis factor-alpha, which result in the development of body aches, fevers, rashes, nausea and vomiting, and flushing, along with other symptoms.1
When it comes to addressing the microbiome, many die-off reactions may be mediated by lipopolysaccharide (LPS), a glycolipid in the outer membrane of gram negative bacteria. In the microbiome, LPS is commonly found in Proteobacteria and Bacteroidetes. Now, there are different types of LPS, with different effects on the immune system, and the LPS found in Proteobacteria seems to be very inflammatory. So if the gut protocol is killing Proteobacteria, die-off reactions may be more likely since we know that LPS is released as a free molecule when these microbes die.2
Within Biomesight, you can see your percentage of gram-negative bacteria under the permeability section.
Since Proteobacteria overgrowth is the most common imbalance in small intestine bacterial overgrowth (SIBO), die-off reactions are quite common in SIBO treatment. Remember, any microbiome stool test does not tell you anything about your small intestine microbiome. When it comes to modulating the large intestine microbiome, die-off symptoms may or may not occur—it depends on what you are modulating and the tools you are using to modulate.
What are the symptoms of die-off?
Die-off originating in the gut looks a little different than die-off from a systemic infection. This is most likely due to the fact that your gut acts as a barrier and you do not absorb 100% of the microbial metabolites and toxins released. In integrative medicine, we see a myriad of die-off symptoms. First, there are the gastrointestinal symptoms. Diarrhea, nausea, heartburn, and abdominal pain may be the most common. But you can also experience bloating, abdominal distention, and constipation. Systemically, we see fatigue, brain fog, body aches, and joint pain frequently. We can also see worsening of skin issues such as rashes and acne or even new skin issues. Practitioners have essentially witnessed worsening of any existing symptom as well as the return of old symptoms and new digestive symptoms.
The experience of die-off is very patient specific. For some, it is very mild and for others it is quite severe. For some, it can last a day and for others, it lasts the entire time they are on the treatment. In general, patients with underlying inflammatory conditions, such as autoimmune disease, have more severe die-off symptoms. Younger patients and patients with no other conditions may not experience die-off at all.
It is important to note that it can be very difficult to differentiate between die-off and side effects. So you need to communicate with your doctor to be sure that you are not using the wrong treatment for you.
Preventing Die-Off Symptoms
To prevent die-off symptoms, we can try to minimize the absorption of microbial metabolites that are released when microbes are killed. It is recommended to first gradually introduce the treatment. Start with a low dose and gradually increase the dose every 3-4 days until you reach the therapeutic dose. If you start to experience symptoms, you can reduce the dose or stop for a few days until the symptoms resolve and then increase the dose again. Depending on your sensitivity, it may take months to reach the therapeutic dose—this is more common when treating fungal species.
The other way to prevent die-off is to use substances that will bind the microbial metabolites. These are best taken about 1 hour after the treatment. This gives the agent time to kill the microbe, but gives your body minimal time to absorb the metabolites. Before using most binders, it is important that you are having one to two bowel movements a day. Many binders can cause or worsen constipation, especially at higher dose. Constipation will worsen die-off symptoms every time.
The most common, affordable, and accessible binder is activated charcoal. There are other products that use different clays and other binders, however, they tend to be more expensive, increase the risk of constipation, and for most people, they do not yield superior results. Alternative substances that can bind LPS include lactoferrin2, serum bovine immunoglobulins3, and cranberry proanthocyanins4.
Managing Die-Off Symptoms
Despite your best efforts, you may still experience die-off symptoms.
For bloating, using carminative herbs such as peppermint can be helpful. This includes enteric-coated peppermint oil as well as peppermint tea. Over the counter remedies such as Gas-X may also be helpful.
For constipation, osmotic or stimulant laxatives may be helpful. This includes high dose vitamin C, magnesium citrate, herbs like Senna, or over the counter remedies like Miralax. (Note added by Rose Walbrugh: The top prebiotic option to improve constipation is Partially Hydrolyzed Guar Guam (PHGG)5, while the top probiotic strain is Bifidobacteria Lactis HN0196)
For diarrhea, you may need to consider Pepto-bismol or loperamide. Talk to your doctor.
For nausea, ginger as a tea or supplement is often helpful.
For heartburn, digestive enzymes or Alka Selzer Gold (without NSAIDS) may be helpful.
It is very important that you talk to your doctor about your symptoms before you try anything new. You need to determine if these symptoms are die-off or a side effect and you also need to be on the lookout for allergic reactions.
- Dhakal A, Sbar E. Jarisch-Herxheimer Reaction. [Updated 2023 Apr 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557820/
- Guerville M, Boudry G. Gastrointestinal and hepatic mechanisms limiting entry and dissemination of lipopolysaccharide into the systemic circulation. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2016;311(1):G1-G15. doi:10.1152/ajpgi.00098.2016
- Utay NS, Somasunderam A, Hinkle JE, et al. Serum Bovine Immunoglobulins Improve Inflammation and Gut Barrier Function in Persons with HIV and Enteropathy on Suppressive ART. Pathog Immun. 2019;4(1):124-146. doi:10.20411/pai.v4i1.276
- Delehanty JB, Johnson BJ, Hickey TE, Pons T, Ligler FS. Binding and neutralization of lipopolysaccharides by plant proanthocyanidins. J Nat Prod. 2007;70(11):1718-1724. doi:10.1021/np0703601
- G Quartarone. Role of PHGG as a dietary fiber: a review article. Minerva Gastroenterol Dietol. https://pubmed.ncbi.nlm.nih.gov/24212352/
- Alvin Ibarra, Mathilde Latreille-Barbier, Yves Donazzolo, Xavier Pelletier, Arthur C Ouwehand. Gut Microbes. 2018; Effects of 28-day Bifidobacterium animalis subsp. lactis HN019 supplementation on colonic transit time and gastrointestinal symptoms in adults with functional constipation: A double-blind, randomized, placebo-controlled, and dose-ranging trial. 9(3):236-251. doi: 10.1080/19490976.2017.1412908. https://pubmed.ncbi.nlm.nih.gov/29227175/