Complientary treatments for Crohn’s disease/IBD, UC

The "Treatments For" series is a Patreon initiative aimed at providing medical providers and informed patients with complementary treatment strategies for complex chronic illnesses. It does not constitute medical advice, nor do the items outlined in these articles represent "cures" or complete solutions on their own. The information provided is for educational purposes only. For medical providers, the series aims to offer a detailed overview of the theoretical mechanisms underlying treatments, as well as dosing, sourcing, clinical use, and implications. Before implementing supplements or peptides, patients should work with an informed integrative physician and consider making adjustments to their diet and lifestyle.

KPV peptide

Lysine-proline-valine (aka KPV) is a naturally occurring tripeptide derived from the parent molecule Alpha-MSH that’s released when you get a tan. You may recall me discussing KPV on a recent Q/A I did with regard to sun exposure:

This is important subtext for KPV, as many of the benefits of the tripepride are also shared with getting adequate sun exposure. Of course, any article on peptides or supplements would be incomplete without drawing the associated parallels to the importance of manipulating our external environment (‘light diet’) in managing complex chronic illness. Back to KPV.

KPV has shown significant promise in the treatment of inflammatory bowel diseases, including ulcerative colitis and Crohn's. Available research shows that KPV can effectively attenuate inflammatory responses in colonic cells, making it a potential therapeutic for managing GI diseases with an inflammatory etiology.

KPV exerts its anti-inflammatory effects in the GI through several mechanisms: it has been shown to inhibit the activation of key inflammatory signaling pathways, specifically NF-KB and MAP kinase pathways. That inhibition leads to a reduction in the secretion of pro-inflammatory cytokines, which are crucial mediators of inflammation in IBD.

The peptide also acts via the transporter hPepT1, which is expressed in both immune and intestinal epithelial cells. This targeting allows KPV to effectively reduce the incidence of colitis induced by chemical agents such dextran sulfate sodium and trinitrobenzene sulfonic acid.

In layman’s terms, KPV protects the intestines from toxic chemicals and carcinogens.

KPV treatment has been observed to decrease levels of pro-inflammatory cytokines like TNF-α, IL-1B, and IL-6 without significantly altering the levels of anti-inflammatory cytokines such as IL-10. This suggests that KPV primarily acts by downregulating inflammation itself AND boosting pro-resolving, anti-inflammatory responses.

Recent studies have highlighted the therapeutic potential of KPV, particularly in the context of UC.

The enhancement of mucosal healing is a critical goal in UC treatment. Studies utilizing electrical impedance sensing technology have shown that wounded epithelial layers treated with KPV suspensions exhibited significant recovery compared to untreated controls. This indicates that KPV not only reduces inflammation but also promotes the healing of the intestinal lining itself.

KPV has excellent biocompatibility, and hasn’t been demonstrated to have any cytotoxicity in cell line studies. Several key findings from recent papers discuss the potential of KPV in treating IBD: In animal models, oral administration of KPV has been shown to significantly reduce weight loss and inflammatory markers associated with colitis. The peptide effectively mitigated the inflammatory changes typically induced by strong compounds like DSS and TNBS.

Interestingly, KPV has also been found to exhibit stronger anti-inflammatory effects than its parent peptide, α-melanocyte-stimulating hormone, which we discussed above. his suggests that KPV could serve as a more effective alternative in managing inflammation associated with IBD compared to alpha-MSH treatments. Aka administering MSH directly (melanotan).

Chronic inflammation in the intestines is a known risk factor for colorectal cancer as well. KPV has been shown to reduce tumorigenesis in models of colitis-associated cancer, indicating its potential not only in treating IBD but also in preventing cancer development linked to the chronic inflammation many of these patients deal with.

While most of the research on KPV is in animal models, many practioners are successfully using KPV in their practice with great results in IBD patients. KPV is safe and very well-tolerated.

How is KPV doses and administered?

Because KPV is a short peptide, it can administered orally. KPV is often injected (preferable) and administered in a nasal spray at 500-1000mcg daily for 1-2 months, cycled off for a month, and then repeat until symptoms are under control. Oral KPV can be found via peptide science and intergrative peptides. Injectable forms of KPV can be found at CanLabs.

Specialized pro resolving mediators

Current treatments in IBD primarily focus on anti-inflammatory agents, but these often have limited efficacy and significant side effects. Pro resolving mediators may provide a signicant advantage over traditional anti-inflammatory as they both 1. Reduce inflammation while 2. Upregulating tissue repair immune phenotypes. Remember, traditional anti-inflammatories BLOCK the inflammatory response and therefore many of the biological signaling necessary to initiate repair.

SPMs are bioactive lipids derived from omega-3 fatty acids that play a big role in resolving inflammation. Remember, resolving is a different game than BLOCKING inflammation outright.

SPM’s include a few distinct molecules: resolvins, protectins, and maresins, which actively promote the resolution of inflammation (reducing it via upregulating repair and waste removal) rather than merely suppressing it. In the context of IBD, SPMs have been shown to modulate inflammatory responses and promote mucosal healing.

SPMs exert their effects through specific receptors, such as the formyl peptide receptor 2 which is implicated in the resolution of inflammation. Activation of these receptors by SPMs leads to the inhibition of pro-inflammatory cytokines and the promotion of anti-inflammatory pathways, which facilitates the healing of intestinal tissues affected by IBD. Pro resolving mediators flip macrophages from inflammatory phenotypes (M1) to anti-inflammatory and REPAIR (M2) phenotypes. They also upregulate the clearance of waste products from damaged cells

The process by which immune cells, particularly macrophages, engulf and clear waste products from damaged cells is known is called phagocytosis. This is a mechanism in the immune response to inflammation (that traditional anti-inflammatories block) , allowing the body to remove cellular debris, pathogens, and dead cells.

Immune cells are attracted to the site of damage or infection by chemical signals released from damaged cells or pathogens. This is upregulate and enhanced by SPM’s. Then the immune cell attaches to the particle or cell it will ingest. This step is crucial for the subsequent ingestion process. The immune cell engulfs the particle, enclosing it in a membrane-bound vesicle called a phagosome.

Phagocytosis is essential not only for clearing pathogens but also for maintaining tissue homeostasis by removing dead or damaged cells. This process is particularly important in inflammatory responses, where the transition from inflammatory (M1) to anti-inflammatory (M2) macrophage phenotypes is a BIG component for tissue repair and resolution of inflammation. pro resolving mediators enhance this transition and promote effective waste clearance, thereby supporting the healing process.

This is extremely important as disease like IBD create structural changes to the intestinal barrier and GI that need to be repaired. facilitating the resolution of inflammation is important and SPMs may signicantly enhance the healing of the intestinal mucosa, potentially leading to longer periods of remission. Patients experiencing fewer inflammatory episodes have signicant improvements in the quality of their life. Therefore, I think SPM’s could be a powerful adjunctive tool in the IBD practioners arsenal.

Some studies have demonstrated that dietary interventions that increase the intake of omega-3 fatty acids can lead to improvements in clinical outcomes for patients with CD and UC. However, those results are mixed. Instead of relying on omega 3 consuming for the deriving of SPM’s, it’s likely better to supplement with them directly

What’s the dosing and application?

For those with severe inflammatory conditions, higher doses of pro-resolving mediators are likely neccessary. The maximum effective dose seems to be somewhere around 3-4 grams (this would be about 6-8 capsules of the meta-genics SPM’s daily) while the minimum effective dose is around 1g (2 capsules). Practioners could likely have success implementing higher doses during flair ups, and then cycling patients on and off the supplement as needed. Initially, I think it’s a good idea to run a bottle or two for 1-2 months straight at higher doses to achieve initial results. Adjustments can be made from there

Tributyrin

Tributyrin is a triglyceride that is naturally found in dairy fats and is a source of butyrate, a short-chain fatty acid produce by your gut bacteria. Butyrate is produced in the gut through the fermentation of dietary fibers by gut microbiota. It plays a crucial role in maintaining gut health, particularly in the colon, where it serves as a primary energy source for colonocytes (the cells lining the colon) and has anti-inflammatory properties.

Because many individuals with IBD have a hard time tolerating fiber (and therefore feeding the neccessary bacteria that produce the butyrate they need to to repair their colons) tributyrin could be an effective intermediary solution for these individuals. It’s important to note that taking butyrate containing supplement long term will reduce the natural production of the molecule. Therefore, butyrate contraining supplements should be used in cycles and or as a bridge to get patients healthy enough to produce their own

There is some research that indicates that butyrate, and by extension tributyrin, may offer several therapeutic benefits for individuals suffering from IBD.

Butyrate has been shown to exert very strong anti-inflammatory effects by inhibiting the activity of histone deacetylases and nuclear factor kappa B, both of which are involved in inflammatory processes. This inhibition can help reduce the inflammatory response in the gut, which is a hallmark of IBD.

Butyrate plays a critical role in maintaining the integrity of the intestinal epithelial barrier. A compromised barrier will lead to increased intestinal permeability, allowing harmful substances to enter the bloodstream and trigger system wide inflammation.

Tributyrin and butyrate can positively influence the composition of gut microbiota, promoting the growth of beneficial bacteria while inhibiting pathogenic species. A healthy gut microbiome is essential for maintaining immune homeostasis and preventing inflammation associated with IBD long term. This may be a good strategy to gently ‘tune’ the microbiome for IBD patients prior to probiotics, especially if a worsening of symptoms happens with spores.

As a primary energy source for colonocytes, butyrate supports cellular metabolism and function. Adequate energy supply is absolutely essential for the repair and maintenance of the intestinal lining, which is almost always damaged in IBD

Some clinical studies have indicated that butyrate supplementation can help reduce inflammation and maintain remission in patients with IBD as well (human data!). direct oral administration of butyrate can be limited by its palatability and absorption issues. tributyrin offers a more acceptable. absorbable alternative

How is it implemented and dose?

Tributyrin is often doses around 3 capsules daily. I like the brand healthyGut. If can cause GI distress and bloating, so it may be good to start off with one capsule. The capsules cannot be opened. Do not chew them as the protective coating is part of the delivery system. Some patients may want to stay on 2-4 capsules anywhere between 4-8 months, and then talk to their practioner about lowering their dose.

The supplements and peptides above can and likely should be used together in some kind of combination approach as seen fit by you (the practioner)

To be continued…

References

KPV

Xiao, Bo, et al. “Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis.” Molecular Therapy, vol. 25, no. 7, July 2017, pp. 1628–1640, 10.1016/j.ymthe.2016.11.020.

Xiao, Bo, et al. “Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis.” Molecular Therapy, vol. 25, no. 7, July 2017, pp. 1628–1640, 10.1016/j.ymthe.2016.11.020.

Viennois, Emilie, et al. “Critical Role of PepT1 in Promoting Colitis-Associated Cancer and Therapeutic Benefits of the Anti-Inflammatory PepT1-Mediated Tripeptide KPV in a Murine Model.” Cellular and Molecular Gastroenterology and Hepatology, vol. 2, no. 3, 16 Feb. 2016, pp. 340–357, www.ncbi.nlm.nih.gov/pmc/articles/PMC4957955/, 10.1016/j.jcmgh.2016.01.006.

SPM’s

Wang RX, Colgan SP. Special pro-resolving mediator (SPM) actions in regulating gastro-intestinal inflammation and gut mucosal immune responses. Mol Aspects Med. 2017 Dec;58:93-101. doi: 10.1016/j.mam.2017.02.002. Epub 2017 Feb 21. PMID: 28232096; PMCID: PMC5797700.

Bioactive lipids in inflammatory bowel diseases – From pathophysiological alterations to therapeutic opportunities,

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids,

Volume 1866, Issue 2,2021,

158854, ISSN 1388-1981,

Pascoal LB, Palma BB, Chaim FHM, de Castro MM, Damázio TA, Franceschini APMF, Milanski M, Velloso LA, Leal RF. New translational and experimental insights into the role of pro-resolving lipid mediators in inflammatory bowel disease. World J Exp Med. 2022 Jan 20;12(1):1-15. doi: 10.5493/wjem.v12.i1.1. PMID: 35096550; PMCID: PMC8771592.

Yang, Ws., Wang, Jl., Wu, W. et al. Formyl peptide receptor 2 as a potential therapeutic target for inflammatory bowel disease. Acta Pharmacol Sin44, 19–31 (2023).

Tributyrin

Gasaly N, Hermoso MA, Gotteland M. Butyrate and the Fine-Tuning of Colonic Homeostasis: Implication for Inflammatory Bowel Diseases. Int J Mol Sci. 2021 Mar 17;22(6):3061. doi: 10.3390/ijms22063061. PMID: 33802759; PMCID: PMC8002420.

Recharla N, Geesala R, Shi XZ. Gut Microbial Metabolite Butyrate and Its Therapeutic Role in Inflammatory Bowel Disease: A Literature Review. Nutrients. 2023 May 11;15(10):2275. doi: 10.3390/nu15102275. PMID: 37242159; PMCID: PMC10221771.

Butyrate in Inflammatory Bowel Disease Therapy Chen, JiezhongVitetta, Luis et al.

Gastroenterology, Volume 158, Issue 5, 1511