14th activator of the Vitamin D Receptor – Butyrate (from gut bacteria, or supplement)

Table of contents

VitaminDWiki - Vitamin D Receptor activation can be increased in 16 ways

Resveratrol,  Omega-3,  Magnesium,  Zinc,   Quercetin,   non-daily Vit D,  Curcumin,   Berberine,  intense exercise, Butyrate   Sulforaphane   Ginger,   Essential oils, etc  Note: The founder of VitaminDWiki uses 10 of the 16 known VDR activators

Long COVID Update: The Importance of Butyrate - Jan 2024

Minn. Personalized Medicine__
Reviewing: Immune damage in Long Covid - Links between the complement and coagulation systems could lead to Long Covid therapies
SCIENCE 18 Jan 2024 Vol 383, Issue 6680 pp. 262-263 DOI: 10.1126/science.adn1077
Strangely, Butyrate does not appear to be in the text

It appears that Butyrate is especially good at allowing more vitamin D to get to colon cells

Valproate and Short-Chain Fatty Acids Activate Transcription of the Human Vitamin D Receptor Gene through a Proximal GC-Rich DNA Region Containing Two Putative Sp1 Binding Sites - June 2022

Nutrients 2022, 14(13), 2673; https://doi.org/10.3390/nu14132673   PDF
by Marta Moreno-Torres 1,2,*,†ORCID,Carla Guzmán 1,Petar D. Petrov 1ORCID andRamiro Jover 1,2,3,*,†ORCID
1 Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria Hospital La Fe, 46026 Valencia, Spain
2 CIBEREHD, Instituto de Salud Carlos III, 28029 Madrid, Spain
3 Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain

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The vitamin D receptor (VDR) mediates 1,25-dihydroxyvitamin D3 pleiotropic biological actions through transcription regulation of target genes. The expression levels of this ligand-activated nuclear receptor are regulated by multiple mechanisms both at transcriptional and post-transcriptional levels. Vitamin D3 is the natural VDR activator, but other molecules and signaling pathways have also been reported to regulate VDR expression and activity. In this study, we identify valproic acid (VPA) and natural short-chain fatty acids (SCFAs) as novel transcriptional activators of the human VDR (hVDR) gene. We further report a comprehensive characterization of VPA/SCFA-responsive elements in the 5′ regulatory region of the hVDR gene. Two alternative promoter DNA regions (of 2.4 and 3.8 kb), as well as subsequent deletion fragments, were cloned in pGL4-LUC reporter vector. Transfection of these constructs in HepG2 and human Upcyte hepatocytes followed by reporter assays demonstrated that a region of 107 bp (from −107 to −1) upstream of the transcription start site in exon 1a is responsible for most of the increase in transcriptional activity in response to VPA/SCFAs. This short DNA region is GC-rich, does not contain an apparent TATA box, and includes two bona fide binding sites for the transcription factor Sp1. Our results substantiate the hypothesis that VPA and SCFAs facilitate the activity of Sp1 on novel Sp1 responsive elements in the hVDR gene, thus promoting VDR upregulation and signaling. Elevated hepatic VDR levels have been associated with liver steatosis and, therefore, our results may have clinical relevance in epileptic pediatric patients on VPA therapy. Our results could also be suggestive of VDR upregulation by SCFAs produced by gut microbiota.

Probiotics and Vitamin D/Vitamin D Receptor Pathway Interaction: Potential Therapeutic Implications in Inflammatory Bowel Disease – 2021

Front. Pharmacol., 24 November 2021 | https://doi.org/10.3389/fphar.2021.747856   PDF
Cristiano Pagnini1*, Maria Carla Di Paolo1,Maria Giovanna Graziani1 and Gianfranco Delle Fave2,3
1 Gastroenterologia ed Endoscopia Digestiva, AO S. Giovanni Addolorata, Rome, Italy
2 Gastroenterologia, Università “Sapienza”, Rome, Italy
3 Onlus “S. Andrea”, Rome, Italy

Inflammatory bowel diseases (IBD) are chronic conditions of unknown etiology and immunomediated pathogenesis. In the last years, the comprehension of the complex mechanisms involved in the intestinal mucosal homeostasis, and the analysis of the alterations potentially leading to inflammatory pathologic states, has consistently increased. Specifically, the extraordinary impulse in the field of research of the intestinal microbiome has opened the door to the investigation of possible novel approaches to the diagnosis, management and therapeutic applications in IBD. In line with that, administration of probiotic bacteria has been intensely evaluated, leading to much more exciting results in experimental models than in clinical practice. Considering the consistent heterogeneity of the available studies on probiotics, the increased knowledge of the properties of the single bacterial species would ideally lead to unravel potential mechanisms of action that may bring therapeutic applications in specific pathologic condition. Among the relevant molecular pathways for mucosal homeostasis maintenance, the vitamin D/vitamin D receptor (VDR) pathway has been intensely studied in the very last years. In fact, besides osteometabolic functions, the vitamin D exerts important homeostatic effects in the organism at multiple levels, such as immunomodulation, inflammation control, and microbiota regulation, which are likely to play a relevant role in intestinal mucosa protection. In the present review, recent findings about probiotic applications in IBD and mechanisms of action linking vitamin D/VDR pathway to IBD are reported. Available evidence for probiotic effect on vitamin D/VDR are reviewed and potential future application in IBD patients are discussed. At present, many aspects of IBD pathogenesis are still obscure, and current therapeutic options for IBD treatment are at best suboptimal. The increasing comprehension of the different pathways involved in IBD pathogenesis will lead to novel findings ideally leading to potential clinical applications. Microbiota manipulation and vitamin/VDR pathway appear a promising field for future research and therapeutic developments.

The Combined Beneficial Effects of Postbiotic Butyrate on Active Vitamin D3-Orchestrated Innate Immunity to Salmonella Colitis - Sept 2021

Biomedicines 2021, 9(10), 1296; https://doi.org/10.3390/biomedicines9101296  PDF
by Fu-Chen Huang 1,*ORCID and Shun-Chen Huang 2
1 Dept of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
2 Dept of Anatomic Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan

Salmonella spp. Remains a major public health problem globally. Biomedicine is the cornerstone of modern health care and could be a solution for antibiotic-resistant Salmonellosis. Although postbiotics seem to be an effective treatment in various clinical conditions, their clinical effects on Salmonella colitis have not been reported. Our previous report revealed that active vitamin D attenuates the severity of Salmonella colitis and invasiveness by reducing inflammation and enhancing the production of antimicrobial peptides. Therefore, we investigated the synergistic effects of Butyrate, the most studied postbiotic, and active vitamin D on the severity of Salmonella colitis, invasiveness of Salmonella, and host immune responses, as well as its novel mechanisms, using in vitro and in vivo studies. We demonstrated that a combination of Butyrate and active vitamin D (1 alpha, 25-dihydroxyvitamin D3) synergically reduced the severity of Salmonella colitis in C57BL/6 mice and reduced cecal inflammatory mIL-6, mIL-8, mTNF-α, and mIL-1β mRNA expression, but enhanced the antimicrobial peptide mhBD-3 mRNA, compared to a single treatment. Additionally, upregulated vitamin D receptor (VDR) plays a critical role in the synergistic effects. This suggests combined benefits of Butyrate and active vitamin D on Salmonella colitis through VDR-mediated antibacterial and anti-inflammatory responses. The combined use of both supplements could be a potential biomedicine for infectious and autoimmune colitis.

Short-Chain Fatty Acids and Colon Cancer Cells: The Vitamin D Receptor—Butyrate Connection – 2003

Vitamin D Analogs in Cancer Prevention and Therapy pp 247–257 https://doi.org/10.1007/978-3-642-55580-0_18

Butyrate and its prodrug tributyrin, as well as 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), have important physiological effects on proliferation and differentiation in a variety of malignant cells. The aim of this study was to elucidate the role of the vitamin D receptor (VDR) in Butyrate-induced cell differentiation and cell cycle arrest in Caco-2 cells, a human colon cancer cell line. Cell differentiation was evaluated by analyzing the activity of alkaline phosphatase (AP). Protein of VDR, cyclins, cyclin-dependent kinases (cdks) and of cdk inhibitors was quantified by Western blot analysis, VDR-mRNA by PCR. Pre-and postconfluent cells were assessed for VDR binding activity. Cell cycle was analyzed by flow cytometry. Tributyrin significantly increased VDRmRNA level (250% vs. control) and VDR binding activity. Butyrate also enhanced VDR protein content in the nucleus in a re-and dose-dependent manner and more potently than other short-chain fatty acids of a related structure. Both Butyrate (640% vs. control) and 1,25-(OH)2D3(350% vs. control) significantly stimulated differentiation, whereas combined treatment with butyrate and 1,25-(OH)2D3 resulted in a synergistic amplification of AP activity (1400% vs. control). In the presence of the VDR antagonist ZK 191732, Butyrate-induced differentiation was completely abolished (150% vs. control). While Butyrate alone increased p21Waf1/Cip1 expression and downregulated cdk 6 and cyclin A, and combined exposure with 1,25-(OH)2D3resulted in a synergistic enhancement of Butyrate-induced changes, expressions did not change from control level after treatment with Butyrate and ZK 191732. G1 cell cycle arrest induced by Butyrate was also abolished after combined treatment with Butyrate and ZK 191732. In conclusion, differentiation and cell cycle arrest of Caco-2 cells induced by Butyrate are mediated by upregulation of VDR, followed by a stimulation of the negative cell cycle regulator p21Waf1/Cip1 and by a down-regulation of cdk 6 and cyclin A, both involved in cell cycle progression.

Fiber-derived butyrate and the prevention of colon cancer – 1997

https://doi.org/10.1016/S1074-5521(97)90111-3 PDF
Christian A.HassigJeffrey K.TongStuart L.Schreiber

Inhibition of the enzyme histone deacetylase by Butyrate results in the direct transcriptional upregulation of the cyclin-dependent kinase inhibitor p21/Cip1/WAF1. We discuss a small-molecule-mediated signaling pathway to explain the suspected anti-colon-cancer properties of fiber-derived Butyrate.

Buty and the beast: the complex role of butyrate in Parkinson’s disease - April 2024

https://doi.org/10.3389/fphar.2024.1388401
Comment by Rhonda Patrick: "Butyrate is a short-chain fatty acid produced by gut microbes during the fermentation of dietary fiber. However, gut microbial composition and metabolic activity are altered in the setting of Parkinson’s disease, likely playing a role in the disease’s onset and progression. This review summarizes the evidence linking gut microbial perturbations, butyrate, and Parkinson’s disease and presents potential strategies for targeting butyrate production to treat the disease."

Note: Neither Vitamin D nor Vitamin D receptors are mentioned

Note: Butyrate (or fiber) might reduce some colon cancer and gut problems

VitaminDWiki - 15 studies in both categories Gut and Vitamin D Receptor

This list is automatically updated

5+ VitaminDWiki pages have BUTYRATE in the title

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Items found: 5
VitaminDWiki - 13 studies in both categories Colon Cancer and Vitamin D Receptor

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>300 suppliers of Butyrate on Amazon as of June 2022

Amazon Butyrate   My wife has found that 4 BodyBio prevent flares

Sodium Butyrate also promotes weight loss - 2 articles

Butyrate to combat obesity and obesity-associated metabolic disorders: Current status and future implications for therapeutic use
Thirza van Deuren, Ellen E. Blaak, Emanuel E. Canfora
Obesity Reviews: 20 July 2022 https://doi.org/10.1111/obr.13498

Summary
Evidence is increasing that disturbances in the gut microbiome may play a significant role in the etiology of obesity and type 2 diabetes. The short chain fatty acid butyrate, a major end product of the bacterial fermentation of indigestible carbohydrates, is reputed to have anti-inflammatory properties and positive effects on body weight control and insulin sensitivity. However, whether butyrate has therapeutic potential for the treatment and prevention of obesity and obesity-related complications remains to be elucidated. Overall, animal studies strongly indicate that butyrate administered via various routes (e.g., orally) positively affects adipose tissue metabolism and functioning, energy and substrate metabolism, systemic and tissue-specific inflammation, and insulin sensitivity and body weight control. A limited number of human studies demonstrated interindividual differences in clinical effectiveness suggesting that outcomes may depend on the metabolic, microbial, and lifestyle-related characteristics of the target population. Hence, despite abundant evidence from animal data, support of human data is urgently required for the implementation of evidence-based oral and gut-derived butyrate interventions. To increase the efficacy of butyrate-focused interventions, future research should investigate which factors impact treatment outcomes including baseline gut microbial activity and functionality, thereby optimizing targeted-interventions and identifying individuals that merit most from such interventions.

7+ Butyrate Benefits + Side Effects & Sources Self Decode (Bio-hacker) March 2023]
Is a major energy source for colon cells
Believed to help prevent colon cancer
Increases mitochondrial activity
Prevents toxins from crossing the gut barrier
Improves insulin sensitivity
Promotes healthy weight
Fight inflammation
Prevents the growth of pathogenic bacteria
Protects the brain

Butyrate at ConsumerLab - March 2022

Question: Butyrate Supplements for Gut Health: Does butyric acid really work and is it safe?

Answer:
Butyrate supplements are promoted for a wide range of digestive health benefits, from improving overall gut health to decreasing symptoms of irritable bowel syndrome and Crohn’s disease. They are also promoted for more general benefits such as decreasing inflammation, boosting the immune system, and increasing energy. Several small preliminary trials suggest potential benefits, but there is not enough evidence to prove that butyrate supplements do all that they promise.

What is butyrate and what is its function in the body?
Butyrate, also known as butyric acid or butanoic acid, is a short-chain fatty acid (SCFA) that is naturally present in dairy foods such as milk, cream, butter, yogurt, certain hard cheeses such as cheddar and parmesan, and some fermented foods such as sauerkraut and fermented soy (Pituch, Prz Gastroenterol 2013).

In the body, butyrate is one of three main SCFAs produced in the colon by the fermentation of dietary fibers and resistant starch (such as potato starch) that are not digested in the small intestine. Although less abundant than the other two key SCFAs, acetate and propionate, butyrate has been of particular interest because it helps to repair and enhance the barrier function of cells that line the colon (Liu, Adv Nutr 2018), being the main source of energy for these cells, and promotes the absorption of water, sodium, and potassium in the colon, which helps to prevent diarrhea (Bedford, Anim Nutr 2018).

Laboratory and animal studies suggest that butyrate also exerts anti-inflammatory and immune-modulating effects, and may inhibit the growth of colon cancer cells (Liu, Adv Nutr 2018; Steliou, Biores Open Access 2012).

Forms of butyrate in supplements

In supplements, butyrate is typically sold in the form of a

  • salt, as sodium butyrate, as a
  • calcium-magnesium butyrate compound, or in the
  • triglyceride form, tributyrate.

Tributyrate is the form of butyrate that that naturally occurs in butter, and preliminary evidence from an animal study suggests that this form may have more beneficial effects in the intestines than sodium butyrate (Xiong, Braz J Poult Sci 2018), although more research in people is needed to confirm this. Unlike tributyrate, a large proportion of sodium butyrate, when taken orally, is absorbed in the upper gastrointestinal tract before it reaches the lower intestine and colon. For this reason, sodium butyrate supplements are sometimes sold in enteric-coated or slow-release formulations.

Health benefits of butyrate supplements

Irritable bowel syndrome (IBS)
Two small studies suggest butyrate may reduce pain and urgency of bowel movements, and may reduce symptoms such as abdominal pain and bloating in some people with IBS, but larger, better-designed studies are needed to prove a benefit.

One study in Italy among 50 men and women with either diarrhea-predominant or constipation-predominant IBS suggested that butyrate supplementation may have a greater benefit in people with diarrhea-predominant IBS. In the study, all of the participants took 420 mg of sodium butyrate combined with inulin (amount not provided) taken as an enteric-coated tablet four times daily (providing a total of 1,000 mg sodium butyrate per day) for one month. At the end of the study, participants with diarrhea-predominant IBS had significant reductions in abdominal pain, bloating and flatulence compared to baseline, while those with constipation-predominant IBS did not have a decrease in symptoms. A greater number of participants with diarrhea-predominant IBS also reported complete improvement compared to those with constipation-predominant IBS (15 vs 4). However, because the supplement included inulin (a prebiotic compound that "feeds" bacteria in the colon), it’s not known which ingredient was responsible for these effects, and the lack of a placebo-control (needed to prove a benefit) limits the significance of these findings (Scarpellini, Dig Liver Dis 2007).

A study in Poland among 66 men and women (average age 32) with mild to moderate IBS (not differentiated by type) found that 150 mg of microencapsulated sodium butyrate taken twice daily (a total of 300 mg per day) for 12 weeks decreased abdominal pain, pain during bowel movements and urgency of bowel movements, but did not reduce abdominal pain, straining during bowel movements, or flatulence, compared to placebo (Banasiewicz, Colorectal Dis 2013).

Crohn's disease
There do not appear to be any randomized, placebo-controlled trials on the effects of butyrate supplementation in people with Crohn’s disease. In a preliminary study in Italy with no placebo control, 8 of 13 adults (average age 40) with mild to moderate Crohn’s disease who took butyrate each day for eight weeks had clinically-meaningful improvement in symptoms, and five of them had complete remission confirmed by endoscopy. The participants took slow-release enteric coated tablets providing 2,000 mg of butyrate twice daily (a total of 4,000 mg of butyrate per day – form of butyrate not provided) in addition to standard medication (mesalazine, 2.4 grams per day). One participant was removed from the study due to worsening symptoms (Sabatino, Aliment Pharmacol Ther 2005).

Diverticulitis
One clinical trial suggests butyrate supplementation may have benefit in people with diverticulitis, a condition in which small, bulging pouches develop at weak places along the intestine, particularly the colon, which can become inflamed, bleed, or perforate. In the study, 52 men and women (average age 64) in Poland who had diverticulitis for an average of about 10 years took either a butyrate supplement (150 mg of microencapsulated sodium butyrate taken twice daily) or placebo, for one year. Over the course of the year, the number of participants who had episodes of diverticulitis was significantly lower among those who took butyrate compared to placebo (2 vs 7). In addition, a greater percentage of those who took butyrate reported adequate relief of abdominal pain and discomfort (56% of participants vs 24%) (Krokowicz, Int J Colorectal Dis 2014).

Alzheimer’s disease
It's been theorized that dysregulation of bacteria in the gut, particularly overgrowth of pro-inflammatory bacteria or lack of bacteria that produce butyrate, may play a role in the neurological diseases such as Alzheimer's via the "gut-brain-axis" – the biochemical communication that occurs between the gut and the central nervous system (Tremlett, Ann Neurol 2017). Laboratory and animal studies also suggest that, in the brain, butyrate may help to protect brain cells, and one study found that giving sodium butyrate improved memory performance in mice with advanced-stage Alzheimer’s like disease (Govindarajan, J Alzheimers Dis 2011). Two small studies have found that older adults with Alzheimer's disease or other forms of dementia were more likely to have a lower proportion of bacteria that can synthesize butyrate, and a higher prevalence of bacteria known to produce inflammatory substances, than those without Alzheimer's (Haran, mBio 2019; Stadlbauer, BMC Geriatr 2020). However, these results do not prove that lack of butyrate causes Alzheimer’s disease or dementia, nor does it prove the butyrate supplementation improves memory or cognition in people with dementia or related conditions. There does not appear to be any research on the effects of butyrate supplementation in people with dementia.

Beneficial gut microbiota

A small, preliminary study among 32 men and women (average age 29) showed that supplementation with 300 mg of tributyrin for 21 days modestly altered the ratio of certain potentially beneficial bacteria and bacteria that produce butyrate in stool, but these changes were not statistically significant compared to placebo, and the study did not measure any clinical outcomes (Grosicki, J Acad Nutr Diet 2021).

Safety
Butyrate supplements appear to be generally well-tolerated. In the clinical studies discussed above, no adverse effects or side effects were reported.

Be aware the supplements containing the sodium butyrate form of butyrate can contain a significant amount of sodium. For example, a suggested 2-capsule daily serving of BodyBio's Sodium Butyrate contains 313.3 mg of sodium.

Products on the market:

The cost of butyrate products on the market vary in cost depending on the form of butyrate and dosage. For example, a 30-day supply (60 capsules) of BodyBio's Sodium Butyrate, which provides 1,200 mg of butyrate per 2-capsule serving and is not enterically coated or slow-release, costs $20.00. Healus Complete Biotic Tributyrin Based Butyrate Supplement, which contains 500 mg of tributyrin per capsule in a delayed-release capsule, costs about three times as much per capsule at $59.99 for a 30-day supply if taking two capsules daily (suggested use is to start with one capsule, and increase to two to three times per day).

Be aware that butyrate and sodium butyrate have a strong odor that many people find unpleasant, which may be noticeable, especially if breaking apart capsules or tablets. Tributyrate has a fainter odor, and some people prefer it for this reason.

Getting (or making) butyrate from food
Consuming dairy product such as butter, yogurt and cheese can provide small amounts of butyrate. Butter, for example, contains 3–4% butyric acid in the form of tributyrate. In addition, consuming foods high in dietary fiber and/or resistant starch, such as beans and legumes, bananas, onions, and asparagus, can naturally increase butyrate levels in the colon (Bourassa, Neurosci Letters 2016).

The bottom line for butyrate:
Small clinical trials suggest that butyrate supplements, in doses from 300 mg to 4,000 mg per day, are generally well-tolerated and may reduce symptoms of certain digestive conditions such as irritable bowel syndrome and diverticulitis. However, due to the lack of details about the formulation used, or lack of placebo controls in some of these studies, more research is needed to prove a benefit. Consuming healthy foods that provide resistant starch or non-digestible fiber (such as legumes, bananas, and onions) may boost butyrate-producing bacteria in the gut.

VitaminDWiki - Microbiome 38 items

15 studies in both categories Microbiome and Gut

This list is automatically updated

Some probiotics provide the bacteria that makes Buyterate naturally in the gut

Note: ~A month of probiotics MIGHT eliminate need for on-going Buyterate supplements

  • Butyricum
  • Prospects for clinical applications of butyrate-producing bacteria - Sept 2021 FREE PDF

See also: Strong interactions between Vitamin D and the gut microbiota via Butyrate and VDR – Dec 2019

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