Implications of butyrate and its derivatives for gut health and animal production ncbi.nlm.nih.gov/labs/pmc/a...
Looks like I won't be dropping butyrate anytime soon.
2. Butyrate in the human colon
The importance of butyrate for human colon health has been demonstrated in many studies with patients suffering from colon inflammatory diseases. The colonocytes of these patients present with an impaired capacity to oxidize butyrate (Hamer et al., 2010, De Preter et al., 2011). Through its function as an HDI, butyrate can exert actions related to cellular homeostasis including anti-diarrhetic, anti-oxidant, anti-carcinogenic, and anti-inflammatory functions (Williams et al., 2003, Mathew et al., 2014, Jahns et al., 2015).
The absorption of butyrate has been shown to promote the absorption of sodium, potassium, and water, the effects that give it antidiarrheal properties (Ruppin et al., 1980). This is significant as diarrhea is a recognized complication in critically ill patients. Additionally, patients with short bowel syndrome often experience significant loss of water and sodium due to the lack of absorption; butyrate supplementation can improve this absorption and reduce the requirement for intravenous electrolyte replacement (Tappenden, 2010). Dysbiosis, a primary cause of diarrhea, is caused by an antibiotic disturbance of the gut microbiota that suppresses their fermentation and production of butyrate (Whelan and Schneider, 2011). With the supplementation of fiber into the diets of jejunal feeding critically ill patients, an increase in butyrate-producing bacteria was observed, and 75% of patients exhibited a cessation of diarrhea (O'Keefe et al., 2011).
The anti-inflammatory properties of butyrate have been shown to be mediated by several mechanisms including: the reduction of pro-inflammatory cytokine expression (interferon gamma [IFN-γ], tumor necrosis factor-α [TNF-α], interleukin-1B [IL-1B], IL-6, IL-8), the induction of IL-10 and transforming growth factor-B (TGF-B) expression and signaling, the induction of nitric oxide synthase and metalloproteinases, and the reduction of lymphocyte proliferation and activation (Kyner et al., 1976, Segain et al., 2000, Matsumoto et al., 2006, Meijer et al., 2010, Fung et al., 2012). The most studied anti-inflammatory pathway of butyrate is via the inhibition of nuclear factor kappa B (NF-kB). This pathway controls the expression of genes encoding pro-inflammatory cytokines, inflammation-inducing enzymes, growth factors, heat shock proteins, and immune receptors (Vinolo et al., 2011).
Several studies have linked impaired butyrate metabolism with mucosal damage and inflammation in patients with inflammatory bowel diseases including ulcerative colitis and Crohn's disease (Roediger, 1980, Den Hond et al., 1998, Duffy et al., 1998, De Preter et al., 2011, Kovarik et al., 2011, De Preter et al., 2012, Morgan et al., 2012), suggesting that treatments to increase butyrate in the GIT of these patients can prove to be beneficial. More data have indicated that intestinal inflammation also affects butyrate transport, and thus its oxidation (Thibault et al., 2007). Various experimental models have shown that monocarboxylate transporter 1 (MCT1) transports butyrate into colonic epithelial cells (Tamai et al., 1995, Ritzhaupt et al., 1998, Cuff et al., 2005), and that MCT1 downregulation is common in patients with ulcerative colitis (Thibault et al., 2010, De Preter et al., 2011). Butyrate intake has shown a positive effect in experimental studies on inflammatory bowel disease (Hamer et al., 2010, Komiyama et al., 2011, Vieira et al., 2012), though clinical studies have shown inconsistent results (Russo et al., 2012). Butyrate irrigation has been shown to improve inflammation symptoms in biopsies from inflammatory bowel disease patients; however, high concentrations are required to illicit these improvements (Segain et al., 2000).
There are several mechanisms by which butyrate can control oxidative stress. In a study with healthy human subjects, the administration of a daily butyrate enema (10,000 mg/kg) for 2 weeks resulted in an increase in the anti-oxidant glutathione, and a decrease in uric acid production compared to those without butyrate treatment (Hamer et al., 2009). However, when a similar study was performed on patients with ulcerative colitis in remission, butyrate showed only minor effects on inflammatory and oxidative stress parameters that seem to be dependent on the level of inflammation (Hamer et al., 2010). In vitro, physiological levels of butyrate have been found to reduce H2O2-induced DNA damage, increase catalase expression (one of the key defense systems against oxidative stress), and reduce cyclooxygenase-2 (COX-2) expression (an indicator of inflammation) in human colonocytes (Sauer et al., 2007). These results also support the potential of butyrate in cancer treatment and prevention, as COX-2 overexpression is found in colon tumors.
Butyrate has been linked to the prevention and inhibition of colon carcinogenesis, largely through the increased intake of dietary fiber, resulting in increased fermentation and butyrate production (Trock et al., 1990, Howe et al., 1992, Bingham et al., 2003). A role for butyrate in colon cancer treatment has been supported by the findings of downregulated butyrate transporters (MCT1 and sodium-coupled monocarboxylate transporter 1 [SMCT1]) in human colon cancer tissue (Lambert et al., 2002, Li et al., 2003), resulting in reduced uptake and metabolism of butyrate in colonocytes. Several rat models have been used to demonstrate a protective effect of butyrate on colorectal carcinogenesis (McIntyre et al., 1993, Kameue et al., 2004, Bauer-Marinovic et al., 2006), but direct evidence for a protective effect of butyrate on carcinogenesis in humans is lacking. One study has investigated the relationship in humans between butyrate and G-protein-coupled receptor GPR109A in the colon (Thangaraju et al., 2009). It was found that butyrate binding to GPR109A can induce apoptosis in colon cancer cells as well as blocking activation of the NF-kB inflammation pathway, potentially mediating inflammatory bowel disease (IBD). Butyrate has also been shown to enhance the effects of anticancer drug therapy including vincristine, celecoxib, cisplatin, and etoposide via its HDI activity, increasing the cytotoxicity of the drugs (Ramos et al., 2004, Kang et al., 2012, Maruyama et al., 2012).
The overall aim for the use of butyrate in humans differs greatly from that for animal production. Although the use of butyrate in humans is desired mainly for the treatment of disease and in animal production is for disease prevention and growth promotion, the functions in enhancing GIT health, releasing stress, and controlling inflammation are commonly desired for both humans and animals. Thus, the mechanisms of butyrate effects revealed by human research can be valuable references to promote the research and application of butyrate and its derivatives in animal production.
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