Anti-inflammation

Intestinal epithelium maintains a low grade of inflammation in order to prepare for constant immunological challenges on the mucosal surface (4861). If the immunological control is disrupted, the enterocytes might suffer from inflammatory and oxidative damages and even cause cancer (6263). Many studies have shown that butyrate can act as an anti-inflammatory agent. Several human and animal studies reported that the proinflammatory cytokines IFN-γ, TNF-α, IL-1β, IL-6, and IL-8 are inhibited, whereas IL-10 and TGF-β are upregulated in response to butyrate (25). The mechanism underlying the anti-inflammatory effect of butyrate is at least in part due to inhibition of the activation of a transcription factor known as NF-κB (64). NF-κB is a transcription factor that regulates the expression of a variety of genes involved in inflammation and immunity, such as proinflammatory cytokines and enzymes, adhesion molecules, growth factors, acute-phase proteins, and immune receptors (4865). Several studies suggested that butyrate suppresses the NF-κB signaling pathways by rescuing the redox machinery and controlling reactive oxygen species, which mediates NF-κB activation (66). Further studies also showed that butyrate is capable of activating PPAR-γ (67), which is a member of the nuclear hormone receptor family and highly expressed in colonic epithelial cells, and its activation is thought to exert anti-inflammatory effects (68). Apart from the inhibition of NF-κB activation and upregulation of PPAR-γ, butyrate may also exert its anti-inflammatory activities through inhibition of IFN-γ signaling (69).

Butyrate and the intestinal barrier

The barrier function of intestinal epithelial cells is an important first line of defense and ensures appropriate permeability characteristics of the epithelial layer (370). Butyrate is known to repair and enhance barrier function of intestinal epithelial cells (7172). A current study by Elamin et al. (73) showed that butyrate exerts a protective effect on intestinal barrier function in Caco-2 cell monolayers. For example, butyrate is capable of upregulating the expression of mucin 2 (MUC2) (74), which is the most prominent mucin on the intestinal mucosal surface and can reinforce the mucous layer, leading to the enhanced protection against luminal pathogens (174). In addition, the expression of trefoil factors (TFFs), which are mucin-associated peptides that contribute to the maintenance and repair of the intestinal mucosa (12), can be increased by butyrate (75). Furthermore, butyrate modulates the expression of tight junction proteins to minimize paracellular permeability (6276). One of several mechanisms in which butyrate enhances barrier function is through activation of AMP-activated protein kinase in monolayers (77). Butyrate can also stimulate the production of antimicrobial peptides, such as LL-37 in humans (78). However, on the basis of in vitro models, Huang et al. (79) showed that the effect of butyrate on the intestinal barrier function may be concentration-dependent. Butyrate promotes intestinal barrier function at low concentrations (≤2 mM) (77) but may disrupt intestinal barrier function by inducing apoptosis at high concentrations (5 or 8 mM) (79). On the basis of the physiologic concentration in mammalian gastrointestinal tract, the recommended concentration of butyrate used in in vitro models is currently 0–8 mM (80). However, considering that the majority of butyrate is metabolized as energy substrate by the colonic epithelium (12), the dosages used for treatment may be quite different between in vivo and in vitro models (4). For example, a dose of 100 mM butyrate by rectal administration was commonly used in clinical practice, which is comparable with physiologic concentrations in the colon of humans after the consumption of a high-fiber diet (81).

Butyrate and intestinal mucosal immunity

In addition to anti-inflammatory properties, SCFAs, especially butyrate, can act as modulators of chemotaxis and adhesion of immune cells (61). Butyrate can modulate intestinal epithelial cell–mediated migration of neutrophils to inflammatory sites, and such an effect is concentration-dependent (8283). In addition, butyrate plays a role in cell proliferation and apoptosis. Butyrate stimulates cell growth and DNA synthesis and induces growth arrest in the G1 phase of the cell cycle (561). Although low concentrations of butyrate enhance cell proliferation (5), high concentrations of butyrate induce apoptosis (57). Overall, butyrate can influence the immune response by affecting immune cell migration, adhesion, and cellular functions such as proliferation and apoptosis.

Butyrate and Obesity: Inhibition or Promotion?

The abnormalities in glycolipid metabolism are a main reason for obesity, diabetes, and other metabolic syndromes (84). So far, the effect of butyrate on glycolipid metabolism remains controversial. We summarized the experimental studies that evaluated the potential relation between butyrate and obesity.

A growing body of evidence indicates extensive communications between the brain and the gut via the gut-brain axis (115116). The gut-brain axis is composed of the central nervous system, enteric nervous system, and different types of afferent and efferent neurons that are involved in signal transduction between the brain and gut (15117). The bidirectional communication between the gut and the brain occurs through various pathways, including the vagus nerve, neuroimmune pathways, and neuroendocrine pathways (118119). As a microbial metabolite, butyrate is capable of exerting its effects on host metabolism indirectly by acting through the gut-brain axis (114120). For instance, butyrate can enhance the proportion of cholinergic enteric neurons via epigenetic mechanisms (121). Moreover, with an ability to cross the blood-brain barrier, butyrate activates the vagus nerve and hypothalamus, thus indirectly affecting host appetite and eating behavior (122123). Some of the beneficial metabolic effects of butyrate are mediated through gluconeogenesis from the gut epithelium and through a gut-brain neural circuit to increase insulin sensitivity and glucose tolerance (124125). For example, butyrate binds to its receptor in the intestinal cells and signals to the brain through the cAMP signaling pathway (126127).


Fruits and Vegetables

Consumption of fruits and vegetables such as green beans, legumes, leafy greens, apples, kiwi and oranges might also increase the plasma butyrate content because of increased fiber content. Fruits also provide several vitamins and minerals and are one of the best and healthy sources of butyrate.