A look at the smelly side of physiology: transport of short chain fatty acids

Abstract

Fermentative organs such as the caecum, the colon, and the rumen have evolved to produce and absorb energy rich short chain fatty acids (SCFA) from otherwise indigestible substrates. Classical models postulate diffusional uptake of the undissociated acid (HSCFA). However, in net terms, a major part of SCFA absorption occurs with uptake of Na and resembles classical, coupled electroneutral NaCl transport. Considerable evidence suggests that the anion transporting proteins expressed by epithelia of fermentative organs are poorly selective and that their main function may be to transport acetate, propionate, butyrate and HCO as the physiologically relevant anions. Apical uptake of SCFA thus involves non-saturable diffusion of the undissociated acid (HSCFA), SCFA/HCO exchange via DRA (SLC26A3) and/or SCFA-H symport (MCT1, SLC16A1). All mechanisms lead to cytosolic acidification with stimulation of Na/H exchange via NHE (SLC9A2/3). Basolaterally, Na leaves via the Na/K-ATPase with recirculation of K. Na efflux drives the transport of SCFA anions through volume-regulated anion channels, such as maxi-anion channels (possibly SLCO2A1), LRRC8, anoctamins, or uncoupled exchangers. When luminal buffering is inadequate, basolateral efflux will increasingly involve SCFA/ HCO exchange (AE1/2, SCL4A1/2), or efflux of SCFA with H (MCT1/4, SLC16A1/3). Furthermore, protons can be basolaterally removed by NHE1 (SCL9A1) or NBCe1 (SLC4A4). The purpose of these transport proteins is to maximize the amount of SCFA transported from the tightly buffered ingesta while minimizing acid transport through the epithelium. As known from the rumen for many decades, a disturbance of these processes is likely to cause severe colonic disease.

Possible influence of free fatty acid receptors on pH regulation in the ruminal epithelium of sheep

“…On the other hand, a stimulation of FFAR2 in the basal compartment of the epithelium might be achieved when butyrate is transported to the basolateral side. Several pathways have already been detected for the transport of luminal SCFAs across the ruminal epithelium: Besides protein‐mediated transport mechanisms (reviewed by Stumpff ), transmembrane diffusion of the undissociated acid is favoured by butyrate's high lipophilicity (Gäbel, Vogler, et al, ; Sehested et al, ). According to the Henderson‐Hasselbalch equation, the reduction in mucosal pH from 7.4 to 6.5 increases the proportion of HSCFAs by a factor of ~8, facilitating their luminal uptake via lipophilic diffusion.…”

“…In addition to ensuring the energy supply of the whole organism, SCFAs (esp. butyrate) also serve as the main energy source of the ruminal epithelium itself (Stumpff, ).…”

“…As the cytosolic pH is 6.8–7.4 (Müller, Aschenbach, & Gäbel, ), HSCFAs rapidly dissociate once they enter the cells (Müller et al, ) and deliver SCFA − and H + intracellularly. As reviewed by Stumpff (), several pathways for SCFA transport across the ruminal epithelium have already been detected, of which not only the permeation of protonated acids via lipophilic diffusion (Gäbel, Vogler, & Martens, ) acidifies the intracellular pH (pH i ), but also the exchange of SCFA − for (Aschenbach, Bilk, Tadesse, Stumpff, & Gäbel, ) and their H + ‐coupled import (Kirat et al, ). Furthermore, a certain proportion of SCFAs is metabolized to ketone bodies and lactate within the epithelium (Sehested, Diernæs, Møller, & Skadhauge, ).…”

Involvement of butyrate in electrogenic K+ secretion in rat rectal colon

“…Short-chain fatty acids (SCFAs: mainly acetate, propionate, and butyrate) are produced by anaerobic bacterial fermentation from dietary fiber within the lumen of the mammalian colon [51]. SCFAs are considered to play important roles as a source of nutrients and suppressant of colonic carcinoma [21].…”

“…SCFA transport is regarded as an important factor that regulates colonic fluid balance, absorption of NaCl, and luminal and intracellular pH [40]. The pKa of SCFAs is approximately 4.8 and, thus, most SCFAs are present as anions at physiological pH 6–7 in the lumen of the colon [18, 51]. The carrier-mediated transport of ionized SCFAs into colonic epithelial cells includes (1) Na + -coupled transporters for monocarboxylates (SMCT1, also referred to as SLC5A8), (2) SCFA − /HCO 3 − exchangers (primarily SLC26A3 with the possible additional involvement of SLC26A6), and (3) H + -coupled monocarboxylate transporters (MCT1, MCT4, and MCT5, also referred to as SLC16A1, SLC16A3, and SLC16A4, respectively) [51].…”