Physiology of the Colon

Eric J. Daniels

Marvin L. Corman

Man and the animals are merely a passage and channel for food, a tomb for other animals, a haven for the dead, giving life by the death of others, a coffer full of corruption.

—LEONARDO DA VINCI: Codice Atlantico, 76

The study of large bowel physiology has historically been overshadowed by concerted efforts to comprehend the workings of the stomach and small intestine. Despite this indifference, which is perhaps in part a consequence of the knowledge that human beings can thrive in the absence of a colon, we have become aware that the large intestine is responsible for maintaining important homeostatic functions. The primary physiologic purposes of the large bowel include the following: further breakdown of ingested materials by microfloral metabolism, absorption of water and electrolytes, secretion of electrolytes and mucus, storage of semisolid matter, and propulsion of feces toward the rectum and anus. These colonic functions act in concert to respond to the needs of the body while concomitantly producing fecal material suitable for evacuation. For example, although the digestive functions of the large bowel are dwarfed by the contributions of the small intestine, the absorptive and secretory capacities of the colonic mucosa are critical for regulating the intraluminal fluid volume and contributing to serum electrolyte balance. In addition, the role of the colon in intermittent storage and propulsion of semisolid matter is central to normal defecation and is the consequence of complex neural and hormonal interactions. The purpose of this chapter is to present a current, general view of normal large bowel physiology to facilitate the discussion of colonic pathophysiologic processes presented subsequently.

▶ FUNCTIONAL CLASSIFICATION

The large bowel is approximately 150 cm (5 ft) in length and consists of the vermiform appendix, cecum, colon (ascending, transverse, descending, sigmoid), and rectum. This somewhat arbitrary segmentation of the large bowel is not strictly anatomic because it is widely appreciated that the large intestine is a heterogeneous organ with regional, biochemical, pharmacologic, and thus functional differences.

Cecum and Ascending Colon (Right Colon)

Digested material entering the large intestine at the ileocecal junction remains in the cecum and right colon for an extended period. Here, the resting propulsion rate is only 1 cm/hour.⁹⁶ This retention and mixing of ileal effluent permit aerobic and anaerobic metabolism of residual carbohydrate and protein by the intestinal flora, thereby producing multiple by-products, most of which are then absorbed through the remaining colon. In addition to being the primary site for bacterial fermentation, the ascending colon (along with the transverse colon) is involved in regulating intraluminal fluid volume as well as sodium and water absorption.³⁷^,³⁸ The importance of these colonic functions can be appreciated by reviewing recorded motility patterns, which demonstrate frequent retropulsive waves extending from the transverse colon back toward the cecum.¹⁵^,⁹⁶

Transverse Colon

The transverse colon is generally believed to serve as a rapid conduit between the proximal (right) and distal (left) components of the large bowel. This belief is supported by the finding that the basal electrical rhythm and muscle-generated pressure waves in this segment occur with a greater frequency than is identified in the right colon. This observation
suggests a rapid, propulsive function.¹⁹^,¹¹⁸^,¹²² As mentioned previously, the transverse colon is also an important site for sodium and water absorption, a function that is critical to volume regulation.

Left Colon

The left colon is the site for final modulation of intraluminal contents before evacuation. The diminished rate of fluid and electrolyte transfer seen in the descending colon is ultimately a result of distinct protein ion channels in the luminal (apical) and serosal (basolateral) membranes of mucosal cells, which exhibit different biochemical and pharmacologic properties when compared with those of the ascending colon. The distal large intestine also is thought to exhibit a reservoir function or storage capacity, which some believe is important in maintaining anal continence. Although the concept is somewhat controversial, it theoretically relies on the physical barrier of the sigmoid angulations and myoelectrical differences between the sigmoid colon and rectum. This is discussed later. With respect to the rectum, in vitro studies have demonstrated that little or no net absorption occurs there.³⁷^,³⁸

▶ DIGESTION

Digestion within the large bowel is an often overlooked issue, given the enormous capacity of the small intestine in this regard. However, despite its poorly recognized participation in the breakdown of foodstuffs to fulfill energy requirements, the healthy colon is capable of salvaging calories from poorly absorbed carbohydrates and proteins.

Flora of the Large Intestine

The digestive processes of the colon are a consequence of the microorganisms that colonize the bowel and thereby participate in a symbiotic relationship with the host. Whereas yeast and other fungi are normally present in very small numbers,³⁰ bacteria clearly dominate the lumen. In humans, the large intestine is the primary site of bacterial colonization, with more than 400 different species of bacteria identified.⁴⁶ Bacterial colonization begins in infancy and occurs predominantly in the cecum and right colon. Studies reveal up to 10¹² bacteria per gram of wet feces.¹⁰³ Given this amount, it is not surprising that bacteria make up 40% to 55% of fecal solids in individuals consuming a typical Western diet.¹¹³

The primary tasks of gut flora can be divided into metabolic, trophic, and protective functions. Metabolic functions include fermentation of nondigestible dietary residue and endogenous mucus, production of short-chain fatty acids (SCFAs), and production of vitamin K. Trophic functions include controlling epithelial cell proliferation and differentiation as well as homoeostasis of the immune system. The protective activity of the colonic flora stems from the ability to serve as a barrier to colonization against pathogens. Although these functions are robust in healthy individuals, a breakdown of the dynamic relationship between the gut flora and its host may lead to disease states.

Guarner and Malagelada reviewed the role of gut flora in health and disease.⁵⁸ The authors note that a dysfunction in the barrier activity of gut flora can result in the translocation of many viable microorganisms, particularly the gram-negative aerobic genera. Once beyond the epithelial reef, the organisms can travel to extraintestinal organs via the lymphatic highway.⁵⁸ Dissemination of enteric bacteria can lead to sepsis, shock, multisystem organ failure, and ultimately death of the patient. The rates of positive blood cultures are significantly higher in individuals with conditions such as intestinal obstruction and inflammatory bowel disease.⁷⁴ O’Boyle and colleagues reported that bacterial translocation is associated with an increase in postoperative sepsis.⁸⁸ In addition to translocation of bacteria, gut flora have been implicated to play an active role in carcinogenesis and inflammatory bowel disease. Bacteria belonging to the Bacteroides and Clostridium genera have been shown to increase the incidence of tumor formation in laboratory animals.⁶⁵ In patients with Crohn’s disease and ulcerative colitis, there is increased secretion of immunoglobulin G, a class of antibody that can damage intestinal mucosa through activation of the complement cascade.¹²^,⁷⁷

Within the complex ecosystem of the large intestine, certain groups of bacteria thrive over others. In principle, those able to transform variable amounts and types of substrate into energy are likely to be present in large proportions. Although Bacteroides organisms (gram-negative rods) are most commonly identified, the gram-positive Eubacterium and Bifidobacterium are also present in large numbers, along with several gram-positive cocci and Clostridium species.³⁰^,⁴⁶^,⁸⁴ It is axiomatic that the surgeon’s knowledge of normal colonic flora is paramount to proper antibiotic management for both prophylactic and postoperative situations.

Substrates for Fermentation

Nondigestible Starch

To appreciate the end products of bacterial fermentation, one must first look at the substrate that passes through the ileocecal junction and is presented to the microorganisms. Quantitatively, the most important is nonhydrolyzed or resistant starch. Christl and colleagues performed breath hydrogen and methane studies using whole-body calorimetry to measure undigested polysaccharide reaching the large intestine.²³ The authors noted that starch is to some degree incompletely digested in the small bowel and is passed to the ascending colon. Others have confirmed this observation.⁴⁴^,⁷³ Generally, it is accepted that approximately 10% of ingested starch will elude small bowel digestion to reach the colon and be available for fermentation in individuals consuming a Western diet.³⁰

Nonstarch Polysaccharides

Nonstarch polysaccharides represent another class of substrate available for bacterial metabolism. These molecules are the derivatives of plant material and include cellulose as well as noncellulose substrates. The degree of nonstarch polysaccharide metabolism is dependent on several physiologic circumstances. For example, the smaller and more hydrophilic the substrate, the more readily digestible it is.⁶²^,¹¹² This and other physiologic variables, such as transit time, ultimately determine the extent of cellulose and noncellulose breakdown by the resident flora. Topping and Clifton contrasted the role of resistant starch and nondigestible starch in human colonic function.¹¹⁷ The authors viewed the actions of resistant starch and nondigestible starch in the context of a balance between luminal passage and fermentation. Fiberrich foods, with a high content of insoluble nonstarch polysaccharides, are not as fermentable by microflora. As such, fiber-rich foods serve well as laxatives. On the other hand,
most resistant starches are readily fermentable by large bowel microflora, giving rise to the SCFAs discussed later. Topping and Clifton state that the greatest difference between resistant starches and nonstarch polysaccharides lies in relation to cancer risk.¹¹⁷ The authors report that whereas the protective effect of resistant starches to chemically induced cancers is inconsistent in small animals,⁷^,⁶¹ there exist strong epidemiologic data pointing to a negative relationship between total starch consumption and large bowel neoplasms.¹¹¹^,¹¹⁶ However, evidence of a discrete benefit for fiber is not as strong, with several low-risk populations ingesting little fiber.⁶³^,⁷¹^,⁸⁹ The authors conclude that although the protective effect of resistant starch is encouraging, the limitations of methodology and small animal models cannot justify a recommendation to increase dietary levels at this time.

Other Substrates

Although most of the substrate made available to the colonic bacteria consists of the starch and nonstarch polysaccharides mentioned earlier, other substances do pass into the cecum and are subsequently metabolized. For example, sugar and sugar alcohols, such as lactose, raffinose, lactulose, and sorbitol, are readily metabolized by the bowel microorganisms.³⁰^,¹¹⁴ In addition to polysaccharides, various peptide substrates are made available for bacterial digestion. Poorly absorbed protein sources include elastin, collagen, and albumins, and most abundant are the pancreas-derived proteases.³⁰ In contrast, urea and ammonia are not generally available as nitrogen sources for the colonic flora.⁴⁸ Overall, the daily ileal effluent will make available 6 to 18 g of nitrogen-containing compounds for bacterial fermentation, compared with 8 to 40 g of carbohydrate.³⁰

Products of Bacterial Metabolism

The principal products of microorganism fermentation of polysaccharides in the large bowel are SCFAs or volatile fatty acids. The production of SCFAs decreases from the proximal to the distal colon, an observation that can be most likely attributed to the different bacterial populations in these regions. These fatty acids contain from one to six carbons and are the predominant colonic anions. The three most abundant are acetate, propionate, and butyrate, with their production accounting for up to 95% of total SCFA generation.³⁰

It has long been thought that dietary intake should have profound effects on fermentation products. However, several investigators have noted that variations in diet have only a minimal effect on SCFA production. Saunders and Wiggins employed three different sugars—mannitol, lactulose, and raffinose—and measured SCFA production.¹⁰⁷ They found no significant variability among the different sugar substrates. This finding has been confirmed by others through a variety of fermentation substrates, including wheat bran.²⁹ Based on these metabolic studies, it has been calculated that the conversion for the amount of SCFAs produced per unit weight of carbohydrate is 50%.

Short-Chain Fatty Acid Absorption

More than 90% of SCFAs produced by bacterial fermentation are taken up by the colonic mucosal cells.⁸¹^,⁹⁵ In small animal models, approximately 60% of the uptake is by simple diffusion of protonated, neutral SCFA. The remainder of uptake (ionized SCFA) occurs by active, cellular uptake.⁴⁷ However, the mechanism for uptake by the colonic epithelium remains unresolved. It is clear, however, that the absorption mechanism differs from that of the long-chain fatty acids absorbed in the small intestine. For example, long-chain fatty acids require emulsification with bile salts.

Experimental models have been used to attempt to clarify the transport mechanisms involved. A large body of evidence exists pointing to the passive diffusion of these fatty acids toward the serosa.²⁴^,¹⁰⁵ As mentioned earlier, SCFAs are weak acids with negative logs of dissociation constant ranging from 4.75 to 4.87, and most of these molecules exist in their ionized form at a pH higher than 5. As charged species, the SCFAs would be unable to traverse the hydrophobic environment of the apical membrane. However, studies of the mammalian gastrointestinal tract have shown SCFAs to be absorbed rapidly at a pH of 7.² In light of this apparent contradiction, some investigators have pursued the possible protonization (binding of a hydrogen ion) of the anionic form of the SCFA, rendering the molecule neutral and thus better able to cross the lipophilic membrane. One proposed mechanism is that protons are generated from the conversion of carbon dioxide and water by intramucosal carbonic anhydrase. This would account for the accumulation of bicarbonate seen with SCFA absorption.⁴^,¹⁰⁴ An additional source of protons may be found in the presence of a sodium ion-proton antiport (exchange), an idea supported by the fact that SCFA absorption has been reported to increase sodium and water absorption.¹⁰⁵ Using in situ perfusion of guinea pig colon, Oltmer and von Engelhardt reported that inhibition of the apical proton antiport and carbonic anhydrase systems resulted in decreased SCFA absorption.⁹⁰ Although neither of these mechanisms can completely explain SCFA absorption, their existence is consistent with the fact that SCFA transport is associated with increased luminal pH, increased bicarbonate ion concentration, and enhanced sodium absorption.⁶⁰

Outside of the passive mechanisms discussed earlier, the presence of an apical, carrier-mediated anionic exchange involving SCFAs and bicarbonate ion has been suggested.⁷⁹^,¹²¹ Harig and colleagues used human luminal vesicles to investigate the transport of N-butyrate.⁶⁰ The authors found that butyrate transport was minimal in the presence of an inward pH gradient but significantly increased by an outward bicarbonate ion gradient. Furthermore, the effects of sodium and chloride on transport were negligible. The authors concluded that the primary mechanism for butyrate transport appears to be through a bicarbonate-SCFA antiport system independent of sodium transport or bicarbonate-chloride anion exchange. As more becomes known about the mechanisms of SCFA transport, it is increasingly clear that this function is a heterogeneous one, with observed segmental differences.⁸⁶^,¹¹⁰

Additional investigations are being conducted on the transport mechanisms responsible for SCFA absorption. This interest is being stimulated by the potential utility of such knowledge in clinical situations, such as promoting caloric intake in patients with short-bowel syndrome, developing SCFA enemas for patients with ulcerative colitis, and understanding mechanisms underlying diarrhea and even colonic neoplasms.

Physiologic Actions of Short-Chain Fatty Acids

The SCFAs produced as a result of bacterial fermentation of poorly absorbed polysaccharides play several important roles in large bowel function. SCFAs are relatively weak acids. Therefore, higher concentrations of SCFAs lower the luminal
pH. Lower pH values can alter the growth profiles of pHsensitive pathogenic bacteria such as Escherichia coli and Salmonella.²⁰ As such, SCFAs have been shown to assist in the treatment of infectious diarrhea. Furthermore, elevation of fecal SCFAs has been shown to diminish the fluid loss and speed of remission during the active phase of cholera.⁹⁴

These acids are readily absorbed by the columnar epithelium, as discussed earlier.¹³^,²⁷^,²⁸ Once absorbed, the SCFAs have been reported to contribute up to 7% of the basal metabolic requirements of humans.²⁸ In fact, the colonic epithelium derives almost 75% of its energy needs from these fatty acids through metabolism to carbon dioxide, ketone bodies, and lipid precursors.¹⁰⁰^,¹⁰¹ In addition to luminal nutrition, SCFAs have been investigated for their anti-inflammatory properties as well as their antitumor effects.¹ They have also been shown to increase regional blood flow and have a demonstrable effect upon gastrointestinal muscular activity. Rectal infusion of SCFA into human surgical patients leads to a 1.5- to 5-fold increase in splanchnic blood flow as well as to a decrease in gastric tone leading to volume expansion.⁸⁵^,¹⁰² Additionally, the absorption of SCFAs is tied closely to the transport of bicarbonate, sodium, and water, thus providing a mechanism for the regulation of intraluminal volume.⁸²^,¹⁰⁸

Other Products of Noncarbohydrate Fermentation

The fermentation of peptides by microorganisms results in substances such as SCFAs, branched-chain fatty acids, isobutyrate, and methylbutyrate. However, not all end products of peptide metabolism are of benefit to the organism. For example, the deamination of amino acids gives rise to ammonia, which has been demonstrated to have toxic effects on colonic epithelium by altering normal cell metabolism.¹²³^,¹²⁷ In addition, the catabolism of amino acids results in the production of phenols, indoles, and amines, which have been implicated in disease states such as hepatic coma and colorectal cancer.³⁹^,⁴⁰^,⁹¹

▶ COLONIC ABSORPTION AND SECRETION

The absorption and secretion of water, mucus, and electrolytes, particularly sodium, are complex and central processes of normal colonic activity. These processes determine the electrolyte and volume content of feces. However, the capacity of the colon to absorb and digest material is not uniform, with the proximal mucosa exhibiting different properties from its distal counterpart. Although colonic epithelium does not participate in active glucose or amino acid absorption,⁹ as occurs in the small intestine, the mechanistic and functional segmental differences of these cells are of importance to the surgeon because the diverse colonic resection procedures have various consequences. As with the evaluation of absorption and secretion in other organs, such as the small intestine and kidney, study of transport in the colon is directed toward an understanding of the epithelial phenomena.

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