Small intestine vs. colon ecology and physiology: Why it matters in probiotic administration

Abstract

Research on gut microbiota has generally focused on fecal samples, representing luminal content of the large intestine. However, nutrient uptake is restricted to the small intestine. Abundant immune cell populations at this anatomical site combined with diminished mucus secretion and looser junctions (partly to allow for more efficient fluid and nutrient absorption) also results in intimate host-microbe interactions despite more rapid transit. It is thus crucial to dissect key differences in both ecology and physiology between small and large intestine to better leverage the immense potential of human gut microbiota imprinting, including probiotic engraftment at biological sensible niches. Here, we provide a detailed review unfolding how the physiological and anatomical differences between the small and large intestine affect gut microbiota composition, function, and plasticity. This information is key to understanding how gut microbiota manipulation, including probiotic administration, may strain-dependently transform host-microbe interactions at defined locations.

Graphical abstract

Figure 1

Anatomy and physiology of the small intestine (SI) versus colon (A) Overview of the gastrointestinal tract displaying spatial distribution of key processes influencing microbial colonization. In the healthy individual, liquid volume presented to the lumen of the SI is 8.5 L per day, for which pancreatic and bile secretion accounts for 1.5 and 0.5 L, respectively; ∼6.5 L are reabsorbed in the SI, while ∼2 L enters the colon. Here ∼1.9 L are reabsorbed and ∼0.1 L are lost in fecal secretions. Both secretion and absorption of liquids are affected by diet and diseases. Acidic ventricle secretion is neutralized by natrium hydrogen carbonate-buffered pancreatic juice in the upper duodenum. Proximal duodenum is also the site of bile acid (BA) secretion from the gall bladder. Nominal amounts of bile are passively absorbed through the entire length of the intestine, while the majority is recirculated by active transport in the distal ileum. Simple carbohydrates and protein are absorbed in the SI with a gradually decreasing absorption from proximal duodenum to distal ileum. Complex carbohydrates and proteins escaping digestion in the SI are converted into short-chain fatty acids (SCFAs) by microbial fermentation in the large intestine. (B) Inner mucus layer (colon): green. Loosely attached mucus layer (outer layer in colon and only layer in SI): blue. Villus: in healthy individuals, most dietary lipids are absorbed in the first 60 cm of the SI, where BA concentrations are highest. As chylomicrons are too large to pass through the fenestrae of villus blood capillaries, they instead enter the lymph through larger inter-endothelial channels of the lacteals. Dietary proteins and carbohydrates are digested by pancreatic and brush border enzymes, respectively. Crypt: crypt-residing Paneth cells secreting abundant amounts of HDPs further protect and nurture the neighboring stem cells. In the transit-amplifying zone, lineage-committed progenitor cells swiftly divide to fuel the rapid intestinal cell turnover. Colon: the outer mucus layer provides a niche for mucolytic bacteria, many of which can ferment complex carbohydrates/dietary fibers, thereby generating SCFAs fortifying barrier function, including goblet cell-mediated mucus secretion. IgA, immunoglobulin A; TA-zone, transit-amplifying zone.

Figure 2

Longitudinal differences along human gastrointestinal (GI) tract (A) The abundance of key taxa in a specific gut area, as averaged across all individuals tested in a given study. Six studies are included based on the requirement that they investigated different gut regions within specific individuals. Despite the differences in sampling and microbial analysis techniques, this revealed the consistent difference between microbial communities of the upper and lower GI tract. One community colonizes the duodenum down to the proximal ileum (generally dominated by Pseudomonadota, Streptococcaceae, and Veillonellaceae) and one colonizes the distal ileum down to the rectum (generally dominated by Bacteroidaceae, Lachnospiraceae, and Ruminococcaceae). (B) Weighted average of all the studies included in (A).

Figure 3

Differences in anatomy and microbiota (on genus level) of the small intestine (SI) between two animal models (mouse and pig) vs. humans Upper part: the length of the SI in comparison with the other gut compartments is shown. Mice have a forestomach and a glandular stomach, while pigs and humans have a glandular stomach, but the pig’s stomach is two to three times larger than the human stomach. Middle part: the anatomical structure of the luminal small-intestinal wall is shown, highlighting the absence of plicae circulares or mucosal folds in mice in contrast to pigs and humans. In mice, the finger-shaped villi are directly oriented on the small-intestinal muscle layer (muscularis mucosa), making the mucosal surface smooth. In pigs and humans, there are plicae circulares in distal duodenum, jejunum, and proximal ileum. Lower part: dominant bacterial genera in the SI.

Figure 4

Regional differences in host-diet-microbe interactions In the healthy SI, conditioned by high-fiber dietary intake, crypt-residing Paneth cells secrete an ample amount of host defense peptides (HDPs). Barrier integrity is further bolstered by the loosely adherent mucus layer ensured by well-functioning goblet cells. Changing dietary habits from a balanced high-fiber diet to a typical westernized diet (low in fiber; high in fat, animal protein, and simple sugars) disrupts immune balance, mucus production, Paneth cell function, and microbiota composition. On a westernized diet, but not a balanced fiber-rich diet, Prevotella copri was able to enhance cross-epithelial transport of branched-chain amino acids (BCAAs), potentiating metabolic syndrome. Next, while dietary fibers are passing through the SI, they are metabolized by colonic microbes. The microbial metabolites from this process, SCFAs, stimulate goblet cell function, hence enhancing barrier integrity by increased mucus production. Conversely, in the inflamed colon—often mediated by disease activity potentiated by westernized diets—decreased mucus production enables bacterial encroachment to the otherwise sterile inner mucus layer. As a host-mediated counterresponse, this process fuels Paneth cell hyperplasia, enabling this cell type that is otherwise restricted to the SI to steadily emerge in the inflamed colon. Here, they secrete HDPs and lysozyme to ward of potential introducers. Since the microbial composition in colon diverges from the SI, so will the physiological response to, e.g., host-mediated defense mechanisms. As an example, Paneth cell-secreted lysozyme is one of the most important protectors of bacterial invasion in the SI. However, when these cells emerge in the inflamed colon, their secreted lysozyme promotes bacterial lysis of microbes. This includes the otherwise beneficial Ruminococcus gnavus, which is overly abundant in colon but not SI. Lysis of, e.g., R. gnavus liberates inflammatory effector molecules potentiating intestinal inflammation.