Colonocyte metabolism shapes the gut microbiota

Abstract

An imbalance in the colonic microbiota might underlie many human diseases, but the mechanisms that maintain homeostasis remain elusive. Recent insights suggest that colonocyte metabolism functions as a control switch, mediating a shift between homeostatic and dysbiotic communities. During homeostasis, colonocyte metabolism is directed toward oxidative phosphorylation, resulting in high epithelial oxygen consumption. The consequent epithelial hypoxia helps to maintain a microbial community dominated by obligate anaerobic bacteria, which provide benefit by converting fiber into fermentation products absorbed by the host. Conditions that alter the metabolism of the colonic epithelium increase epithelial oxygenation, thereby driving an expansion of facultative anaerobic bacteria, a hallmark of dysbiosis in the colon. Enteric pathogens subvert colonocyte metabolism to escape niche protection conferred by the gut microbiota. The reverse strategy, a metabolic reprogramming to restore colonocyte hypoxia, represents a promising new therapeutic approach for rebalancing the colonic microbiota in a broad spectrum of human diseases.

Figure 1:. Epithelial metabolism shapes the colonic microbiota.

(A) During gut homeostasis, obligate anaerobic bacteria convert fiber into fermentation products, such as butyrate, to maintain differentiated colonocytes in a C2-skwed metabolic state. The metabolism of C2-colonocytes is characterized by high oxygen consumption, which maintains epithelial hypoxia (<1 % oxygen) to limit the amount of oxygen diffusing into the gut lumen. The color scale on the bottom indicates oxygen (O₂) levels, which are between 3 % and 10 % in normoxic tissue (85). (B) Disruption of the gut microbiota by antibiotic treatment depletes microbe-derived fermentation products, causing a metabolic reorientation of terminally differentiated colonocytes towards a C1-skewed metabolism, which is characterized by high lactate release, low oxygen consumption and elevated synthesis of iNOS, an enzyme that generates nitric oxide (NO). Conversion of nitric oxide into nitrate (NO₃⁻) in the gut lumen together with oxygen (O₂) emanating from C1-colonocytes provide electron acceptors that drive an expansion of facultative anaerobic bacteria. (C) Epithelial injury activates epithelial repair responses, including a release of R-spondin-2 to stimulate cell division of undifferentiated transit-amplifying cells. Excessive cell division of undifferentiated transit-amplifying cells leads to colonic crypt hyperplasia and an increased epithelial oxygenation. Nitrate and oxygen emanating from the mucosal surface during colonic crypt hyperplasia drive an expansion of facultative anaerobic bacteria. PM, pericryptal myofibroblast; SC, stem cell, TA, undifferentiated transit-amplifying cell; C2, terminally differentiated C2-colonocyte; C1, terminally differentiated C1-colonocyte; GC, goblet cell.

Figure 2:. Extending the M1/M2 paradigm to colonocytes.

(A and B) Cytokine signaling can polarize macrophage metabolism and function, a process that is reversible. (A) Interleukin (IL)-4 and IL-13 stimulate polarization into alternatively-activated M2 macrophages by inducing STAT6 signaling to drive a PPARγ-dependent activation of mitochondrial β-oxidation and concomitant repression of the Nos2 gene. (B) Pro-inflammatory signals, such as gamma interferon (IFN-γ), stimulate polarization into classically-activated M1 macrophages by shifting the host cell metabolism towards anaerobic glycolysis. (C) The microbiota converts fiber into fermentation products, such as butyrate, which stimulates a metabolic polarization into homeostatically-activated C2 colonocytes by inducing a PPARγ-dependent activation of mitochondrial β-oxidation, thereby lowering epithelial oxygenation. (D) Pro-inflammatory signals stimulate a metabolic polarization into C1 colonocytes by shifting the host cell metabolism towards anaerobic glycolysis, thereby increasing epithelial oxygenation, which results in oxygen (O₂) emanating from the epithelial surface. Lactate produced during anaerobic glycolysis is released into the gut lumen, whereas nitric oxide (NO) produced by iNOS is converted to nitrate (NO₃⁻). CO₂, carbon dioxide.

Figure 3:. Enteric pathogens overcome niche protection by manipulating colonocyte metabolism.

(A) S. enterica (Salmonella) uses its virulence factors to trigger neutrophil transepithelial migration, which leads to a depletion of Clostridia, thereby lowering the luminal concentration of short-chain fatty acids, such as butyrate. The consequent metabolic reprogramming of the epithelium increases the luminal bioavailability of oxygen (O₂) and lactate. The inflammatory response generates additional electron acceptors, including tetrathionate (S₄O₆^2-) and nitrate (NO₃⁻). These host-derived resources drive an expansion of the facultative anaerobic pathogen. (B) Virulence factors of C. rodentium (Citrobacter) cause epithelial injury, thereby triggering epithelial repair responses leading to colonic crypt hyperplasia. The resulting increase in epithelial oxygenation drives a C. rodentium expansion by aerobic respiration. APC, antigen presenting cell; PMN, neutrophil; SC, stem cell, TA, undifferentiated transit-amplifying cell; C2, terminally differentiated C2-colonocyte; C1, terminally differentiated C1-colonocyte; GC, goblet cell.