Luminal nutrient signals for intestinal adaptation in pythons

Python intestine responds rapidly to luminal nutrients by increasing mass and upregulating nutrient transport. Candidates for luminal signals triggering those responses include mechanical stimulation, single or several dietary nutrients, and endogenous secretions. To identify signals, we infused into the python's small intestine either a nonnutrient solution (saline) or a single- or multinutrient solution. Python intestine failed to respond trophically or functionally to luminal infusions of saline, glucose, lipid, or bile. Infusion of amino acids and peptides, with or without glucose, induced an intermediate response. Infusion of nutritionally complete liquid formula or natural diet induced full intestinal response. Intact meals triggered full intestinal responses without pancreatic or biliary secretions, whereas direct cephalic and gastric stimulation failed to elicit any response. Hence neither physical stimulation (cephalic, gastric, or intestinal) nor the luminal presence of glucose, lipids, or bile can induce intestinal response; instead, a combination of nutrients is required (even without pancreaticobiliary secretions), the most important being amino acids and peptides. This is understandable because pythons, as carnivores, have a high-protein diet.     

Enteric neurons and systemic signals couple nutritional and reproductive status with intestinal homeostasis

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Highlights? A metabolic behavior revealing a key homeostatic role for the invertebrate intestine ? Enteric neurons couple reproductive state with intestinal physiology ? An insulinergic brain-gut neuronal circuit adjusts feeding to nutritional conditions ? A vasopressin-like system of central neurons is essential for water homeostasis     

Evidence that neurotensin mediates postprandial intestinal hyperemia in the python, Python regius

Digestion of large meals in pythons produces substantial increases in heart rate and cardiac output, as well as a dilation of the mesenteric vascular bed leading to intestinal hyperemia, but the mediators of these effects are unknown. Bolus intra-arterial injections of python neurotensin ([His(3), Val(4), Ala(7)]NT) (1 - 1,000 pmol/kg) into the anesthetized ball python Python regius (n = 7) produced a dose-dependent vasodilation that was associated with a decrease in systemic pressure (P(sys)) and increase in systemic blood flow (Q(sys)). There was no effect on pulmonary pressure and conductance. A significant (P < 0.05) increase in heart rate (f(H)) and total cardiac output (Q(tot)) was seen only at high doses (>30 pmol/kg). The systemic vasodilation and increase in Q(tot) persisted after beta-adrenergic blockade with propranolol, but the rise in f(H) was abolished. Also, the systemic vasodilation persisted after histamine H(2)-receptor blockade. In unanesthetized pythons (n = 4), bolus injection of python NT in a dose as low as 1 pmol/kg produced a significant increase in blood flow to the mesenteric artery (177% +/- 54%; mean +/- SE) and mesenteric conductance (219% +/- 74%) without any increase in Q(sys), systemic conductance, P(sys), and f(H). The data provide evidence that NT is an important hormonal mediator of postprandial intestinal hyperemia in the python, but its involvement in mediating the cardiac responses to digestion may be relatively minor.     

Balancing signals in the intestinal niche

During intestinal regeneration, opposing gradients of Wnt and BMP signaling ensure successful differentiation along the crypt/villus axis. In this issue of The EMBO Journal, Horiguchi et al ( 2017 ) show how intestinal subepithelial myofibroblasts can influence cell fate decisions in the regenerating intestine via autocrine secretion of angiopoietin‐like protein 2 (ANGPTL2).     

Local and systemic signals in the wound response

An injury applied to one site on a plant lead to changes in gene expression in the region of the wound and in distant unwounded regions of the organism. This implies that local and systemic signals must operate to link the initial stimulus to the wound-induced effects. Current evidence for the involvement of chemical and physical signalling mechanisms is critically reviewed, drawing on data from studies of the wound response in planta, mutant analyses and the use of bioassays.     

Diffusible amyloid oligomers trigger systemic amyloidosis in mice

AA (amyloid protein A) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an intravenous injection of protein extracted from AA-laden mouse tissue. Previous findings affirm that AA fibrils can enhance the in vivo amyloidogenic process by a nucleation seeding mechanism. Accumulating evidence suggests that globular aggregates rather than fibrils are the toxic entities responsible for cell death. In the present study we report on structural and morphological features of AEF (amyloid-enhancing factor), a compound extracted and partially purified from amyloid-laden spleen. Surprisingly, the chief amyloidogenic material identified in the active AEF was diffusible globular oligomers. This partially purified active extract triggered amyloid deposition in vital organs when injected intravenously into mice. This implies that such a phenomenon could have been inflicted through the nucleation seeding potential of toxic oligomers in association with altered cytokine induction. In the present study we report an apparent relationship between altered cytokine expression and AA accumulation in systemically inflamed tissues. The prevalence of serum AA monomers and proteolytic oligomers in spleen AEF is consistent to suggest that extrahepatic serum AA processing might lead to local accumulation of amyloidogenic proteins at the serum AA production site.     

Luminal iron levels govern intestinal tumorigenesis after Apc loss in vivo

It is clear from epidemiological studies that excess iron is associated with increased risk of colorectal cancer; however, questions regarding the mechanism of how iron increases cancer risk, the source of the excess iron (circulating or luminal), and whether iron reduction represents a potential therapeutic option remain unanswered. In this study, we show that after Apc deletion, the cellular iron acquisition proteins TfR1 and DMT1 are rapidly induced. Conversely, restoration of APC reduces cellular iron due to repression of these proteins. To test the functional importance of these findings, we performed in vivo investigations of the impact of iron levels on intestinal tumorigenesis. Strikingly, depletion of luminal (but not systemic) iron strongly suppressed murine intestinal tumorigenesis, whereas increased luminal iron strongly promoted tumorigenesis. Taken together, our data definitively delineate iron as a potent modifier of intestinal tumorigenesis and have important implications for dietary iron supplementation in patients at high risk of colorectal cancer.     

Postprandial morphological response of the intestinal epithelium of the Burmese python (Python molurus)

The postprandial morphological changes of the intestinal epithelium of Burmese pythons were examined using fasting pythons and at eight time points after feeding. In fasting pythons, tightly packed enterocytes possess very short microvilli and are arranged in a pseudostratified fashion. Enterocyte width increases by 23% within 24 h postfeeding, inducing significant increases in villus length and intestinal mass. By 6 days postfeeding, enterocyte volume had peaked, following as much as an 80% increase. Contributing to enterocyte hypertrophy is the cellular accumulation of lipid droplets at the tips and edges of the villi of the proximal and middle small intestine, but which were absent in the distal small intestine. At 3 days postfeeding, conventional and environmental scanning electron microscopy revealed cracks and lipid extrusion along the narrow edges of the villi and at the villus tips. Transmission electron microscopy demonstrated the rapid postprandial lengthening of enterocyte microvilli, increasing 4.8-fold in length within 24 h, and the maintaining of that length through digestion. Beginning at 24 h postfeeding, spherical particles were found embedded apically within enterocytes of the proximal and middle small intestine. These particles possessed an annular-like construction and were stained with the calcium-stain Alizarine red S suggesting that they were bone in origin. Following the completion of digestion, many of the postprandial responses were reversed, as observed by the atrophy of enterocytes, the shortening of villi, and the retraction of the microvilli. Further exploration of the python intestine will reveal the underlying mechanisms of these trophic responses and the origin and fate of the engulfed particles.     

The mechanical properties of the systemic and pulmonary arteries of python regius correlate with blood pressures

Pythons are unique amongst snakes in having different pressures in the aortas and pulmonary arteries because of intraventricular pressure separation. In this study, we investigate whether this correlates with different blood vessel strength in the ball python Python regius. We excised segments from the left, right, and dorsal aortas, and from the two pulmonary arteries. These were subjected to tensile testing. We show that the aortic vessel wall is significantly stronger than the pulmonary artery wall in P. regius. Gross morphological characteristics (vessel wall thickness and correlated absolute amount of collagen content) are likely the most influential factors. Collagen fiber thickness and orientation are likely to have an effect, though the effect of collagen fiber type and cross‐links between fibers will need further study. J. Morphol. 276:1412–1421, 2015. © 2015 Wiley Periodicals, Inc.     

Cardiovascular actions of python bradykinin and substance P in the anesthetized python, Python regius

The cardiovascular actions of python bradykinin (BK) and substance P (SP) have been investigated in the anesthetized ball python, Python regius. Bolus intra-arterial injections of python BK (0.03-3 nmol/kg) produced concentration-dependent increases in arterial blood pressure, heart rate (HR), and cardiac output concomitant with small decreases in systemic resistance and stroke volume. Intra-arterial injection of 3 nmol/kg python BK produced a tenfold increase in circulating concentration of norepinephrine, but epinephrine levels did not change. BK-induced tachycardia was attenuated (>90%) by the beta-adrenergic receptor antagonist sotalol, and the hypertensive response was attenuated (>70%) by the alpha-adrenergic receptor antagonist prazosin, indicating that effects of python BK are mediated at least in part by activation of the extensive network of adrenergic neurons present in vascular tissues. Bolus intra-arterial injections of python SP in the range 0. 01-30 pmol/kg produced concentration-dependent decreases in arterial blood pressure and systemic peripheral resistance concomitant with increases in cardiac output and stroke volume but with only minor effects on HR. The data suggest that kinins play a physiologically important role in cardiovascular regulation in the python.     

Hemodynamic effects of python neuropeptide gamma in the anesthetized python, Python regius

The effects of python neuropeptide gamma (NPgamma) on hemodynamic parameters have been investigated in the anesthetized ball python (Python regius). Bolus intra-arterial injections of synthetic python NPgamma (1-300 pmol kg-1) produced a dose-dependent decrease in systemic arterial blood pressure (Psys) concomitant with increases in systemic vascular conductance (Gsys), total cardiac output and stroke volume, but only minor effects on heart rate. The peptide had no significant effect on pulmonary arterial blood pressure (Ppul) and caused only a small increase in pulmonary conductance (Gpul) at the highest dose. In the systemic circulation, the potency of the NK1 receptor-selective agonist [Sar9,Met(0(2))11] substance P was >100-fold greater than the NK2 receptor-selective agonist [betaAla8] neurokinin A-(4-10)-peptide suggesting that the python cardiovascular system is associated with a receptor that resembles the mammalian NK1 receptor more closely than the NK2 receptor. Administration of the inhibitor of nitric oxide synthesis, L-nitro-arginine-methylester (L-NAME; 150 mg kg-1), resulted in a significant (P<0.05) increase in Psys as well as a decrease in Gsys, but no effect on Ppul and Gpul. Conversely, the nitric oxide donor, sodium nitroprusside (SNP; 60 microg kg-1) produced a significant (P<0.05) decrease in Psys along with an increase in Gsys and pulmonary blood flow. However, neither L-NAME nor indomethacin (10 mg kg-1) reduced the cardiovascular responses to NPgamma. Thus, nitric oxide is involved in regulation of basal vascular tone in the python, but neither nitric oxide nor prostaglandins mediate the vasodilatory action of NPgamma.     

Ultraweak signals can cause synaptic depression and adaptation

Synaptic depression at conventional synapses is usually caused by strong or prolonged stimuli, like tetanic bursts of afferent fiber discharge at high frequencies. In this issue of Neuron, Dunn and Rieke report that, in the retina, even the weakest stimuli, single photons, can lead to synaptic depression at ribbon-type synapses and adaptation of neuronal output to ambient light levels.     

Acceleration and velocity signals trigger otolithic eye movements during lateral translation

Since it is still controversial what kinds of driving signals are effective in otolith [correction of otholith] ocular responses, we attempted to compare eye movement responses between the step and sinusoidal modes of lateral translation.     

Astroglial Ca2+ signals trigger pathological behaviour in optogenetic mouse

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Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons

Drug seeking and drug self-administration in both animals and humans can be triggered by drugs of abuse themselves or by stressful events. Here, we demonstrate that in vivo administration of drugs of abuse with different molecular mechanisms of action as well as acute stress both increase strength at excitatory synapses on midbrain dopamine neurons. Psychoactive drugs with minimal abuse potential do not cause this change. The synaptic effects of stress, but not of cocaine, are blocked by the glucocorticoid receptor antagonist RU486. These results suggest that plasticity at excitatory synapses on dopamine neurons may be a key neural adaptation contributing to addiction and its interactions with stress and thus may be an attractive therapeutic target for reducing the risk of addiction.     

Dimerization controls the activity of fungal elicitors that trigger systemic resistance in plants

The soilborne fungus Trichoderma virens secretes a small protein (Sm1) that induces local and systemic defenses in plants. This protein belongs to the ceratoplatanin protein family and is mainly present as a monomer in culture filtrates. However, Hypocrea atroviride (the telomorph form of Trichoderma atroviride) secretes an Sm1-homologous protein, Epl1, with high levels of dimerization. Nonetheless, the molecular mechanisms involved in recognition and the signaling pathways involved in the induction of systemic resistance in plants are still unclear. In this report, we demonstrate that Sm1 and Epl1 are mainly produced as monomer and a dimer, respectively, in the presence of maize seedlings. The results presented show that the ability to induce plant defenses reside only in the monomeric form of both Sm1 and Epl1, and we demonstrate for the first time that the monomeric form of Epl1, likewise Sm1, induces defenses in maize plants. Biochemical analyses indicate that monomeric Sm1 is produced as a glycoprotein, but the glycosyl moiety is missing from its dimeric form, and Epl1 is produced as a nonglycosylated protein. Moreover, for Sm1 homologues in various fungal strains, there is a negative correlation between the presence of the glycosylation site and their ability to aggregate. We propose a subdivision in the ceratoplatanin protein family according to the presence of the glycosylation site and the ability of the proteins to aggregate. The data presented suggest that the elicitor's aggregation may control the Trichoderma-plant molecular dialogue and block the activation of induced systemic resistance in plants.     

Epithelial hedgehog signals pattern the intestinal crypt-villus axis

Morphological development of the small intestinal mucosa involves the stepwise remodeling of a smooth-surfaced endodermal tube to form finger-like luminal projections (villi) and flask-shaped invaginations (crypts). These remodeling processes are orchestrated by instructive signals that pass bidirectionally between the epithelium and underlying mesenchyme. Sonic (Shh) and Indian (Ihh) hedgehog are expressed in the epithelium throughout these morphogenic events, and mice lacking either factor exhibit intestinal abnormalities. To examine the combined role of Shh and Ihh in intestinal morphogenesis, we generated transgenic mice expressing the pan-hedgehog inhibitor, Hhip (hedgehog interacting protein) in the epithelium. We demonstrate that hedgehog (Hh) signaling in the neonatal intestine is paracrine, from epithelium to Ptch1-expressing subepithelial myofibroblasts (ISEMFs) and smooth muscle cells (SMCs). Strong inhibition of this signal compromises epithelial remodeling and villus formation. Surprisingly, modest attenuation of Hh also perturbs villus patterning. Desmin-positive smooth muscle progenitors are expanded, and ISEMFs are mislocalized. This mesenchymal change secondarily affects the epithelium: Tcf4/beta-catenin target gene activity is enhanced, proliferation is increased, and ectopic precrypt structures form on villus tips. Thus, through a combined Hh signal to underlying ISEMFs, the epithelium patterns the crypt-villus axis, ensuring the proper size and location of the emerging precrypt compartment.     

Diet-induced adaptation of intestinal fructose absorption in the rat.

The effect of dietary sucrose, fructose and glucose on the intestinal absorption of fructose and glucose was investigated in adult rats in vivo: Glucose absorption was not affected by the type of dietary carbohydrate, while the absorption of fructose was increased by the ingestion of the sucrose or fructose diet, as compared with the glucose diet. An almost maximal increase of fructose absorption was already observed when the quarter of the total dietary carbohydrates was replaced by fructose. Faecal fructose elimination declined during the feeding experiment. The enhanced intestinal absorption of the fructose load in rats fed the fructose diet was manifested by higher concentrations of fructose, but also of glucose and lactate in the hepatic portal blood.