Stimulating nutrient absorption -
Vitamin C deficiency is rare in developed countries but may occur with a limited diet that provides less than 10 mg daily for one month or longer. In developed countries, situations at greatest risk for deficiency include eating a diet restricted in fruits and vegetables, smoking or long-term exposure to secondhand smoke, and drug and alcohol abuse.
The following are the most common signs of a deficiency. The contents of this website are for educational purposes and are not intended to offer personal medical advice. You should seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition.
Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The Nutrition Source does not recommend or endorse any products. Skip to content The Nutrition Source. The Nutrition Source Menu. Search for:.
Home Nutrition News What Should I Eat? Recommended Amounts RDA: The Recommended Dietary Allowance for adults 19 years and older is 90 mg daily for men and 75 mg for women.
For pregnancy and lactation, the amount increases to 85 mg and mg daily, respectively. Smoking can deplete vitamin C levels in the body, so an additional 35 mg beyond the RDA is suggested for smokers. UL: The Tolerable Upper Intake Level is the maximum daily intake unlikely to cause harmful effects on health.
The UL for vitamin C is mg daily; taking beyond this amount may promote gastrointestinal distress and diarrhea. Only in specific scenarios, such as under medical supervision or in controlled clinical trials, amounts higher than the UL are sometimes used.
Vitamin C absorption and megadosing The intestines have a limited ability to absorb vitamin C. However, adverse effects are possible with intakes greater than mg daily, including reports of diarrhea, increased formation of kidney stones in those with existing kidney disease or history of stones, increased levels of uric acid a risk factor for gout , and increased iron absorption and overload in individuals with hemochromatosis, a hereditary condition causing excessive iron in the blood.
Chronic diseases Although some epidemiological studies that follow large groups of people over time have found a protective effect of higher intakes of vitamin C from food or supplements from cardiovascular disease and certain cancers, other studies have not.
Age-related vision diseases Vitamin C has also been theorized to protect from eye diseases like cataracts and macular degeneration.
References Carpenter KJ. Gallstones are hardened deposits that can form in the gallbladder, affecting bile flow. Gallstones may prevent or reduce the release of bile, leading to inefficient fat digestion and absorption of fat-soluble vitamins A, D, E, and K. In cases where gallstones or inflammation become severe, the gallbladder may need to be removed.
This procedure can alter the dynamics of bile release and also affect nutrient absorption. Bitter foods and herbal bitters are known for their ability to stimulate the production of bile. Bile, stimulated by bitter foods, emulsifies fats, breaking them down into smaller particles for better absorption.
When fat is better absorbed via bile, the body can then properly absorb fat-soluble vitamins. Including bitter foods in your diet or taking an herbal bitter supplement before meals may support better digestion and nutrient absorption.
Your gut bacteria has a bidirectional relationship with vitamins and minerals. For example, certain nutrients can affect the diversity and composition of your gut microbiome.
On the other hand, gut bacteria can influence nutrient absorption and even produce essential vitamins like vitamin K and biotin. Dysbiosis is when there is an imbalance of gut bacteria. This can cause many other problems downstream, but it can also negatively affect nutrient absorption.
Eating an anti-inflammatory diet rich in fruits, vegetables, nuts, seeds, and whole grains while limiting added sugar can support the growth of healthy gut bacteria. We also recommend one of our most commonly used probiotics, MegaSporeBiotic.
Read more about our favorite soil-based probiotic. Synergistic Nutrient Absorption Certain nutrients enhance each other's absorption and effectiveness. For example, vitamin C enhances the absorption of iron. Say 'No' to Alcohol: Substances like alcohol and diuretics such as coffee are not only known to decrease the number of digestive enzymes in your gut, but they also cause damage to the cell lining of your stomach as well as your intestines.
Focus on Managing Your Stress Levels: It has already been proven by doctors and healthcare experts around the globe that negative stress can weaken or cause damage to your digestive system.
Always Keep Your Body Hydrated: This is one of the most important factors that has the power to make or break your digestive system. Conclusion: We hope that this article gave you the precise information that you had been looking for.
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Body shape transformation tips all abxorption those foods that we Stimulating nutrient absorption eating together: peanut Stimulating nutrient absorption and jelly, watermelon and feta, Stimulating nutrient absorption jutrient berries. But wbsorption turns wbsorption there may be a reason to combine certain foods nurient one sitting beyond simply the taste. How you combine foods can majorly impact the benefit you get from them: increasing the absorption of important nutrients and boosting the effectiveness of antioxidants. See which surprising food combos nutritionists recommend the most. To best absorb non-heme iron, aka plant-based iron, you need to give it a little boost by pairing it with a source of vitamin C. Absorpiton a Stumulating diet, correcting Stimulating nutrient absorption deficiencies, and supporting gut health with Effective long-term weight management proper abaorption healing protocol can help heal the gut from gluten damage. An Nutrieny diet is a short-term diet aimed to identify food sensitivities. Unlike food allergies, food sensitivities often develop over time and may cause a wide variety of symptoms. Articles How to Increase Nutrient Absorption. How to Increase Nutrient Absorption. Published: Dec 4, Nutrient absorption is a crucial aspect of maintaining optimal health and providing the necessary vitamins, minerals, and other essential nutrients.Stimulating nutrient absorption -
Your small intestine pushes food along its nearly foot long canal using wave-like muscle movements. The small intestine is where your pancreas, gallbladder, and liver release more digestive juices, bile, and enzymes to further breakdown your food for proper absorption into the bloodstream.
Finally, the colon is responsible for absorbing water, digesting fibers, and processing waste to be eliminated through the stool. Gut Health and Nutrient Absorption The health of your gut plays a pivotal role in overall well-being and nutrient absorption.
Adequate stomach acid is essential for breaking down food and preparing it for further digestion in the intestines. Low stomach acid may particularly affect the absorption of minerals, like calcium, magnesium, and iron. People with low stomach acid are also more likely to be deficient in vitamin B This is because adequate stomach acid is required for your body to effectively absorb this vitamin.
Furthermore, individuals taking medications to lower stomach acid like omeprazole Prilosec or ranitidine Zantac are at an even greater risk of vitamin b12 deficiency 1. If you suspect low stomach acid, consider trying our digestive enzymes with betaine hydrochloride the main component of stomach acid with meals.
Digestive Enzymes One easy-to-swallow capsule that helps you optimize gut health by improving your digestion of protein, fats, and carbohydrates at each meal. Gallbladder Conditions Your gallbladder plays a significant role in digestion by storing and releasing bile—a substance needed for fat digestion and the absorption of fat-soluble vitamins.
Gallstones are hardened deposits that can form in the gallbladder, affecting bile flow. Gallstones may prevent or reduce the release of bile, leading to inefficient fat digestion and absorption of fat-soluble vitamins A, D, E, and K. In cases where gallstones or inflammation become severe, the gallbladder may need to be removed.
This procedure can alter the dynamics of bile release and also affect nutrient absorption. Bitter foods and herbal bitters are known for their ability to stimulate the production of bile. Bile, stimulated by bitter foods, emulsifies fats, breaking them down into smaller particles for better absorption.
Absorption does not differ if obtaining the vitamin from food or supplements. Vitamin C is sometimes given as an injection into a vein intravenous so higher amounts can directly enter the bloodstream.
This is usually only seen in medically monitored settings, such as to improve the quality of life in those with advanced stage cancers or in controlled clinical studies.
Though clinical trials have not shown high-dose intravenous vitamin C to produce negative side effects, it should be administered only with close monitoring and avoided in those with kidney disease and hereditary conditions like hemochromatosis and glucose 6-phosphate dehydrogenase deficiency.
Vitamin C is involved with numerous metabolic reactions in the body, and obtaining the RDA or slightly higher may be protective against certain disease states.
However, a health benefit of taking larger amounts has not been found in people who are generally healthy and well-nourished. Cell studies have shown that at very high concentrations, vitamin C can switch roles and act as a tissue-damaging pro-oxidant instead of an antioxidant.
There is interest in the antioxidant role of vitamin C, as research has found the vitamin to neutralize free radical molecules, which in excess can damage cells. Does this translate to protection from certain diseases?
Although some epidemiological studies that follow large groups of people over time have found a protective effect of higher intakes of vitamin C from food or supplements from cardiovascular disease and certain cancers, other studies have not.
Randomized controlled trials have not found a benefit of vitamin C supplements on the prevalence of cardiovascular disease or cancer. The inconsistency of the data overall prevents the establishment of a specific vitamin C recommendation above the RDA for these conditions.
Vitamin C has also been theorized to protect from eye diseases like cataracts and macular degeneration. Human studies using vitamin C supplements have not shown a consistent benefit, though there appears to be a strong association between a high daily intake of fruit and vegetables and decreased risk of cataracts.
Reviews of several studies show that megadoses greater than mg daily of supplemental vitamin C have no significant effect on the common cold, but may provide a moderate benefit in decreasing the duration and severity of colds in some groups of people.
Fruits and vegetables are the best sources of this vitamin. Vitamin C deficiency is rare in developed countries but may occur with a limited diet that provides less than 10 mg daily for one month or longer.
In developed countries, situations at greatest risk for deficiency include eating a diet restricted in fruits and vegetables, smoking or long-term exposure to secondhand smoke, and drug and alcohol abuse. The following are the most common signs of a deficiency. The contents of this website are for educational purposes and are not intended to offer personal medical advice.
You should seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. a Mechanisms of small intestinal lipid sensing.
The hydrolysis of chylomicrons by nearby enterocytes on the basolateral membrane may lead to increased LCFAs that can activate basolateral GPR40 to induce peptide release.
b Mechanisms of small intestinal carbohydrate sensing. However, ileal glucose sensing may stimulate the release of GLP-1 independent of SGLT1.
In response to high-fat feeding or obesity, small intestinal SGLT1 expression is reduced, leading to an impairment of glucose sensing, GLP-1 secretion, and glucose control.
c Mechanisms of small intestinal protein sensing. Luminal small oligopeptides and amino acids are taken up by PepT1 and amino acid transporters, respectively, into the enterocyte and enteroendocrine cells. Small intestinal protein sensing stimulates the release of CCK and GLP-1 and regulates feeding and glucose homeostasis potentially via PepT1 dependent mechanisms.
In addition, amino acids stimulate peptide release via the membrane-bound calcium-sensing receptor, the umami taste receptor, and G-protein-coupled receptor 6A. However, the downstream mechanism mediating the peptide release remains elusive.
In parallel, amino acids are also transported to the basolateral side, and studies implicated that they may activate the calcium-sensing receptor to stimulate GLP-1 secretion.
Vagal afferent fibers mediate the anorectic effects of intestinal lipid-sensing and are activated by several gut peptides Vagal afferents contain CCK-1 receptor CCK-1R and selective knockdown of CCK-1R in vagal afferents abolishes the ability of CCK to lower food intake However, the impact of vagal CCK-1R on small intestinal lipid-induced CCK signaling has not been established Vagal afferents also express GLP-1R 42 , and at least one study reports that GLP-1 signaling mediates the suppressive effects of jejunal linoleic acid infusion However, GLP-1R-expressing vagal afferent neurons were also reported to detect stomach and intestinal stretch but have no impact on nutrient-sensing Thus, the effect of GLP-1R on intestinal lipid sensing remains unclear.
It is possible that the enteric nervous system, which contains GLP-1R, may mediate the gut—brain effect instead 18 , Utilizing pancreatic—euglycemic clamps with plasma insulin levels maintained at a basal non-stimulated condition, upper small intestinal lipid infusion lowers hepatic glucose production In contrast, a study with human participants reports that during the pancreatic—euglycemic clamps, no difference in glucose production is detected in response to intraduodenal infusion of lipid vs control group However, this observation is made in the presence of a progressive rise in plasma insulin and glucose levels prior to the start of the lipid or control infusion, and a parallel progressive drop in both plasma free fatty acids and glucose production in both groups Thus, it is not surprising that glucose production is not further lowered by intraduodenal lipid vs.
saline infusion in a state that mimics the postprandial state, in which hepatic glucose production is already inhibited. Similar to lipid-induced reductions in food intake, the ability of small intestinal lipid infusion to lower hepatic glucose production is dependent on CCK and GLP-1 signaling during the pancreatic basal insulin -euglycemic clamps 45 , Further, inhibiting CCK-1R signaling during refeeding, which activates nutrient-sensing pathways, results in postprandial hyperglycemia The specific mechanisms leading to the release of CCK and subsequent effects on glucose homeostasis are not fully understood, although the esterification of fatty acids to fatty acyl-CoA via acyl-CoA synthetase and the subsequent activation of mucosal protein kinase C PKC -δ are necessary for rats 46 , This is consistent with the fact that LCFA induces CCK release in intestinal secretin tumor cells via PKC-δ activation In parallel, the formation of chylomicron is also implicated in CCK release 50 , but the underlying mechanisms of how lipids stimulate CCK to release overall remain elusive Fig.
Further, the specific role of vagal GLP-1R signaling in mediating the glucoregulatory effect of lipids remains to be clarified. In addition to lowering hepatic glucose production via a gut—brain axis 45 , 46 , small intestinal lipid-sensing could regulate glucose homeostasis via GLPinduced increase in insulin or suppression of glucagon secretion, as lipid-sensing increases GLP-1 release 45 ,.
However, GLP-1 induced increase in insulin secretion requires the presence of elevated circulating glucose levels Thus, it is possible that while an infusion of lipid alone increases GLP-1, this would not substantially elevate plasma insulin levels in the absence of a concomitant rise in blood glucose levels, as reported in human studies 52 , Despite this, increasing circulating active GLP-1 levels during an Intralipid intestinal infusion via DPP-IV inhibition inhibits degradation of GLP-1 decreases glucose and increases insulin levels In addition, while GLP-1 is known to suppress glucagon secretion, glucagon is consistently increased with Intralipid infusion 52 , Although it has not been evaluated, this unexpected effect of Intralipid on glucagon could be due to the concurrent CCK release, as CCK lowers the inhibitory effect of glucose on glucagon secretion A high-fat diet HFD impairs lipid-induced gut—brain feedback regulating both energy and glucose homeostasis.
Intestinal sensing of lipids is impaired during HFD in both rodents and humans 55 , however, it is still contentious as to whether this is due to chronic exposure to HFD or induction of obesity.
For example, studies in rats have shown that the combination of an HFD with a genetic background that is predisposed to obesity, is associated with reduced intestinal-lipid sensing 56 , Furthermore, HFD decreases postprandial active GLP-1 and CCK levels in obese-prone rats compared to obese-resistant rats, potentially due to decreased intestinal expression of GPR40 and GPR, receptors that are implicated in lipid-sensing induced secretion of gut peptides 56 , 57 , 58 Fig.
The importance of interaction between diet and obesity for nutrient-sensing is also supported by human data. A 2-week high-fat dietary regimen in humans does not impair the suppressive effects on appetite or the CCK and GLP-1 response to an intralipid duodenal infusion However, individuals with obesity are less responsive to the satiating effects of dietary fat 60 , Obesity is also associated with reduced postprandial gut peptide levels 62 , and specifically for lipid-sensing, CCK release is blunted in individuals affected by obesity following intraduodenal oleic acid Therefore, future studies need to delineate the effect of diet vs.
phenotype, which may be due to the ability of the gut microbiota to mediate this interaction between the diet and host physiology discussed in more detail below.
Besides reductions in lipid-induced gut peptide release, it is possible that diminished sensitivity to gut peptides contributes to the reduced responsiveness to intestinal fat sensing in feeding control. The anorectic effect of CCK is impaired in HFD-fed mice and rats 55 , as is vagal afferent activation 55 , although this has not been fully examined in humans.
Further, CCK-1R expression in vagal nerves is decreased in HFD induced obese rats 56 , ultimately contributing to reduced nodose ganglia cocaine and amphetamine-regulated transcript CART expression, a neuropeptide regulating energy homeostasis, in association with increased food intake and body weight However, vagal CCK resistance during obesity could also be due to obesity-associated leptin resistance, as the leptin receptor is co-expressed with CCK-1R in the vagal afferent neurons 65 and leptin potentiates the suppressive effect of CCK on appetite and increases vagal afferent activation following CCK administration 66 , Using both genetic and viral approaches, the knockdown of leptin receptors in vagal afferent neurons impairs CCK responsiveness and induces hyperphagia Taken together, it is possible that impairments in CCK signaling both at the level of secretion and vagal activation could drive reduced lipid-induced satiation, although much of this remains to be tested in humans.
HFD also impairs the ability of upper small intestinal lipid sensing to improve glucose tolerance and lower hepatic glucose production 45 , The loss of effect of lipid-sensing following short-term 3-day HF feeding is partly due to impaired vagal CCK-1R signaling as both Intralipid and CCK but not upstream activation of vagal protein kinase A fail to lower glucose production in HF rats 25 , 46 , In parallel, HFD lowers upper small intestinal long-chain acyl-CoA synthetase-3 expression and disrupts long-chain acyl-CoA synthetase-3 dependent small intestinal fatty acid metabolism to regulate glucose homeostasis.
However, transplantation of healthy microbiome to HF rats rescues the glucoregulatory effect of lipid-sensing via upregulation of long-chain acyl-CoA synthetase-3 expression in a small intestinal farnesoid x receptor FXR dependent fashion The underlying mechanism of how HF-induced changes in small intestinal microbiome alter bile acid pool, FXR, acyl-CoA synthetase-3, and lipid sensing remains elusive.
Nonetheless, we hypothesize that enhancing long-chain acyl-CoA synthetasedependent upper small intestinal fatty acid metabolism could increase GLP1 action to regulate glucose homeostasis in spite of CCK-1R vagal resistance Fig.
Intraduodenal infusion of glucose dose-dependently suppresses food intake in rodents 72 , and reduces food intake 73 , 74 or favorably influences subjective appetite ratings 73 in humans. Intravenous infusion of glucose to match the levels observed in blood following intestinal infusion of glucose does not inhibit food intake in rodents and humans 72 , 75 , highlighting the role of preabsorptive intestinal glucose-sensing.
GLP-1R antagonist Exendin-9 abolishes the anorectic effect of both intragastric and voluntary sucrose loads in rats 76 , indicating that GLP-1 action mediates the effect of carbohydrate-sensing on food intake. Glucose-induced GLP-1 secretion from small intestinal EECs is dependent on sodium-glucose luminal transporter-1 SGLT-1 As non-metabolizable sugars transported via SGLT-1 also induce GLP-1 release 79 , glucose-sensing appears to be dependent on the transport of glucose via SGLT-1 but independent of subsequent cellular glucose metabolism.
This finding has been confirmed in the human small intestine However, recent studies report that non-caloric sweeteners do not induce GLP-1 release in primary L-cells and rodents 79 , 83 , and in humans, noncaloric sweeteners fail to induce gut peptide release and have no effect on appetite It is possible that the suppressive effect of glucose on food intake depends on the specific site of the small intestine where glucose is sensed.
For instance, a greater reduction of energy intake associates with higher CCK levels in humans receiving duodenal versus jejunal infusion of glucose However, in another study 86 , glucose infusion into the ileum, but not duodenum, suppresses food intake, and a rodent study similarly found that ileal glucose infusion suppresses food intake to a greater degree than duodenal glucose infusion These studies support the notion that ileal nutrient-sensing regulates gut motility 88 but later proposed by many to also regulate food intake In contrast to the upper small intestine, this may be due to SGLT-1 independent glucose-mediated GLP-1 release 90 Fig.
Small intestine infusion of glucose impacts glucose homeostasis and the effects are not only due to glucose absorption into circulation. First, it is well established that the GI tract contributes to insulin secretion via the incretin effects of GLP-1 and GIP, which stimulate insulin secretion from the pancreas.
Direct infusion of glucose into the duodenum in humans also increases circulating insulin levels, as does jejunal infusions, while glucagon levels either decrease or remain unchanged This discrepancy in glucagon is likely due to the differing actions of GIP and GLP-1, as GIP paradoxically increases while GLP-1 inhibits glucagon secretion While both GLP-1R and GIPR knockout mice exhibit reduced insulin release in response to intestinal glucose, each model only exhibits mild glucose intolerance.
However, dual GLP-1R and GIPR knockout mice exhibit substantially impaired glycemic control and oral glucose-stimulated insulin release as compared to single incretin receptor knockout mice Further, GIP was found to be a more powerful incretin hormone than GLP-1, but its overall effect on glucose homeostasis is likely masked by the concomitant rise in glucagon As such, the common hepatic branch of the vagus, as well as celiac and gastric branches, are all implicated in contributing to the glucoregulatory effects of GLP-1 action 94 , For example, selective knockdown of GLP-1R in the nodose ganglia impairs glucose response to a mixed meal but interestingly does not impair oral glucose tolerance This implies that the impaired response to a mixed meal challenge is not dependent on altered intestinal glucose-sensing.
Further, the impact of genetic knockout of GLP-1R in vagal neurons on oral glucose tolerance is contentious 22 , However, selective restoration of the islet and pancreatic duct GLP-1R in global GLP-1R knockout mice was sufficient to improve impaired oral glucose tolerance, although the reason for this is unknown as there was no change in glucose-stimulated insulin release among the groups Thus, the mechanism of glucose-induced GLP-1 regulation on insulin secretion remains elusive.
Direct infusion of glucose into the upper small intestine or jejunum given at a dose that does not increase portal glucose levels activates small intestinal SGLT-1 and lowers hepatic glucose production in parallel to an increase in portal GLP-1 levels 97 , 98 Fig.
Similar to the mechanism of glucose-sensing in the regulation of food intake, infusion of non-metabolizable sugar 3-OMG that is transported via SGLT-1 into the upper small intestine recapitulates the glucoregulatory effect of glucose-sensing 97 , suggesting that upper small intestinal glucose-sensing in inducing GLP-1 release is dependent on the electrogenic capacity of SGLT-1 but independent of cellular glucose metabolism.
Further, the effect of small intestinal glucose sensing on hepatic glucose production regulation is abolished when glucose is co-infused with GLP-1R antagonist exendin-9 97 , strengthening the role of GLP-1 as the mediator of intestinal glucose-sensing on hepatic glucose production Despite the prevalence of carbohydrates in the diet, few studies have investigated the effect of obesity or HFD on intestinal glucose sensing.
In rodents, both diet-induced and genetic models of obesity exhibit reduced satiation in response to intraduodenal carbohydrate infusion, although the effect is less pronounced than what is observed with intestinal lipids and is observed in some but not all studies 57 , Moreover, there are no differences in the response to duodenal infusion of glucose between participants with and without obesity In contrast, obesity is associated with reduced postprandial GLP-1 levels and sensitivity to GLP-1 in rodents , , although gut peptides other than GLP-1 may mediate the anorectic effect of intestinal carbohydrates Despite these unknowns, research with human participants suggests that the incretin effect is impaired in diabetes, which is likely due to reduced GLP-1 secretion and impaired potency of GLP-1 to induce insulin secretion Similarly, HFD in rodents impairs the ability of upper small intestinal glucose infusion to lower glucose production, likely due to reduced GLP-1 secretion This reduction in GLP-1 secretion during HFD is associated with decreased upper small intestinal SGLT-1 levels In line with this, HFD reduces SGLT1 expression in small intestinal L-cells, resulting in impaired GLP-1 response to glucose in primary cultures Fig.
High protein diets in both humans and rodents reduce body weight and adiposity in association with intestinal protein sensing-related increases in gut peptide levels.
In humans, duodenal infusion of whey protein hydrolysate decreases food intake without a change in subjective appetite ratings , but in parallel to increased GLP-1 and CCK levels , In addition, casein infusion into the ileum of humans also decreases food intake, whereas infusion into the duodenum or jejunum has minimal effect.
This is possibly explained by the fact that ileal casein infusion resulted in the greatest rise in GLP-1 levels compared to duodenal or jejunal infusion In rodents, various protein solutions potentially reduce food intake more potently than isocaloric and isovolumetric carbohydrate infusions , and the underlying mechanisms may involve CCK release and subsequent activation of CCK-1R on vagal afferent neurons , , , although GLP-1R signaling was not investigated.
Thus, future studies are needed to more definitively identify the specific effects of different types of protein and the intestinal site of protein sensing on the regulation of food intake and gut peptide release. High protein diets improve glucose homeostasis in both rodents and humans , , even in the absence of weight loss in patients with diabetes or during pair-feeding in rodents , In humans, duodenal whey protein hydrolysate impacts circulating glucose, insulin, and glucagon , , while duodenal, jejunal, or ileal casein infusion leads to a substantial increase in insulin levels with no change in glucose Moreover, infusion of leucine alone into the duodenum dose-dependently increases insulin, with slight decreases in glucose, but no change in glucagon These effects are mediated by peptide transporter-1 PepT1 , a di- and tri-peptide proton-coupled transporter located in the brush border membrane of the intestinal epithelium Fig.
Recent evidence using isolated intestinal perfusion technique indicates that dietary protein induces gut peptide secretion via transport of oligopeptides into cells via PepT1.
Cellular oligopeptides are broken down into individual amino acids that are released to the basolateral side of the intestine to activate amino acid receptors Taken together, these data indicate that both apical PepT1 and basolateral CaSR could be critical for peptone-mediated GLP-1 release Fig.
Nonetheless, more work is needed to determine the exact mechanism linking intestinal protein sensing to gut peptide release, and which specific amino acids and sensors are required. In contrast to lipids and carbohydrates, sensitivity to intestinal protein-sensing appears to be maintained during obesity, highlighting the potential of protein-sensing as a therapeutic target for weight loss.
There are no differences in energy intake or CCK and GLP-1 responses between individuals with and without obesity following intraduodenal whey protein infusion In line with this data, rats fed an HFD for either 3 or 28 days, with the latter resulting in increased adiposity, still responded to small intestinal casein infusion by lowering hepatic glucose production In addition, high protein intake improves metabolic outcomes, like body weight, adiposity, insulin sensitivity, and food intake, in both rodents and humans , , , and improves glucose tolerance and lowers blood glucose levels in patients with diabetes This may be explained by the fact that intestinal proteins more potently stimulate gut peptide secretion as compared to isocaloric lipids or carbohydrates Future research is warranted to uncover the mechanisms of how intestinal protein sensing, but not lipid or carbohydrate sensing, is maintained during metabolic dysregulation.
Changes in the gut microbiota affect obesity and related metabolic disorders, and the mechanisms linking the gut microbiota to energy and glucose homeostasis have been extensively reviewed , However, the majority of the studies have focused on the role of the microbiota in the large intestine, and few studies have examined the metabolic impact of the small intestinal microbiota.
While there are several orders of magnitude greater abundance of bacteria in the large intestine than in the small intestine, nutrient-sensing, and gut—brain feedback mechanisms are localized to the small intestine, as nutrient absorption limits ingested macronutrients from reaching the large intestine.
Further, the protective barrier of a mucus layer in the small intestine is much less established , allowing for an increased potential for intimate interactions between the host epithelial cells and the gut bacteria. For example, restoring the gut microbiome in germ-free mice results in an acute, transient phase, followed by a homeostatic phase that impacts jejunal transcriptomics and metabolomics involved in lipid and glucose metabolism and uptake However, the initial acute response is not observed in the ileum or colon, highlighting the sensitivity of the upper small intestine to the microbiome.
Evidence suggests that the microbiota could also greatly impact nutrient-sensing mechanisms. First, microbial metabolites, especially short-chain fatty acids SCFAs , are known to induce gut peptide secretion from EECs , Most bacterially derived metabolites like SCFAs are produced predominantly in the distal intestine but are also present in small amounts in the ileum and can reduce glucose production via a gut—brain axis , Other metabolites, like indole, are highly abundant in the small intestine and also regulate GLP-1 release from EECs Secondly, the gut microbiota impacts EEC physiology.
For example, isolated cells expressing GLP-1 obtained from germ-free and conventional mice exhibit different transcriptomes, which is rapidly altered after only one day of microbiome colonization, suggesting a more direct effect of the bacteria on the EECs vs.
an indirect effect from altered physiology of the germ-free model Further, intestinal expression and circulating levels of gut peptides are altered in germ-free mice , Similarly, HFD converts zebrafish EECs into a nutrient-insensitive state dependent on gut microbiota, as germ-free zebrafish are resistant to the induction of EEC nutrient-insensitivity while an Acinetobacter strain was able to induce EEC nutrient-insensitivity In line with this, bacterial species directly influence GPR, a receptor linked with lipid-induced gut peptide secretion, and GLP-1 expression in vitro Third, LPS, a bacterial byproduct, blunts vagal activation by intestinal nutrients, leptin, or CCK , Thus, there exists a precedent for the ability of small intestinal microbiota to impact nutrient-induced small intestinal gut—brain signaling Fig.
We put forward a working hypothesis for the mechanistic links between small intestinal nutrient-sensing, microbiota, peptide release, and metabolic regulation.
Bacterial by-products such as LPS can impair lipid and glucose sensing and potentially disrupt ACSL3 and SGLT1 dependent pathways that regulate glucose and energy homeostasis. Bile salt hydrolase of bacteria contributes to the bile acid pool and regulates bile acid metabolism.
As a result, changes in bile acids can alter GLP-1 release and metabolic regulation via intestinal FXR and TGR5 signaling. High-fat feeding reduces the abundance of small intestinal Lactobacillus species e. gasseri and consequently inhibits ACSL3 expression and impairs lipid sensing.
Lastly, metformin increases the abundance of upper small intestinal Lactobacillus and enhances SGLT1 expression and glucose sensing, while also reducing the abundance of Bacteroides fragilis that results in ileal FXR inhibition and improvement in glucose metabolism.
Bariatric surgery enhances small intestinal nutrient sensing mechanisms and consequently lowers glucose levels, while changes in bile acid metabolism and FXR are necessary for the glucose-lowering effect of bariatric surgery.
In parallel, gut microbiota alters the bile acid pool and thereby potentially affects nutrient sensing and glucose and energy homeostasis.
Conjugated bile acids are produced in the liver and released into the duodenum, where they are either absorbed or de-conjugated by the bile salt hydrolase of bacteria. Bile acids act as signaling molecules in the intestine and elsewhere, binding to FXR and G protein-coupled receptor 19 also known as TGR5 Most, but not all, studies indicate that inhibition of intestinal FXR improves energy and glucose homeostasis , and FXR signaling represses transcription of GLP-1 and inhibits GLP-1 release from L-cells Interestingly, TGR5 signaling increases GLP-1 release from L-cells , thus complicating the role of bile acid signaling in the intestine Fig.
HF-feeding, obesity, and diabetes are all associated with unique microbial profiles in the large intestine. However, evidence suggests that HF-feeding also alters the composition of small intestinal gut microbiota. In rodents, the majority of the small intestinal bacteria are Lactobacillius , and HF-feeding results in a drastic reduction in the relative abundance of this genus 45 , Recent work indicates that altered small intestinal microbiota during HFD drives impairments in intestinal lipid-sensing, as the transplant of the small intestinal microbiota of short-term HF fed rats into chow-fed rats abolished the ability of small intestinal lipid infusion to improve glucose tolerance and lower hepatic glucose production.
Treatment of HF-fed rats with a small intestinal infusion of Lactobacillus gasseri enhances upper small intestinal lipid-sensing, via restoration of long-chain acyl-CoA synthetase ACSL3 gasseri exhibits bile salt hydrolase activity and can thus alter the composition of the bile acid pool.
Small intestinal L. gasseri increases ACSL3 and subsequent lipid-sensing through a mechanism dependent on reduced FXR signaling. These findings are consistent with the fact that bile acid sequestrants i.
Recent evidence-based on studies with the anti-diabetic medicine metformin indicate that the glucoregulatory impact of intestinal glucose-sensing is mediated by the small intestinal microbiota.
While metformin directly influences hepatic metabolism , as an orally administered drug metformin concentrations in the small intestine are much greater than in the serum Oral metformin reduces blood glucose levels more than intravenous or portal vein administration , demonstrating a role for intestinal-mediated mechanisms of action in improvements in glucose homeostasis.
Pretreatment of HF-fed rats with metformin restores the ability of upper small intestinal glucose infusion to lower glucose production via increased portal vein GLP-1 levels and small intestinal SGLT-1 expression and in parallel changes the composition of small intestinal microbiota This is in line with several other studies that highlight the importance of the gut microbiota in mediating the beneficial effects of metformin , In addition, individuals with newly diagnosed diabetes treated with metformin for three days exhibit alterations in the gut microbiota including increased Lactobacillus and reduced Bacteroides fragilis abundance, which result in inhibition of FXR signaling to improve glucose metabolism This observation is similar to the ability of L.
gasseri to increase intestinal lipid-sensing to improve glucose homeostasis via FXR 45 Fig. Collectively, these studies highlight small intestinal nutrient-sensing mechanism mediates the beneficial effects of metformin through changes in gut microbiota and bile acids.
Evidence is emerging on the impact of the small intestinal microbiota also in the efficacy of gastric bypass. Despite extensive evidence of an overall role of the large intestinal microbiota in mediating the effects of bariatric surgery , at least one study demonstrated that gastric bypass alters the microbiota of the duodenum, jejunum, and ileum In addition, while the jejunal nutrient-sensing mechanism at least partly mediates the beneficial effects of duodenal—jejunal bypass surgery on glucose homeostasis 98 , the glucose-lowering effect of vertical sleeve gastrectomy is dependent on both the gut microbiota and bile acid signaling Fig.
While technological advancements begin to detail the role of intestinal nutrient-sensing in gut—brain neuronal signaling, they concurrently expand the field.
One example of this is the use of single-cell RNA sequencing to understand vagal afferent signaling. Several groups distinctly labeled nodose ganglion neurons according to their expression profile, however, the results are expansive and sometimes contradictory 44 , Based on these studies, vagal afferent neurons containing GLP-1R have no impact on intestinal nutrient-sensing mechanisms, which are instead regulated by GPRpositive neurons Indeed, various neurons terminating in the intestinal mucosa, that likely sense gut peptides released in response to intestinal nutrients, have no effect on food intake, and only direct activation of a subset of IGLE neurons that detect intestinal stretch and not gut peptides suppresses food intake A subset of EECs called neuropods exist that directly synapse with vagal neurons, and rapidly signal via glutamate to the nucleus of the solitary tract in a single synapse to relay initial spatial and temporal information about the meal that could later be followed by more traditional gut peptide signaling Despite these interesting and exciting advances and the discovery of new nutrient sensory cells, the exact neurons that mediate the gut—brain signaling and nutrient sensing in regulating metabolism are complex and warrant future investigations.
Future studies are needed to start teasing apart these complexities, while also integrating the gut microbiota and metabolites into the picture.
For instance, while the gut microbiota can impact EECs, it is plausible that vagal afferents themselves can be impacted by bacterial metabolites In contrast to energy intake, the impact of nutrient-induced gut—brain vagal signaling on energy expenditure has been poorly characterized.
Intestinal lipids regulate brown fat thermogenesis via vagal afferents and possibly via GLP-1R signaling , and vagal knockout of the transcription factor peroxisome proliferator-activated receptor-γ, which is activated by fatty acids and could thus be involved in lipid-sensing, affects thermogenesis Likewise in humans, intraduodenal infusion of intralipid increases resting energy expenditure Nutrient infusions into the duodenum of rats modulate energy expenditure Future work is needed to detail the connections between nutrient-sensing mechanism, gut microbiota, and impact on energy expenditure via thermogenesis in brown or browning white adipose tissue Overall, extensive evidence indicates that targeting nutrient sensing in the small intestine impacts energy and glucose homeostasis during normal physiology and in the context of obesity and type 2 diabetes.
Given the distinct effects of HFD and obesity on the diminution of nutrient-sensing dependent gut—brain pathways, future studies examining the gene and environmental interactions are warranted to further the development of personalized medicine approaches. Similarly, the expansive role of the gut microbiota in host metabolic health further highlights the need for personalized approaches to treating metabolic diseases.
As such, studies in humans and rodents beginning to unravel the interactions between the gut microbiota, small intestinal EECs, and vagal signaling, are laying the groundwork for the development of therapeutics targeting small intestinal nutrient sensing to treat obesity and type 2 diabetes.
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Schwartz, G.
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