Associated Data

In , a fur trapper accidentally shot a year-old man named Alexis St. Army surgeon William Beaumont successfully patched up St. Martin, but the trapper was left with a hole in his stomach's abdominal wall, which is called a fistula. The fistula allowed Beaumont to investigate the workings of the stomach in entirely new ways. Over the next decade, Beaumont conducted experiments on St. Martin, some of which involved sticking food directly into his patient's stomach. He drew a number of important inferences from his work, including that fever can affect digestion, and that digestion was more than just a grinding motion of the stomach but also required hydrochloric acid.

Cells along the inner wall of the stomach secrete roughly 2 liters 0. If hydrochloric acid sounds familiar to you, it may be because the powerful chemical is commonly used to remove rust and scale from steel sheets and coils, and is also found in some cleaning supplies, including toilet-bowl cleaners. To protect itself from the corrosive acid, the stomach lining has a thick coating of mucus. But this mucus can't buffer the digestive juices indefinitely, so the stomach produces a new coat of mucus every two weeks.

Peptic ulcers are painful sores on the lining of the esophagus, stomach or small intestine, and they affect approximately 50 million Americans each year, according to a study in the journal American Family Physician. Physicians long thought that stress and spicy food caused people to develop the sores — an explanation that seemed to make sense, given that ulcer patients often complain about burning pain after eating spicy food. So for almost years, doctors prescribed a treatment involving rest and a bland diet.

In , Australian researchers Barry Marshall and Robin Warren discovered that the real culprit behind ulcers is the bacterium Helicobacter pylori , which burrows into the stomach's mucosal lining. Thanks to this finding, doctors have come up with a better treatment for ulcers: When the tract is empty, however, borborygmi are louder because there's nothing in there to muffle the sound. After the stomach empties its contents into the small intestine, it sends signals to the brain. The brain responds by telling the digestive muscles to commence the process of peristalsis.

The muscle contractions ensure that no excess food was left in the stomach, and the resulting growls signal to you that your body needs food. Follow Joseph Castro on Twitter. Digestive system image via Shutterstock. Here are 11 facts about the digestive system that may surprise you. Upside down kid photo via Shutterstock. Stained shirt photo via Shutterstock. Villi image via Shutterstock.


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All of these features help the small intestine to better absorb food. Strange smell photo via Shutterstock.

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The digestive system cannot break down or absorb certain components of foods, and those substances simply get pushed along the tract, and make their way into the large intestine. Hordes of intestinal bacteria get to work, releasing a variety of gases in the process, including carbon dioxide, hydrogen, methane and hydrogen sulfide which gives flatulence its rotten-egg stench. Endoscopy illustration via Shutterstock. Stomach illustration via Shutterstock. Stomachache photo via Shutterstock.

Introduction

Stomach ulcer illustration via Shutterstock. Furthermore, our study revealed rapid degradation of milk miRNAs in intestinal fluid. Together, our results indicate a nutritional rather than gene-regulatory role of miRNAs in the milk of newborn mice. They can play important regulatory roles in plants, animals, and humans by targeting mRNAs for degradation or translational repression, thereby influencing the output of many protein-coding genes 1.

Major functions of miRNAs include helping to maintain a particular differentiation state and to preserve cellular identity in fully developed tissues 2 as well as influencing responses to physiological and pathophysiological stress 3. Additionally, dysregulation of miRNAs has been correlated with various disease states, including metabolic dysfunction and cancer 4 , 5. Apart from their cell-autonomous functions, miRNAs are also present in numerous body fluids, including blood, saliva, urine, amniotic fluid, and milk 6.

The existence of extracellular miRNAs raises the interesting questions of whether they are released in a regulated fashion and whether circulating miRNAs in mammals act at a distance in intertissue communication 7. Moreover, the concept of miRNA regulation from distant cells within the same organism and, potentially, even from different organisms has led to the question of whether miRNAs from exogenous sources such as food could affect gene expression in human tissues.

Although the uptake of nutritionally derived miRNAs was originally demonstrated in 8 , this notion has since been rejected by multiple studies demonstrating that miRNAs originating from dietary sources, crossing the intestinal barrier and regulating gene expression exogenously, is highly unlikely 9 — Milk in lactating mothers has been shown to be a particularly rich source of secreted miRNAs.

Food doesn't need gravity to get to your stomach.

Sequencing and microarray analysis of miRNAs in the milk of various mammalian species has led to the discovery of hundreds of miRNAs in bovine 13 — 15 , porcine 16 , 17 , rat 18 , and human milk 19 — Furthermore, several studies have suggested that milk miRNAs may survive degradation in the digestive tract because they have been shown to be particularly resistant to harsh treatment such as incubation under acidic conditions and at high temperatures, likely because of their presence in exosomes 14 , 15 , 17 , Therefore, although it may appear as though miRNA transfer from the milk to offspring would contradict the numerous failures to demonstrate the uptake of nutritionally derived miRNAs in adult rodents and humans, it is plausible that same species-derived milk miRNAs encapsulated in exosomes may be taken up in the neonatal period when the intestinal barrier is not fully developed.

Several in vivo studies have been performed in an attempt to understand whether milk miRNAs are subject to uptake by offspring. A second study 9 reported a dose-dependent increase in plasma miRb and miRc in human subjects who consumed 0. Finally, a more recent study has revealed no evidence of miRNA uptake in murine offspring consuming milk overexpressing miRb Importantly, all of these studies share an inability to distinguish between endogenous and exogenous copies of the miRNAs in question. This study was designed to help resolve the issue of whether miRNAs can be taken up from milk and regulate gene expression by canonical miRNA function in tissues of newborn and young mice during the lactation period.

Subsequently it has also been found to be expressed in a variety of other tissues, to be down-regulated in some cancers 26 , and to play a role in immunity Importantly, both miR and miRc have been detected in rat milk whey 18 and have been found to be among the top 10 most expressed miRNAs in porcine milk exosomes 17 and, in the case of miRc, in human milk as well Denatured milk was collected from the stomachs of WT offspring aged 2 days D , 8 days, and 14 days, representing the early, mid, and late stages of lactation, with two replicates each.

Single reads were then sequenced on an Illumina HiSeq Homozygote breedings were set up to generate WT or KO litters. New pups were wrapped in bedding of the original litter to take up its scent, which was sufficient to induce mothers to care for the new litter.

11 Surprising Facts About the Digestive System

Pups of Groups 1 and 4 Fig. Blood was collected as described below. Milk was collected from the stomach by incision at the greater curvature and gentle removal of its contents. GlycoBlue coprecipitant Life Technologies was used as a carrier. RNA from milk clots and plasma was isolated using the miRNeasy kit Qiagen following the supplementary protocol for purification of RNA from serum or plasma. Samples were spiked with 20 fmol synthetic cel-miR as an internal control for extraction efficiency adapted from Kroh et al. RNA quality was checked on a Bioanalyzer Agilent.

Relative miRNA expression was analyzed using the ddCt method, with sno as an internal control. The detection limit of each miRNA assay was designated as the highest Ct value within the linear range of the standard curve generated using serially diluted synthetic miRNAs. Gene expression was analyzed using the ddCt method with 36b4 as the endogenous control. Following RNA extraction, the protocol proposed by Kroh et al. Data normalization was performed using cel-miR as described, and normalized Ct values were used for absolute quantification and representation of data as copy number per microliter of plasma.

ImageJ National Institutes of Health was used for density quantification. Hepatocytes were isolated as described previously 33 , plated, and infected in quadruplicates with a recombinant adenovirus expressing miR Ad-miR 24 at 7 multiplicities of infection: To ensure equal virus titer per sample, an adenovirus expressing AldoA cDNA with a stop codon at amino acid residue 10 and a mutated miR seed Ad-AldoA Stop Mut 33 was used to bring the total virus titer up to a multiplicity of infection of , therefore excluding any virus-specific effects.

For absolute quantification of miR in hepatocytes, non-infected hepatocyte lysates were spiked with serially diluted synthetic miR as well as miR and miR as controls. Assuming a mean RNA content of Multiplication of relative miR expression levels in Ad-miRinfected hepatocytes by baseline expression generated values of copy numbers per hepatocyte.

Potential target genes were selected by cross-referencing hepatocyte mRNA sequencing data with predicted targets from TargetScan version 6. ApoM was used as negative control and 36b4 as internal control. Data were plotted against miR copy number adjusted for baseline expression, enabling quantitative correlation between miR and target gene levels in hepatocytes.

Expression of the four selected target genes was measured in experimental livers, resulting from KO pup swaps. The small intestine was removed and opened longitudinally, and contents were removed gently. To determine whether milk miRNAs can be degraded by the mouse digestive system, murine digestive conditions were mimicked by incubating the gastric milk of D14 KO offspring receiving WT milk with the intestinal contents of KO offspring receiving KO milk in each case pooled from eight offspring , in this manner eliminating all sources of miR other than the milk itself.

A set volume of 2. Statistical significance was determined by unpaired Student's t test for pairs of data and analysis of variance followed by Tukey post hoc testing for multiple groups. Offspring data were analyzed in two pairs by Student's t test: Pairwise comparisons of sequencing data were calculated using Spearman's rank-order correlation.

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Statistical analysis was carried out using GraphPad Prism version 5. To determine which miRNAs are expressed in whole murine milk, small RNAs 18—30 nucleotides were sequenced in WT milk clots collected from offspring at days D 2, 8, and 14 of lactation. Characterization of miRNAs in murine milk. D , the top 10 most highly expressed miRNAs in milk as determined by sequencing per lactation day. To further examine expression patterns throughout lactation, miR and two representative members of the miR family, miRa and miRc, were absolutely quantified in milk from pups ranging in age from day 1—14 of lactation.

Furthermore, although there was some variation in miRNA expression within and between lactation days, the copy number always remained within the same order of magnitude. We therefore selected D14 as the main focus for this study, with D3 included for some experiments to account for any potential age-dependent and developmental differences that may affect milk miRNA uptake. For the miR portion of this study, offspring of the WT and KO genotypes were generated by setting up appropriate matings, and litters were exchanged immediately after birth to generate the following four study groups: The source of miR in WT pups drinking milk from KO foster mothers likely comes from epithelial cells of the stomach because miR is highly expressed in this tissue data not shown.

Interestingly, this contamination was of greater importance in D3 than in D14 samples, perhaps because of smaller milk clot size and, therefore, a greater surface-to-volume ratio, although some variation in D14 was apparent, as demonstrated by the relatively high miR expression detected in other WT pup, KO milk samples by Northern blot analysis Fig.

Nevertheless, the data show that, for D14 milk, the majority of miR comes from the milk itself because there was no significant difference between WT pups and KO pups receiving WT milk Fig. Similar results were obtained from an analogous experiment utilizing cKO mice Fig.

Gastrointestinal Anatomy and Physiology

These comparisons reveal that miR and miRc are genuinely highly expressed in milk clots and are not solely the result of contaminating cells or secretions. Offspring exchange breeding scheme and analysis. Pups were given to foster mothers within 1 day of birth. The breeding scheme was carried out using both KO and cKO mouse models. F , density quantification of miR Northern blot analysis normalized to the mammary gland. To determine whether miRNAs are taken up from maternal milk into offspring tissues, miR expression was evaluated at several potential levels of uptake in D14 offspring from the study groups described previously.

The absorptive cells of the intestinal epithelium were deemed the first potential site of uptake. Furthermore, miR uptake was also undetectable in gastric epithelium data not shown. Further analysis of downstream tissues, including liver and spleen, also provided no evidence of uptake Fig.

This lack of miRNA absorption via the intestine was corroborated further in enterocytes, plasma, and livers of D3 pups Fig. Importantly, the miR copy number across all tissues and plasma samples in KO pups, regardless of milk, was always at or below the detection limit of qPCR. Relative expression was calculated using the ddCt method with sno as an internal normalizer and setting WT pup WT milk as 1.

Copy number per microliter of plasma was normalized to spiked-in cel-miR The dotted lines represent the detection limit of the qPCR. To further establish whether other miRNAs may be taken up from milk, D14 enterocytes, plasma, and liver samples were analyzed for miRc expression in the analogous cKO experiments Fig. Again, there was no evidence of uptake of miRc from milk despite its fold higher levels in milk compared with miR Fig.

Determination of a qPCR detection limit was not instructive in this case because of cross-detection of other miR family members, although the lack of change between cKO pups receiving WT milk versus cKO milk suggests a negligible uptake. To quantitatively assess the copy number of miR necessary for target gene repression, we used primary hepatocytes that were infected at increasing multiplicities of infection of Ad-miR as a model system.

Four predicted miR target genes, Khsrp , Pop4 , Chsy1 , and Slc16a2 , revealed dose-dependent repression with increasing miR copy number in infected hepatocytes Fig. Assuming that one hepatocyte contains roughly This clearly indicates that, even if minimal miRNA uptake from milk were to occur, perhaps undetectable via qPCR, then it would not be sufficient to enable miR to carry out its canonical role of repressing gene expression. Finally, to confirm this hypothesis, we measured the four validated target genes in D14 offspring liver samples.

As expected due to unaltered miR copy numbers, expression levels remained unchanged for all targets, suggesting insufficient uptake of miR to have any functional output in the liver Fig. Evaluation of miR target gene regulation using hepatocytes as a model. The copy number detected was on the basis of a standard curve prepared in water. B , miR target gene fold-change relative to miR copy number in Ad-miRinfected hepatocytes. ApoM was used as a negative neg control.