Title Page

DOES ELECTRICAL RESISTIVITY OF FOOD HAVE A ROLE IN RESPONSES OF THE GASTRO-INTESTINAL TRACT TO FOOD?

Or How does the stomach know whats in a meal?

Author.

J Andrew Sutton, MD(London), FFARCSI Independent consultant in clinical pharmacology. 4, Elmleigh, Midhurst, West Sussex. GU29 9HA Telephone 01730 817150 Email: drasutton@gmail.com

This hypothesis has evolved over many years independently from any host institution or grant. The author is not aware of any conflicting interest.

Running title: Osmo-resistivity of food constituents Keywords. Resistivity of food, duodenal electroreceptors, osmolarity,

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Abstract

Our complex response to food involves differentiating carbohydrate, protein and lipids (CPL) by unknown mechanisms prior to releasing specific digestive enzymes. CPL have different electro-resistivities

(ER) in solution or suspension so this article discusses how ER could be the basis for that differentiation. It would require electroreceptors that have never been suspected in man but there are morphological and historic reasons to think that they could exist. Their output combined with concentration data derived from osmoreceptors would produce a sensitive and quantitative monitoring process so that the appropriate amount of enzymes would be released. By monitoring the action of digestive enzymes, bile and acid the digestive system could cease to produce enzymes when they ceased causing changes in ER-osmolarity. This implies that the pre-absorption phase of digestion is complete when digesta becomes both isosmotic and iso-resistive since that would be expected to facilitate transport across mucosal membranes. If so it may be possible to design more easily digested meals for patients with gastro-paresis. Several ways to test this new theory are suggested.

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Bioimpedance background Food has resistance to electrical current which is used to monitor gastric filling and emptying by the epigastric impedance method.1.2 Fig 1 shows a trace when that method monitored gastric filling when a volunteer drank 500ml of 10% glucose solution. There was a positive increase because 10% glucose solution in de-ionised water is more resistant (or impedic with alternating current) than the body norm, or iso-impedic point. By contrast the deflection would be negative when the subject drinks a liquid such as salty tomato juice which is conductive, or sub-iso-impedic, showing what a wide range of effect can exist in common fluids. The decline from peak has been shown to mirror gastric emptying. 1.2

Figure 1: A diagram of an Epigastric Impedance Trace.

There is a wide range of impedances in biological fluids. Fig 2 shows that de-ionised water has a specific impedance about 18.31 Mega ohm-cm, which is 3 orders of magnitude greater than tapwater at about 20 Kilo -cm (3) which shows the effect of a small concentration of ionized particles such as Cl . Normal saline and 10% glycerin solution are another 2 orders less impedic at approximately 80110 -cm, while the protein fibrinogen at physiological concentrations is approximately 309 -cm. (4) The value is affected by the bulk and ionized state of the molecules in solution or suspension, so large molecule lipids (L) without charges will have higher impedances than smaller molecule carbohydrate (C) or proteins (P) that usually have ionized radicals on their surfaces. Hence, if the digestive system does use this characteristic of food it has a wide range in which to work. Page 3 of 9

Figure 2 De-ionised water and normal saline have specific impedances that are orders of magnitude apart.

The wide range of resistivity in physiological fluids

100000000 10000000 1000000 100000 10000 .cm-1 1000 100 10 1

Ultra Pure Water Tapwater Normal Saline

Electro-Receptors? To do that would require electro-receptors, which seems to be a remote possibility because they have never been identified. However, they have never been specifically excluded or, it seems even sought because nobody has suspected their existence. There is an interesting parallel in, of all species, the monotreme mammal the duck-billed platypus. That animal was known to detect its prey of small crustacean and worms in muddy water, at night and often with its eyes closed, so how did it do it? Eventually someone recognized the similarity to the behaviour of fish and sharks that track their prey by electroreceptors that detect the minute electrical currents emitted by the muscles of their prey. Proske et al5 described how monotreme electroreceptor structure gave no clue to its function when they wrote:

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The ability of animals to be able to detect weak electric fields in their environment was recognized only relatively recently, perhaps because we, ourselves, are unaware of any but the strongest fields. Thus, the ampullae of Lorenzini in elasmobranch fish were first thought to be mechanoreceptors, then thermoreceptors and chemo-receptors. It was not until the late 1950s that convincing behavioural evidence was provided for an electroreceptive role. At about the same time the tuberous receptors of mormyrid and gymnotid fish were recognized as electroreceptors. It was not until the 1980s that electroreceptors were described in urodele amphibians and monotremes.

Figure 3. The structure of platypus electroreceptors.

Platypus bill's two kinds of pore. The electrosensitive pore (far left) is the opening of a mucus gland duct while the touch-sensitive pore on the far right contains a pushrod device that triggers nerves when compressed by a mechanical wave in the water or when it comes into contact with an object (Australian Geographic).

Drawings of electroreceptors as in Fig 3 show a central, mucus-filled compartment that provides a conductive pathway down to the nerve endings at its base. The resemblance of this compartment to human mucus glands was noted by Andres et al (1991)6 who wrote: Monotreme electroreceptors have similar structures to classic, human duodenal mucus glands and were even designated sensory mucous glands. Therefore it seems possible that human mucus-producing glands in the duodenal mucosa, commonly called Brunners glands, could also have an electroreceptor function.

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Osmoreceptors? Osmoreceptors are long established and their output influences production of gastric secretions and pancreatic digestive peptides.7-12 but they could not distinguish between CP and L at equal concentrations, unlike the situation when osmolarity is combined with resistivity as Fig 4 attempts to portray.

Figure 4.

Gastric hydrochloric acid would cause different effects on the impedance and

osmolarity of carbohydrate, protein and lipid suspensions...

Adding Hydrochloric Acid

Some ionisation and molecular splitting? ? ?

Osmolarity

Protein

CHO

? Pure water
Zero osmolarity

Oils and Fats

Conductive

Impedic

Effects of acid and enzymes Digestion itself would cause changes in the osmo-electrical nature of the gastric contents and the proposed system could monitor them, providing a feedback loop by which the need for more enzyme would be identified. Equally, when enzyme or acid increments cause no change it would be a signal to cease producing them. Fig 4 attempts to illustrate the effect of acid separating CPL but clearly specific CPL enzymes would have more specific effects, such as lipase increasing the osmolarity of lipids by fragmenting molecules. Bile would reduce lipid resistivity Page 6 of 9

by adding charged particles to the lipid during micelle formation, and since micelles are aggregated lipid molecules it would also reduce osmolarity, but it would not affect carbohydrate.

The pattern of gastric emptying includes a sampling period. It is possible that gastric emptying includes a sampling period when electro and osmo receptor data are processed. The plateau seen in Fig 1 during the decline from peak impedance may represent such a period. It has appeared frequently in traces from individual subjects although group data tended to revert towards the classic mono-exponential mean of textbooks. It was detected by epigastric impedance partly by its continuous record of gastric volume, unlike a periodic sampling method such as scintigraphy where sampling occurs at intervals of comparable duration to the plateau itself. A second reason is that epigastric impedance normally monitors liquid test meals, partly because liquid specific impedance is more easily manipulated and measured than solid meals and liquids provide more uniform and interpretable profiles. A mechanical aspect of this plateau was shown to me by Professor Heading in Edinburgh in a video of ultrasound images of gastric emptying from a volunteer who had swallowed water laced with biscuit-crumbs. They shone like stars in a black background and it was surprising to see them moving repeatedly back and forth between the antrum and duodenum in an oddly purposeful way as though some kind of sampling was occurring.

Discussion We make a complex response to food, yet there is no convincing theory of its orchestration despite decades of research into many aspects of it, such as the digestive peptides. We do not know what triggers specific responses to CPL or why the responses cease as digestion is completed. Such a deep mystery requires a radical solution and to propose the existence of human electroreceptors is certainly that. Unlikely as they must seem, there is a precedent in the work of Andres et al 6 who pointed out that electroreceptors in monotreme mammals were not suspected for decades despite the fact that their structure was well known. Clearly it is feasible, if currently improbable, that mucus glands of the human duodenum have the required sensors at their depths but they have been credited with functions concerned with mucus production. Proske et al suggested that that this was partly due to a general lack of awareness of the functions of electroreceptors and their extraordinary sensitivity in particular. Platypus and echidna use them to detect the minute currents emitted by the muscles of river crustaceans and worms. Electroreceptors in elasmobranch species are amongst the most sensitive receptors known. For example, sharks that can detect 0.01 microvolt/cm(14, 15) which has been illustrated by the Reefquest Shark protection organizations website as the equivalent to the electric field of a Page 7 of 9

flashlight battery connected to electrodes some 10,000 miles (16,000 kilometres) apart in the ocean.(16) In freshwater fish species electroreceptors are reported to detect 0.1-10 mv/cm.(14) The parallel in human digestion is the lack of awareness of the possible advantages of electroreceptor data, particularly of a highly sensitive nature; the main one being quantification of the CPL contents of digesta so that responses are also accurately quantified. Not only would that minimise wasteful production of enzymes but it would enable responses to small amounts, so making the most advantage of the food available. This becomes possible when electroreceptor data is combined with osmolarity. An appealing aspect of this theory is that it enhances the role of osmoreceptors. Their output on concentration without knowing the CPL content of the suspension could only trigger a non-specific response. Likewise, electroreceptor data alone cannot quantify CPL, but combined with concentration it can do so. An innovative hypothesis should suggest ways to test its assumptions and predictions and in this case the list includes the following: 1. Measure resistivities of selected meals, including within simulated duodenal suspensions. Differences should be large enough to be detected by electro-receptors and follow the predicted pattern. 2. Examine duodenal mucous glands for nerve endings that could function as electroreceptors. 3. Test the correlation between enzymatic and hormonal responses to test meals of prescribed resistivity and CPL constitution. There should be smaller responses to meals nearer to the iso-resistive point than those further from it. 4. Devise meals that could be taken by patients with gastroparesis to show whether absorption is facilitated the nearer the meals are to isoresistive. 5. Measure the permeability of gut membranes to liquids of varying resistivity. Isoresistive fluids should pass more easily through them than hyper or hypo resistive liquids 6. Assess the resistivity and osmotic changes caused by digestive enzymes acting on their usual substrates, such as lipases on lipids. Do they cause a shift towards isoresistivity as the theory predicts? Conclusion This theory, or series of speculations, describes a possible way for the human gut to respond quantitatively to food. The wide range of electro-resistivity in carbohydrate, protein and lipid solutions or suspensions offers a feasible way for the gut to distinguish them, particularly if they change in consistent and distinctive ways in the presence of digestive enzymes. Page 8 of 9

Acknowledgement I thank Professor Nicholas Spyrou of the department of medical physics at Surrey University for his inspiration and friendship over many years while we developed the gastric monitor, the basis for inventing this hypothesis. References
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