And what’s new.
Imagine swallowing a pill about the size of a standard vitamin tablet, which when excreted tells you how your diet has affected various aspects of your well being, right from letting you know whether your mild depressive episode was caused by actual symptoms beyond your immediate control, or as a result of that Double Cheese Pizza you consumed with a large soda at 2:00AM binge-watching your favourite TV show? Imagine being diagnosed with severe clinical depression, Obesity, IBS, Crohn’s disease, what-have-you, and have an app tell you whether constituents of the gut might have played a role in it, without the need for painful, invasive and expensive surgeries? Imagine, as a woman, having access to the ever changing hormonal landscape of your body, in a new and informative way, by observing the diversity of your gut bacteria? Diversity is always good, be it gender, nationality, race, religion, or bacteria within the gut. But that is an article for another time.
Scientists have known for a while now, that the nutrients obtained through food regulate moods in some way, and that the enteroendocrine system or the “Second Brain” is responsible for this. Initially, it was thought that the enteroendocrine cells communicate with the nervous system by releasing hormones in response to the food or bacteria that they sense, which then modulates behaviour. Researchers have recently demonstrated experiments to show that this connection is more direct. Using 3D imaging techniques, the authors observed the presence of tiny microvilli and a foot-like extension on the enteroendocrine cells, similar to dendrites and axons of neurons in the brain. They were also able to show that the cells interacted with each other through real physical synapses, much like neurons of the brain, and not through the release of hormones as previously thought.
Better imaging technology, new materials that are biocompatible, and miniaturisation of electronics are some improvements that are helping with a mechanistic and interpretive function of the microbiome. This article aims to briefly describe ongoings in the world of ingestible pills -what is sensed in the gut using existing technologies, and novel sensing methods that are being developed. Ingestible pills have already been consumed by more than half a million people worldwide. The sensors within them can measure physical parameters like temperature and pressure, or chemical and biochemical parameters like gas, which are direct byproducts of bacterial activity from the food we consume.
Known parameters that can be measured, vary based on which region of the gut is being sensed. For example, Saliva in the mouth provides information about the metabolism of the body, and acts as a biomarker for diseases like HIV and Cancer. Swallowed food passes through the oesophagus, which connects the mouth to the stomach. If you’ve ever had acid reflux, the burning chest pain you feel occurs in the oesophagus, where to test for inflammation or lacerations in severe cases, doctors use techniques like Endoscopy to access the oesophagus wall. The next organ is the stomach, followed by the small intestine. The presence of bacteria like H.Pylori in the stomach is associated with stomach cancers. pH levels, balance of electrolytes, metabolites and bacterial counts are useful parameters to monitor. Primary sensing targets of the small intestine include concentration of electrolytes, gases, and bacteria counts which help in identifying overgrowth of bacteria, etc. Finally, any remaining biological products move to the colon, where the quality of mucosa, nutrient absorption, and chemical analysis of certain compounds indicates the presence of wounds, infections, or even cancer. About 1.5kg of the ~2kg of bacteria hosted in the body lives in the colon. The use of ingestible pills would be effective replacements for colonoscopies, endoscopies, and other methods of current access into the gut.
The major electronic components within the typical pill include sensors for temperature, pH, and gas, that collect and transmit data to a receiver usually worn as a handheld device outside the patient’s body.
Imaging capsules were first approved by the FDA in 2001, and more than 2000000 capsules have been ingested since then. Aptly named Mouth-To-Anus (M2A®; Given®Imaging, Yoqneam, Israel) this technology is popular now as Wireless Capsule Endoscopy. It greatly minimised the need for Endoscopies and repeated screenings that come with it. Today, there are AI based algorithms to help identify lesions and haemorrhages within the gut wall from images captured by the pills, which reduces human effort in diagnosis of gut disorders. What’s in them? Simple miniaturised electronic components comprising a camera and LED interfaced to a microcontroller that transmits data to a receiver. The basic electronic interface can be built by a high school kid using an Arduino board and a mini camera module, although it won’t be ingestible. The real challenge would lie in making it biocompatible, reducing capsule retention, securing data transmission, managing power requirements and ensuring that patients who ingest the pill would not require surgical intervention to remove it for whatever reason; that it passes out safely with the rest of the biological waste.
Downsides of the Image-based, and the more powerful Video-based variants, include that they are not very insightful into the activity of the gut bacteria per se, but merely provide a way to visually inspect the gut wall. The ingestion procedure requires that a patient have a completely clean gut which is achieved by fasting. This means that observing activity in the presence of food or other obstructions is simply not possible with this pill. Another issue is with determining where it is located at any given time in the gut. The location is correlated using Ultrasound imaging, or external magnetic influence that can also guide, rotate, and steer the pill. Nonetheless, Image-based pills have many advantages that make them a popular choice amongst doctors and patients.
pH sensors measure the acidity of a given region within the gut. The stomach is highly acidic due to the presence of gastric juices and secretion of Hydrochloric Acid. A sudden increase in pH (>3 units) from the baseline, indicates the transition of the pill from the stomach to the intestine which is more alkaline. Thus, pH sensors also provide a measure of where in the gut the pill currently is. This is especially useful in measuring the gastric emptying time and colonic transit time, which is fancy medical jargon for the amount of time the food takes to exit your stomach and enter the small intestine, and from your colon till excretion respectively. Chronic constipation is associated with longer gastric emptying and colonic transit times. pH based sensing is also the gold standard used by doctors to diagnose diseases related to gastroesophageal reflux diseases. Suggested times for exiting each gut region have been established, but are not set in stone. This is because Gastrointestinal motility varies based on body characteristics, diet and water intake, and many other factors. The consensus is that fibre intake slows down the pills journey through the small intestine, but feeds bacteria in the colon which helps excrete food faster. According to major manufacturers (Medtronic Given Imaging, Olympus), pH signals are noisy and the method is costly for the small amount of information it provides. The figure below shows an example of how pH and temperature profiles obtained from ingestion of the pills look. The pH drop at the black arrow indicates gastric emptying time, and the red arrow indicates the colon transit time.
The most recent development in the world of smart pills is gas-based sensing. The first human pilot trial using a gas-sensing pill was published in Nature Electronics in 2018. The key idea is that constituents of certain gases in the gut make efficient biomarkers for various diseases and diet plays a role in the fermentative activity of bacteria. Therefore, being able to monitor gas profiles and understand gaseous activity is of diagnostic value. Traditional approaches to doing this include breath tests, flatus analysis (AKA scientific analysis of farts), faecal analysis and tube insertions, which provide useful information in their own way; for example we know from breath tests that having higher content of Methane/Hydrogen positivity in your breath is associated with higher BMI or body fat percentage. But these methods are limited because gas concentrations are present in low amounts (in the order of parts-per-million) leading to low signal-to-noise ratio. Another limitation is the inability to pick up where in the gut the gas activity originated from.
The pill comprising gas sensors to measure levels of Oxygen, Carbon Dioxide and Hydrogen aims to overcome said limitations while acting as a safe and accurate monitoring tool for gut health. The authors establish gas profiles for patients with varying amounts of fibre intake and show how the small intestine and colonic transit times vary. Details of the crossover study and results from it can be found here.
The figure below shows the pill with the electronic components and the packaged gas capsule with the receiver.
The gas sensor used is a metal oxide semiconductor which operates at high temperatures (200–300⁰C). It has to be calibrated to be selective to known gas types and concentrations. In clean air, Oxygen gets deposited onto the Metal Oxide surface of the gas sensor, and free electrons from the heater element bind to Oxygen due its high electron affinity. The measured voltage/output is low. In the presence of reducing gases like Hydrogen, redox reactions occur and Oxygen is no longer available for the free electrons to bind to. They are now available for conduction and the measured voltage/output increases. Once resistance values have been established, mathematical equations are used to determine the gas concentration. The outputs of the sensors are digitised using microcontrollers and RF transmission at 433GHz with a data transmission rate of 2.7Mb/s is typically used. The Reed switch based power supply is made using Silver oxide coin batteries operating at ~3V. These are standard values for electronic components encapsulated in ingestible pills.
Only “healthy volunteers” who had met inclusion criterion such as no history of gut disorders and other chronic conditions, no implantable pacemakers, not pregnant, non-alcoholic and non-smokers etc. were administered the pill. Controlling for only one parameter, i.e. fibre intake, led to varied gas profiles in healthy volunteers in this pilot study. The technology is still new, so the gas sensors don’t work very well just yet. The baselines for the sensors are unstable, and the selectivity towards gases is not very strong. Despite that, the initial results look promising; perhaps this technology will become commercial soon.
The field is still in its infancy, but what does this technology have in store for the future? In what ways will it transform healthcare delivery? The truth is that the functionality of the gut is still being understood by researchers and doctors; no two individuals have the same gut flora. Knowledge of what enzymatic and metabolic activity occurs, and how they respond to food intake, environment, and other factors etc. is not fully known. Developing ingestible pills capable of discovering new knowledge about the gut would be tremendously insightful in delivering highly personalised healthcare for each individual on the planet.