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Wiley Interdiscip Rev Syst Biol Med

. Author manuscript; available in PMC: 2014 Nov 6.

Published in final edited form as: Wiley Interdiscip Rev Syst Biol Med. 2010 Jan-Feb;2(1):65-79. doi: 10.1002/wsbm.19

Abstract

The functions of the gastrointestinal (GI) tract include digestion, absorption, excretion, and protection. In this review, we focus on the electrical activity of the stomach and small intestine, which underlies the motility of these organs, and where the most detailed systems descriptions and computational models have been based to date. Much of this discussion is also applicable to the rest of the GI tract. This review covers four major spatial scales: cell, tissue, organ, and torso, and discusses the methods of investigation and the challenges associated with each. We begin by describing the origin of the electrical activity in the interstitial cells of Cajal, and its spread to smooth muscle cells. The spread of electrical activity through the stomach and small intestine is then described, followed by the resultant electrical and magnetic activity that may be recorded on the body surface. A number of common and highly symptomatic GI conditions involve abnormal electrical and/or motor activity, which are often termed functional disorders. In the last section of this review we address approaches being used to characterize and diagnose abnormalities in the electrical activity and how these might be applied in the clinical setting. The understanding of electrophysiology and motility of the GI system remains a challenging field, and the review discusses how biophysically based mathematical models can help to bridge gaps in our current knowledge, through integration of otherwise separate concepts.

The gastrointestinal (GI) system has a number of sophisticated and autonomous functions coordinated over a range of length and time scales. Recent years have seen major advances in determining the mechanisms and interactions responsible for these functions. A substantial challenge involves reintegrating this detailed knowledge into coherent descriptions of single cell, tissue, and organ function, and this review highlights significant early progress towards this goal.

The primary functions of the GI tract are digestion, absorption, excretion, and protection. These functions are achieved through a series of organs with distinct roles from mouth to anus. The stomach and small intestine are principally responsible for digestion and absorption, a process incorporating both physical (e.g., retropulsion in the stomach) and chemical (e.g., bile and enzymes in the small intestine) mechanisms. The large intestine is primarily concerned with desiccation and compaction of waste, with storage in the sigmoid colon and rectum prior to elimination.

Describing and predicting the behavior of integrated systems over multiple scales is a complex task, and physiologists now commonly approach this challenge with the aid of mathematical computational modeling. Recognizing the potential of this approach, the International Union of Physiological Sciences has fostered the Physiome Project to progress these modeling aims.¹ The term comes from 'physio-' (life) and '-ome' (as a whole). The Physiome Project is a worldwide public domain effort to provide a computational framework for understanding the physiology of an individual or species. It aims to develop integrative models at all levels of biological organization, from genes to the entire organism via gene regulatory networks, protein pathways, integrative cell function, tissue, and whole organ structure/function relations. Multiscale GI models are thus a key strategy in forming integrative systems descriptions of GI function, and models of gastric motility are emphasized in this review.

The review is organized into a scale of hierarchies: cellular and subcellular relationships are considered first, followed by tissue level, organ, and lastly, whole body relationships, before clinical directions are discussed (as illustrated in Figure 1). This organization mirrors our present 'multiscale' knowledge of physiological events such as peristalsis, which encompasses vast spatial and temporal scales from nanometers and microseconds (such as, voltage-gated ion channel behavior) to centimeters and hours (for example, meal transit time through the stomach).¹

FIGURE 1.

Illustration of the different spatial scales of models involved in the representation of the gastrointestinal system. An anatomical torso geometry is represented at the broadest scale. An anatomical model of the human stomach is an example of the models at organ level, while at the tissue level, the different muscle layers and their cell types must be represented. At the cellular level, smooth muscle cells in the circular direction (SMC CM) and interstitial cells of Cajal (ICC MY) are shown. The intracellular calcium [Ca ²⁺] i signaling pathways in the Faville et al.² ICC model are illustrated as an example of subcellular level models. The Faville et al ² ICC model states that [Ca ²⁺] i is modulated by a number of transmembrane Ca ²⁺ specific ion channels, which include an inward Ca ²⁺ (I Ca), non-selective cation channel (I SNCC), and Ca ²⁺-ATPase (I PM). In addition, [Ca ²⁺] i sequestration is also influenced at the subcellular level by the actions of the endoplasmic reticulum (ER) and mitochondria (MT).

This review will focus on the research of the electrical activity of the stomach and small intestine, and more specifically the underlying electrical activity that organizes motility. This is the area where the most detailed systems descriptions and mathematical models of GI function have been based to date,³⁻⁵ and from where efforts are beginning to yield clinically relevant outcomes (e.g., Ref 6). As other GI tract organs share a similar pattern of organization, this review will be of relevance to future research directions for the GI system as a whole.

CELLULAR LEVEL

GI motility is underpinned by omnipresent electrical activity. The fundamental event in the stomach and small intestine is the 'slow wave', a continuous, undulating change in membrane potential that propagates through the GI musculature in a coordinated fashion.⁷ Slow waves serve to induce and organize phasic contractions⁸ by moving the smooth muscle cell (SMC) membrane potential from a state of low open-probability for voltage-dependent Ca ²⁺ channels (−80 to − 55 mV) to a potential with elevated probability of channel opening (−40 to − 25 mV).⁷ Sufficient Ca ²⁺ influx in the wake of electrical slow waves may lead to SMC contraction, depending on additional regulatory input from neuronal, hormonal, paracrine, and inflammatory signals (see Ref 9 for more detail).

We now know that the interstitial cells of Cajal (ICCs) and not the SMCs, such as those illustrated in Figure 2, are responsible for initiating and propagating slow waves.⁷ Experiments with W/Wv mice which have a c-kit (a receptor necessary for the normal development of ICCs) mutation have revealed a decrease in particular ICC populations and a corresponding lack of intestinal slow wave activity.¹⁰ The mechanism by which ICCs are thought to generate slow waves is via the summation of many small amplitude membrane fluctuations termed 'unitary potentials' (UPs), which result from inward-directed ionic conductances through unique pacemaker channels in ICC cell membranes. When a certain depolarization threshold is reached within ICCs, UP coordination and summation leads to a rapid upstroke depolarization, followed by a regenerative potential reflected by the plateau phase of the slow wave.⁷ Because UP summation is achieved via a voltage-dependent mechanism, depolarization of adjacent interconnected ICCs leads to cell-to-cell entrainment and active propagation of slow wave events through ICC networks.², ⁷

FIGURE 2.

Schematic diagram of an Interstitial Cell of Cajal (ICC) and an associated smooth muscle cell (SMC) of the circular muscle (CM) along with membrane potential (V m) traces from an ICC and SMC. Both the ICC and SMC membrane activities demonstrate a periodicity of 3 cpm. The amplitude of the ICC membrane potential (~45 mV) is higher than that of the SMC (~34 mV). The membrane potential traces are reproduced from Ref 11.

Simultaneous intracellular recordings have confirmed that slow waves begin in ICCs before conducting passively to adjacent SMCs to which they are weakly coupled through sparse gap junctions forming a functional syncytium (behaving with cytoplasmic continuity).¹² SMCs are unable to actively propagate slow waves, such that, without ICCs, slow waves rapidly decay in GI tissue in accordance with the conduction properties of the smooth muscle syncytium.¹³ During the plateau phase of slow waves, high-frequency (>30 cpm) oscillations of membrane potentials often referred to as 'spikes' may occur in SMCs.¹⁴ These threshold events represent true smooth muscle action potentials. Spikes are not essential for excitation-contraction coupling in GI smooth muscle, but their occurrence is associated with more forceful contractions.⁹

Computer-based mathematical models have proved to be useful tools for characterizing integrated GI cellular electrophysiology. The approaches that have been used to model the cellular events in ICCs and SMCs can be generalized into two categories: phenomenological models and biophysically based models. Phenomenological models reproduce the electrical events using relatively simple mathematical equations without a direct relationship with the underlying electrophysiology. Since the 1960s, GI electrical activity (GIEA) has been modeled as a chain of coupled Van der Pol relaxation oscillators.¹⁵ Sarna et al. expanded on the relaxation-oscillator concept to simulate gastric and intestinal electrical activity using a network of coupled oscillators.¹⁶, ¹⁷ These early relaxation oscillator models were acknowledged as a sufficient way to represent the GIEA for the subsequent two decades, until discovery of the role of ICCs raised questions about the validity of using only one type of coupled network to represent the GIEA. In a more recent review by Daniel et al.,¹⁸ the question was raised as to what the intrinsic periodic activity of the oscillator unit actually represented. As the pacesetting role of ICCs was becoming evident, an updated oscillator-based model was proposed by Aliev et al.¹⁹ Most importantly, this model acknowledged for the first time the differentiated functions of ICCs and SMCs as two interconnected electrical domains (see the ICC response in Figure 3). However, the limitations intrinsic to the relaxation oscillator-based models were still evident. In particular, Publicover and Sanders²⁰ argued that the plasticity of the relaxation oscillator waveform limited it from modeling the experimentally recorded membrane potentials, and the effects of pharmaceutical agents cannot be investigated via phenomenological models.

FIGURE 3.

Simulated gastric electrical activity (GEA) using computer-based mathematical models. Shown in (a) is simulated unitary potentials (UPs) which are believed to generate pacemaker potentials in summation, using the Faville et al.² ICC model. The simulated UPs contain an autonomous frequency of 3 cpm, amplitude of 3 mV, and resting V m of 70 mV. Shown in (b) is the simulated membrane potential (V m) of an ICC, which is known as the pacemaker potentials, using the Aliev et al.¹⁹ model. The simulated pacemaker potentials contain an autonomous frequency of 3 cpm. The peak and resting membrane potential (V m) have to be scaled in order to match experimental data, as the Aliev model is a phenomenological model. Shown in (c) are simulated pacemaker potentials using the Corrias and Buist²¹ ICC model. The simulated pacemaker potential has an autonomous frequency of 3 cpm, an amplitude of 45 mV, and a resting V m of -70 mV. Shown in (d) is the simulated V m of canine gastric smooth muscle cells (SMCs), which is also known as slow waves, using the Corrias and Buist²² SMC model. This cell model requires a pacemaker potential as an input to depolarize the V m (an output of the SMC model). The simulated slow wave has a frequency of 3 cpm, amplitude of 35 mV, and resting V m of -70 mV.

Biophysically based models take into consideration the roles of ion gating variables in cellular action potentials. Much progress has been made in recent decades on simulations of nerve and cardiac electrical activities.²³⁻²⁵ As details of ion channels and intracellular activities of ICCs and SMCs have begun to be understood over recent years, a small number of biophysically based models of GIEA have been proposed. This reflects a trend towards modeling the GIEA from the cellular level using the core conduction (biophysically based) models proposed initially by Hodgkin and Huxley in 1952.²³ In general, the biophysically based models allow individual ion currents to be inspected quantitatively under effects of parameters which carry physical quantities, such as temperature, ion concentration, and voltage, which would not be possible with the relaxation oscillator-based models.

Edwards and Hirst²⁶ first proposed an ICC model based on unitary potential theory. The ion channels of the Edwards and Hirst ICC model are biophysically based. However, the unitary potentials in this model had a phenomenological representation, and therefore, the intracellular Ca ²⁺ dynamics could not be captured with this model. Currently, there are three whole-cell biophysically based models specifically for simulating ICC pacemaker activity. The Youm et al.²⁷ ICC model outlined seven ion conductances categorized into three ionic components (Ca ²⁺, K⁺, and Na⁺) and a series of intracellular Ca ²⁺ dynamics based on the Luo and Rudy²⁵ (cardiac) approach to simulate intestinal pacemaker potentials. The Corrias and Buist²¹ ICC model described 10 ion conductances and the intracellular Ca ²⁺ dynamics based on the mitochondria-ER relationship proposed by Fall and Keizer.²⁸ The Faville et al.² model is the first ICC model that contains a biophysically based representation of unitary potentials (see Figure 3). This model contains a series of Ca ²⁺ dynamics derived from experimental data specifically derived from ICCs, and therefore, has more authenticity in terms of the intracellular Ca ²⁺ dynamics relative to the other two biophysically based ICC models. In contrast, there is only one biophysically based GI SMC model to date, which consists of eight ion conductances.²²

Integration of different types of mathematical models is essential for building an appropriate systems-based understanding, for example, the SMC model requires an ICC cell model to provide the pacemaker potential. The CellML language provides a medium to standardize the scripting of models through an open-source XML markup language database.²⁹ CellML aims to simplify the exchange of computer-based mathematical models between different software platforms. It also enables them to reuse components from one model in another, thus accelerating model building. At present, there are a large number of different cellular descriptions available in the CellML model repository, with the majority relating to electrophysiology, calcium dynamics, and signal transduction, although, as noted above, there are only a handful of models that are related to the GI system. Currently the models in the CellML repository include the Faville et al.,² Youm et al.,²⁷ Corrias and Buist²² ICC models and the Corrias and Buist²¹ SM cell models.

TISSUE LEVEL

The above GI cellular elements described above, ICCs and SMCs, are anatomically united at the tissue level in a myenteric network capable of sophisticated autonomous behavior, as shown in Figure 4. The mucosa and submucosa do not directly contribute to motility, and have not been considered in tissue level models of motility. SMCs in the GI muscularis propria are organized in bundles of >1000 parallel fibers, orientated in circular (CM), longitudinal (LM) and oblique (OM; stomach only) directions.³⁰

FIGURE 4.

Schematic diagram illustrating the organization of Interstitial cells of Cajal (ICCs) and smooth muscle (SM) cells in the canine gastric antrum.³¹ SM are arranged in the longitudinal direction (LM) and the circular direction (CM) of the stomach. ICCs are distributed between the intermittent spaces of SM, which include myenteric ICCs (ICC MY), intramuscular ICCs (ICC IM), and septal ICCs (ICC SEP). Also shown on the right is the representation of the ICC and SM cells in an anatomically based computational model.

Different classes of ICCs have been identified by morphology, location, and function. The most relevant class to this review is ICC-MY, which are arranged in a network between the SM layers. The ICC-MY are normally responsible for slow wave generation and propagation. Another class of ICCs intermixed with SM fibers (ICC-IM) modulate and augment the response of SMCs to the ICC-MY-generated slow waves. ICC-IM also play an important role in the integration of enteric nervous signals, and may transduce neural or stretch signals to mediate changes in slow wave frequency (Refs ⁷,³² for more detail). In addition, ICC-IM are thought to have the capability to act as the pacemakers cells, instead of ICC-MY, under certain circumstances, such as vagal stimulation.³³

In an intact ICC network, slow waves entrain in accordance with the site of highest intrinsic ICC pacemaker frequency found in the network.⁷ Slow waves, thereafter, spread to adjacent ICC and SM layers in accordance with the three-dimensional structure of the cellular tissue networks. Slow waves propagate simultaneously along SM fibers in the circumferential and longitudinal directions. However measurements in isolated tissue samples demonstrate that circumferential slow wave velocity is approximately 23 mm/s compared to approximately 11 mm/s in the longitudinal direction³⁴ (refer to Figure 5). The net effect of these different propagation velocities is to create a transverse dominant contraction that spreads distally through tissue as a coordinated peristaltic wave front.

FIGURE 5.

Illustration of the origin and relative propagation of the gastric slow waves. The slow wave originates in the mid-corpus region on the greater curvature and rapidly spreads in a circumferential dominant manner around the stomach, as well as propagating at a slower rate down the length of the stomach.³⁴.

Experimental slow wave measurements at the cellular level have involved fine intracellular recordings describing membrane potentials, intrinsic frequencies, and ion conductances.¹¹ At the tissue level, experimental recordings offer a macroscopic view (up to many cm) of the profile and patterns of slow wave propagation. The common serosal recording technique has involved sparse placement of typically four to eight electrodes along electrically active regions of the GI tract.³⁵ More recently, Lammers et al.³⁶ have significantly expanded GI electrical tissue mapping capability using high-resolution electrode arrays containing up to 256 electrodes recording simultaneously (discussed further below), allowing detailed spatiotemporal mapping of slow wave activity.

Continuum modeling may be employed to represent the electrical activity within the musculature of the tissue. The bidomain equations have been used to govern the spread of electrical activity within excitable tissue since the late 1960s.³⁷⁻⁴⁰ These equations describe the flow of ions within and between two domains (the volume within the cells and the remainder of the volume external to the cells). The bidomain framework has been widely used within the cardiac field for many years,⁴¹⁻⁴⁶ however, it has only recently been applied to the GI system.⁵, ⁶ In the computational framework presented by Pullan et al.,³ the different muscle layers have been subdivided into layers corresponding to the anatomical ICC and SMC layers and shown in Figure 4.

ORGAN AND TORSO LEVEL

The stomach is the most dilated portion of the GI tract, and communicates proximally via the cardiac orifice with the esophagus, and distally with the duodenum via the pylorus. Three other gastric regions are typically described: the proximal distensible fundus, the distal funnel-like antrum, and the corpus of the stomach between the fundus and antrum (see Ref 47).

The pathway of normal and abnormal gastric slow wave propagation has not been extensively characterized between gastric regions, but a general description is known. There is no gastric 'pacemaker node' akin to the cardiac pacemaker nodes, but rather, slow waves are thought to arise in a diffuse pacemaker zone corresponding to that part of the ICC network with the highest intrinsic rate of pacemaking activity.⁷ This zone (shown in Figure 5) is located near the greater curvature half of the orad corpus.⁴⁸ The fundus has been termed electrically 'silent', being free of slow wave activity, however at the cellular level, slow fluctuations of a relatively depolarized resting membrane potential are found that give rise to tonic muscular functions.⁷ From the greater curvature, slow waves track toward the pylorus at approximately 3 cycles/minute⁴⁹ with increasing velocity and amplitude.⁵⁰ A quiescent zone has recently been identified near the pylorus, where no slow waves can be recorded,⁵¹ and in which ICC-MY are found in significantly reduced quantities.⁵² This zone represents an effective electrical barrier, where gastric slow waves are decoupled from small intestinal slow waves. Spike activity may, however, traverse this area, presenting a possible means of gastroduodenal coordination.⁵³

The small intestine begins distal to the pylorus. It is comprised of three sections (due denum, jejunum and ileum) with an average length of 4-6 m. Digesting contents (chyme) are propelled distally at 5-20 mm/s by weak peristaltic contractions, thereby taking 3-5 h to progress from the pylorus to the ileocaecal valve.⁵⁴ The small intestine has intrinsic pacemaker activity along its length, decreasing from an intrinsic rate of approximately 12 cpm in the duodenum to 8-9 cpm in the terminal ileum.⁵⁵, ⁵⁶ It was previously thought that slow wave activity in the small intestine propagates only over a few centimeters at a time, naturally organizing small intestinal motility into segmental contractions, serving to slowly mix and spread chyme for digestion.⁷ However, a recent multichannel (240 electrode) study⁵⁷ performed on the feline small intestine reported that the majority (73%) of slow waves did propagate continuously from the proximal duodenum to the ileocaecal junction, with conduction of the remaining waves being blocked, mostly at certain specific sites along the tract. The segmentation patterns that characterize small intestinal activity, therefore, likely result from the limited propagation of individual 'spikes', which occur in the wake of slow waves.⁵³

In recent years, anatomically realistic models of the stomach have been developed with the aim of building an integrated physiological description of the spatial orientation of slow wave activity.³ These models have been integrated with tissue and cell-level models, and are beginning to demonstrate predictive capability with application to the diagnosis and treatment of gastric diseases.⁵⁸ A gradient of intrinsic pacemaker potential frequency is assigned to the ICC layer of these mathematical models, to reproduce the propagation of entrained slow waves in the smooth muscle layer. It can be shown that the pacemaker potentials with lower frequency 'phase-lock' to those of higher frequency. Active propagation of slow waves is achieved once the 'phase-locking' becomes constant (entrainment). Future mathematical models of small bowel activity must faithfully represent the new multielectrode understanding of slow wave propagation and block, as described above.

Anatomical models of GI organs have been reported since the 1970s. The earlier methods of quantitatively capturing the anatomy of the intestines involved photographing of the in vitro duodenum during longitudinal smooth muscle contractions.⁵⁹ As more advanced medical imaging modalities became available, the in vivo stomach configurations were captured using plain radiography, ultrasound, and in recent years, magnetic resonance (MR) imaging.⁶⁰, ⁶¹ However, registration of the individual images remains a challenge to the reconstruction of a three-dimensional anatomical model. Many computational techniques have been proposed to circumvent the problem of image registration. In particular, Kita⁶² used an elastic stomach model to project the distorted contours of individual images onto the model, thereby identifying the same parts of the stomach in x-ray images. Liao et al.⁶³ fitted a three-dimensional linear mesh of a rat stomach and then used an algorithm to smooth the surface of the stomach model.

To date, the Visible Human Project⁶⁴ remains one of the best sources of high-resolution images of human anatomy, and it has been widely used for numerical simulations of human function. The outlines of the stomach in the Visible Human abdominal slices has been digitized and stacked to form a data cloud of the shape of the stomach, which has then been iteratively fitted using cubic Hermite basis functions and a nonlinear fitting procedure to create an anatomical stomach model.³, ⁶⁵ The Visible Human data has also been used to model the anatomy of the gastroesophageal-junction,⁶⁶ the intestines,⁶⁷ and the pelvic floor.⁶⁸ It is important to note, however, that the VH anatomy may not provide a true representation of in vivo human anatomy due to the loss of the natural tone of the muscles. For example, the average length of the human small intestine has been found to be upwards of 3 m shorter in life than in death.⁶⁹ For this reason, digitizing CT or MR images obtained in vivo has more recently been viewed as the preferred method of obtaining anatomical stomach models for computational simulations of GEA.⁵, ⁷⁰ An average model (in terms of stomach shape and volume) of many subject-specific models created in this way may be used in representative simulations, to overcome the problem of variability encountered between individual subjects.

In order to generate descriptive models for use in body-surface investigations such as electrogastrography (EGG) and magnetogastrography (MGG) (discussed in the following section), it is necessary to relate organ-level electrical activity to the body surface. The most common approach for projecting the electrical activity from the stomach to the body surface involves forward computation of current dipole sources. Smout⁷¹ presented one of the first models to use the dipole theory to represent GIEA within a cylinder. Others' models used a single dipole to represent the electrical sources⁷², ⁷³ followed by a larger band of moving dipoles to provide a more distributed representation of the slow wave.⁷⁴⁻⁷⁷ Each of these models, however, have used a simplified geometric representation of the stomach and torso, ranging from cylinders to cones to ellipses. More recently, the Aliev et al.¹⁹ model has been integrated with the bidomain equations, and solved using a structured finite element method to represent gastric electrical activity in an anatomical model of the human stomach.³ The gradient of the transmembrane potential over the stomach was then used to calculate equivalent dipole sources to compute electromagnetic fields external to the torso.⁷⁸, ⁷⁹

CLINICAL APPLICATIONS

The stomach and small intestine share important electrophysiology similarities with the heart, including pacemaker activity and electromechanical coupling. Just as cardiac electrical dysfunction underlies many important disorders of cardiac mechanical activity, it is widely assumed that abnormalities in electrical activity may underlie many GI motility disorders. For example, dysrhythmic GEA has been described in relation to common clinical problems such as gastroparesis³⁵ and functional dyspepsia,⁸⁰ and disorganized electrical activity is thought to play a role in postoperative ileus.⁸¹ However, whereas electrical activity is routinely measured and manipulated in cardiology practice with electrocardiograms (ECGs), pharmacology, and electrical stimulation, diagnostic and therapeutic electrophysiology has failed to enter routine gastroenterology practice up to the present time.

Improved methods of defining, diagnosing, and treating pathologies of GIEA are an important focus of ongoing research. Mathematical GI models of integrated cell, tissue, and organ function are increasingly being employed in this research challenge, where their predictive capability is being used to compliment standard biophysically based approaches. The current status of this research is reviewed below.

Serosal and Mucosal Recordings

Gastric electrograms can be made by placing electrodes either against the inner or outer surfaces of the stomach, to provide detailed information regarding slow wave activity of a particular stomach region.³⁶, ⁸² Serosal recording necessitates an invasive procedure (either laparoscopy or laparotomy), which precludes it as an everyday clinical application. Endoscopic placement of electrodes on the mucosal surface is less invasive, but impractical for prolonged periods due to the discomfort of a nasogastric tube and potential for the electrodes to dislodge. Via serosal recordings in an animal model, Lammers et al.⁸³ have recently described complex abnormal GI electrical events, like those known to occur pathologically in the heart, such as multiple ectopic pacemakers and re-entrant arrhythmias. However, further research is required to define the role such events may play in human disease. New methods that are appropriate for human research are now emerging, such as easily sterilized flexible printed circuit board (PCB) electrodes, that will facilitate future advances in this field.⁸⁴

Du et al.⁵⁸ have recently performed simulations of GEA across a virtual section of stomach musculature using a biophysically based computation model. Early results suggest good concordance with direct serosal recordings of GEA (refer to Figure 6). It is hoped such models may become a future platform to simulate GI disease states, for example, by generating predictions regarding ICC cell loss or network disruption on the propagation of slow wave activity.

FIGURE 6.

Illustration of gastric serosal recordings using a 32-channel electrode array (E1-E32), which was placed in the orientation on a porcine stomach as shown in (a). Shown in (b) are recorded extracellular traces corresponding to eight electrodes (out of 32) with slow wave activation times marked by the red vertical lines. The locations of the red lines were determined by the most negative deflection during a slow wave event. Also shown is (c) an activation times map corresponding to the signals in (b), the isochrones of activation times indicate that slow waves propagation was in the aboral direction (E32 towards E1). Shown in (d) is a simulated slow wave event with the activation times sampled over the same dimensions as the array of electrodes (a).The activation times and direction of the simulated slow waves (d) are in a reasonable agreement with the experimental recording (c).

Electrogastrography

EGG is a non invasive recording of GEA carried out by placement of cutaneous abdominal electrodes.⁸⁵ EGG is convenient, and recordings correlate with measurements taken directly from the gastric serosa.⁸⁶ However, because EGG is a summation of all gastric electrical activity occurring simultaneously, it lacks discriminative ability to demonstrate electrical differences among various stomach regions, and analysis, to date, have largely been limited to frequency dynamics.⁸⁷ Gastric dysrhythmias such as bradygastria (<2 cpm) and tachygastrias (>5 cpm) have been described by EGG in association with clinical conditions including gastroparesis, functional dyspepsia, gastroesophageal reflux disease (GERD), and unexplained nausea and vomiting.⁶⁷ However, EGG has not found a place in routine clinical practice because of the poor correlation with symptoms, gastric emptying, and manometry.⁸⁸ Multichannel EGG has been proposed as a possible method to derive more detailed information, such as slow wave propagation and uncoupling,⁸⁹ but this awaits more extensive validation.

Anatomically realistic multiscale models of GEA have been integrated within torso models to describe the conductance of EGG signals on to the body surface. Using this approach, it was shown that EGG is unlikely to be able to discriminate between normal and functionally uncoupled GEA in terms of the dominant frequency component caused by a retrograde pacemaker site.⁶ This finding awaits definitive physiological validation; although one study has suggested that multichannel EGG can discriminate severe uncoupling in a canine model by EGG and computer-assisted processing.⁹⁰

Magnetogastrography and Magnetoenterogram

Most biological electrical fields have a corresponding magnetic field associated with them. The magnetic fields can be recorded via the use of a Superconducting QUantum Interference Device (SQUID) magnetometer. SQUID magnometers provide an attractive option for characterizing electrical activity in the GI system as the recordings can be made noninvasively and without direct contact of the skin. Electrical fields are a scalar quantity, while magnetic fields are a vector field with an orientation and a magnitude. Although the majority of SQUID sensors only measure one component of the magnetic field (typically the director orthogonal to the body) appropriate SQUID sensors are capable of measuring the three orthogonal magnetic fields at a given point. It has been shown in past studies that there is significant information present in the full vector field that may not be obtained by a single-channel measurement.⁹¹, ⁹² In addition, because of the spatial filtering effects, the spatial resolution of the SQUID magnetometer is considered to be greater than what can be achieved with a surface electrode array.

Figure 7 illustrates the magnetic and electrical field caused by a horizontally aligned dipole within the stomach. The magnetic field is represented by gold arrows located at a plane just above the body, and the electrical potential distribution on the body surface is indicated by the colored field.

FIGURE 7.

Anterior and sagittal views of simulated electric and magnetic fields due to a current dipole. A horizontal dipole (green arrow) in the stomach produces electric fields on the body surface (represented by the colored field; blue is negative and red is positive potential) and the magnetic field external to the body (represented by the gold arrows), with the length of the arrow indicating the strength of the magnetic field.

Recordings of magnetic fields resulting from GEA are known as magnetogastrograms (MGGs).⁹³, ⁹⁴ Recordings of magnetic fields resulting from GEA are known as magnetoenterograms (MGGs). Although small intestinal signals are much weaker in nature, they have also been recorded using a SQUID⁹⁵, ⁹⁶ and are referred to as magnetogastrograms (MENGs). This intestinal activity has never been reliably recorded using cutaneous electrodes. The difference in signal-to-noise ratio between the EENG and the MENG arises principally on account of the alternating tissue layers with high and low conductivities.⁹⁷ The surface EENG is affected to a larger degree by this layered conductive structure, as well as the presence of local noise sources such as subdermal muscle activity. Although the use of SQUID technology has a number of advantages it has yet to gain widespread clinical acceptance, and is an active area of ongoing research. There is a need for additional computational simulations and modeling techniques to aid the interpretation of the magnetic field recordings.⁷⁰

Gastric Electrical Stimulation

Gastric electrical stimulation (GES) has been attempted for over 40 years as a strategy to manipulate gastric electrical activity in order to treat several major diseases. Three main strategies have been employed: gastric pacing (low-frequency GES), high-frequency GES and neural GES (NGES).

Gastric pacing involves delivery of external impulses at frequencies near the intrinsic 3-cpm activity, with the aim of entraining slow wave activity.⁹⁸ Most pacing studies have attempted to entrain slow waves in the normal (aboral) direction, aiming to promote gastric motility when it is deficient, as in postoperative ileus⁹⁹ or gastroparesis.¹⁰⁰, ¹⁰¹ One noncontrolled human gastroparesis trial to date has demonstrated the therapeutic feasibility of gastric pacing, by demonstrating significantly decreased gastric retention, reduced symptoms, and a decreased need for supplemental jejunostomy feeding in treated patients.¹⁰¹ Some recent studies have also attempted to entrain gastric slow waves in the reverse (retrograde) direction, as a means to restrict motility and reduce gastric emptying, as a treatment for obesity. Trials in obese Zucker rats,¹⁰² chronically instrumented dogs,¹⁰³ and normal human volunteers,¹⁰⁴ have demonstrated the potential of this strategy, by successfully showing reductions in solid food intake, without inducing intolerable symptoms.

The second stimulation strategy, high-frequency GES, involves delivery of stimuli far beyond the normal 3-cpm slow wave frequency (~14 Hz range). Commercial devices are available, including the Enterra device, (Medtronic, MI) for gastroparesis, and Transcend (Transneuronix, NJ) for obesity. The therapeutic mechanism of this strategy is presently unknown.¹⁰⁵ The Enterra device has shown promise in noncontrolled trials to substantially improve symptoms of nausea and vomiting in severe gastroparetic, but awaits further validation in well controlled trials.¹⁰⁶ The Transcend device has achieved modest success in clinical trials (20-30% excess weight loss).¹⁰⁷

In the third stimulation strategy, NGES, ultra-high-frequency (>40 Hz range) stimuli are used to induce intramural cholinergic fibers to release acetylcholine, invoking gastric contractions.¹⁰⁸ Retrograde NGES has also achieved significant reductions in food intake and weight in a canine pilot study (p < 0.05).¹⁰⁹

One of the most pressing research problems in GES is to identify the optimum stimulation protocols to achieve the desired clinically relevant slow wave and motility outcomes. Technically, there are an infinite number of parameters to evaluate, including electrode placements, pulse frequency, pulse width, and pulse amplitude. Researchers are also attempting to find an effective means to reduce the power consumption of implantable pacing, or NGES devices.¹⁰³ To date, GES research has proved a technically tedious exercise, requiring laborious trial and error experiments on animal models.¹¹⁰ More recently, biophysically based computational models of GIEA, such as those of Du et al.,⁵⁸ have shown potential to act as hypothesis-testing tools for use in defining effective protocols for improved GI stimulation. This strategy may result in increased research efficiency, by transfer of developmental work to a computational rather than animal models.

CONCLUSION

Clinical applications of gastric electrophysiology remain in their relative infancy in comparison with the diagnostic and therapeutic cardiac applications of cardiac electrophysiology. However, there are a number of research approaches that have significant potential to aid with the diagnosis and treatment of GI disorders. Computational modeling using biophysical methodology which takes into account subcellular, cell, tissue, organ, and body elements has become an important adjunct in advancing our understanding of integrative physiology, and will help to develop predictions for clinical hypotheses testing.

Acknowledgments

This work was funded in part by a grant from the National Institutes of Health (R01 DK64775) and a NZ Society of Gastroenterology Research Fellowship. Peng Du is supported by a University of Auckland Doctoral Scholarship, and Greg O'Grady through a New Zealand Health Research Council Clinical Research Training Fellowship.

References

38. Muler AL, Markin VS. Electrical properties of anisotropic nerve-muscle syncytia - I. Distribution of the electrotonic potential. Biofizika. 1977;22:307-312. [PubMed] [Google Scholar]

45. Henriquez CS. Simulating the electrical behavior of cardiac tissue using the bidomain model. Crit Rev Biomed Eng. 1993;21:1-77. [PubMed] [Google Scholar]

55. Christensen J, Schedl HP, Clifton JA. The small intestinal basic electrical rhythm (slow wave) frequency gradient in normal men and patients with variety of diseases. Gastroenterology. 1966;50:309-315. [PubMed] [Google Scholar]

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The functions of the gastrointestinal (GI) tract include digestion, absorption, excretion, and protection. In this review, we focus on the electrical activity of the stomach and small intestine, which underlies the motility of these organs, and ...

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. Author manuscript; available in PMC: 2021 Mar 1.

Abstract

This review summarizes the key results of recently published studies on the effects of dietary change and nutritional intervention on the human microbiome from around the world, focusing on the USA, Canada, Europe, Asia, and Africa. It first explores mechanisms that might explain the ability of fiber-rich foods to suppress the incidence and mortality from westernized diseases, notably cancers of the colon, breast, liver, cardiovascular, infectious, and respiratory diseases, diabetes, and obesity ( 1, 2). It summarizes studies from Africa which suggest that disturbance of the colonic microbiome may exacerbate chronic malnutrition and growth failure in impoverished communities and highlights the importance of breast feeding. The American section discusses the role of the microbiome in the swelling population of patients with obesity and type 2 diabetes, and examines the effects of race, ethnicity, geography and climate on microbial diversity and metabolism. The studies from Europe and Asia extoll the benefits of whole foods and plant-based diets. The Asian studies examine the worrying changes from low fat high carbohydrate diets to high fat low carbohydrate and the increasing appearance of westernized diseases as in Africa and documents the ability of high fiber traditional Chinese diets to reverse type-2 diabetes and control weight loss. In conclusion, most of the studies reviewed demonstrate clear changes in microbe abundances and in the production of fermentation products, such as short chain fatty acids and phytochemicals following dietary change, but the significance of the microbiota changes to human health, with the possible exception of the stimulation of butyrogenic taxa by fiber rich foods, is generally implied and not measured. Further studies are needed to determine how these changes in microbiota composition and metabolism can improve our health and be used to prevent and treat disease.

Keywords: Diet, Microbiome, Metabolome, Fiber, Fat, colon cancer, obesity, type 2 diabetes, westernized diseases, Prebiotics, Probiotics, Short chain fatty acids, Bile acids

The Human Gut Microbiome and its Metabolites in Health and Disease

The human gut contains trillions of bacterial cells that are reported to be at a ratio of approximately 1:1 with our own cells ( 3). Thus, they form a vibrant living population that has a metabolic activity similar to the liver. There is consequently a move to describe the microbiota as a whole a new human organ. Their intimate association with the intestinal mucosa, which is also highly biologically active with a high cellular turnover rate, can be expected to have a major impact on human health and the prevention or precipitation of disease. The gut microbiota has a symbiotic relationship with the host, playing a role in maintaining health and metabolic homeostasis through the production of many metabolites. The collective genomes of these micro-organisms that inhabit the gut refer to the metagenome. The development of the gut microbiome begins at birth and in healthy individuals is largely completed within three years, but can be modified by environmental factors, particularly diet composition and volume, and antibiotic therapy ( 4). This review will focus on the modulatory effects of diet.

Research on the microbiome has expanded rapidly worldwide providing novel insights into both human and animal diseases and interventions designed to alleviate them ( 5, 6). Bacterial populations inhabit the entire length of the human gut from the oral cavity to the rectum. The density and composition of the resident microbial communities, however, differ markedly between anatomical sites and depend on transit rates, host secretions, environmental conditions, substrate availability, and the integrity of the gut wall ( 7). Overall the predominant bacterial groups in the microbiome are gram positive Firmicutes and gram negative Bacteroidetes ( 8). The bacteria that reside in the distal parts of the gut contribute to host health through biosynthesis of vitamins and essential amino acids and by production of important metabolites from nondigestible food components ( 9). Short chain fatty acid (SCFA) metabolites, notably butyrate, propionate and acetate are the byproducts of bacterial fermentation of indigestible carbohydrates, mostly fiber, and act as the major energy source for the colonic epithelial cells and therefore strengthen the mucosal barrier and defense ( 10).

Dietary Fiber and The Microbiome

The microbiota is dependent on food residues for survival and metabolism. Recent reviews by ourselves ( 11) have shown that the fermentation of carbohydrate residues, namely fiber releases metabolites that not only provide food for the colonic epithelium, but also exert a remarkable variety of regulatory effects on colonic mucosal inflammation and proliferation. This helps explain the epidemiological studies from throughout the world that have shown that high fiber consumption maintains colonic health and prevents colon cancer ( 11). Furthermore, high fiber intakes provide high rates of butyrogenesis which exceed the metabolic requirements of the colonic mucosal and enter the blood stream to exert epigenetic and immunomodulatory effects on other organs in the body. This, in turn, explains the association between high fiber intakes and a reduction in incidence and mortality from all westernized diseases, including cancers of the colon, breast, liver ( 1, 2), cardiovascular, infectious, and respiratory diseases, diabetes, and obesity ( 12- 14). Similar conclusions were drawn by Reynolds based on nearly 135 million person-years of data from 185 prospective studies and 58 clinical trials with 4635 adult participants comparing the highest dietary fiber consumers with the lowest. Here they found a 15-30% lower rate in all-cause and cardiovascular-related mortality, in addition to a lower incidence and mortality in colorectal and breast cancer, coronary heart disease, stroke, and type 2 diabetes. These studies were recently quoted by O'Keefe in his viewpoint for Lancet GI ( 1) where he updated the evidence supporting Burkitts fiber hypothesis that the deficiency of fiber in the westernized diet can explain much of the morbidity and mortality associated with westernized diseases.

Nutrition and the Gut Microbiome in Africa

Diseases of undernutrition and overnutrition that pose widespread health challenges in Africa are viewed as being 'microbiota-dependent' and hence, their mitigation would benefit from 'microbiota-directed' interventions ( 15). Understanding the role of the microbiota in their pathogenesis is indispensable in informing intervention strategies. Research of the past five years on human microbiome and nutrition in Africa, as reviewed in this section, is dominated by intervention trials of childhood undernutrition and exploration of the effect of urbanization on the rising incidences of westernized diseases. In general, studies on undernutrition (summarized in Table 1) investigate impairments of the developing gut microbiome associated with malnutrition and its treatment sequelae while research on westernized diseases aims at finding how the changes in diet and lifestyle affect the gut microbiome and contribute to the increasing risk of these diseases in communities where the incidences were historically low.

Table 1:

Location of study and reference

Disease or condition

Age of participants

Number and/or nutritional status of participants

Study design

Study outcomes

Malawi Ordiz et al. 2017
Environmental enteric dysfunction (EED)

12-23 months

n=81; 47 boys and 34 girls

Legume intervention trial

Gut microbiota, gut absorption, morbidity

Niger & Senegal
Million et al. 2016

SAM

<60 months

n=86; not in feeding programs; prior to supplements

2 prospective case-control studies

Gut microbiota, Aerotolerant odds ratio, gut redox potential, Methanobrevibacter smithii

Undernutrition

6 months

n=29 healthy; n=59 severe stunting

Sub-study of 2 randomized controlled single-blind parallel group trials

Germ-free mouse and piglet studies

HMO composition, infant gut microbiota, growth

SAM

0-30 months

8 monozygotic healthy twin pairs; 12 dizygotic twin pairs (6 twin pairs discordant for kwashiorkor; and the other 6 discordant for marasmus)

Longitudinal studies, follow-up of the Malawian discordant twin trial

Germ-free mouse study

Gut microbiota DNA viromes, nutritional outcomes

Malawi
Dewey et al. 2015

Diet-dependent enteropathy in SAM

21 months

One monozygotic twin pair discordant for kwashiorkor

Longitudinal studies, follow-up of the Malawian discordant twin trial

Germ-free mouse study

IgA⁺ bacterial taxa of the fecal microbiota, Weight loss, sepsis

Undernutrition and the Gut Microbiome

Undernutrition is a global health challenge accounting for 45% of childhood mortality and, higher morbidities in sub-Saharan Africa and South Asia ( 16). Malnutrition is a complex of disorders arising from inadequate nutrition that include gut microbiota dysbiosis, metabolic, immune and intestinal barrier dysfunction, as well as micronutrient deficiencies. It is often exacerbated by enteropathogenic and HIV infections, enteropathy, diarrhea, and chronic inflammation. It manifests as severe or moderate, acute or chronic, edematous or nonedematous forms, all of which are managed through hospitalization and subsequent nutritional rehabilitation coupled with antibiotic therapy ( 17). The challenge in Africa is that, despite the implementation of the World Health Organization (WHO)-recommended treatment protocol, there is still high mortality among children undergoing treatment. It is thought that severe acute malnutrition (SAM) is complicated by co-occurrence in a vicious cycle with infections culminating in death ( 18). Malnutrition results in adverse health outcomes such, stunting, immune dysfunction and cognitive impairments ( 15). In 2011, Gordon and colleagues proposed a hypothetical model of relationships between the gut microbiota, the immune system and diet, which underlie the development of malnutrition ( 19). Years later, they provided evidence that gut microbiota dysbiosis is causally linked to childhood undernutrition, based on longitudinal studies involving Malawian infants and children with varying degrees of undernutrition and corresponding growth rates of gnotobiotic mice to which the kids' fecal samples had been transplanted ( 15, 20). Since then, several intervention and observational studies ( 21), completed ( Table 1) ( 22- 32) and ongoing ( 33) have sought to understand the role of gut microbiota in nutritional outcomes, childhood morbidities and enteropathy associated with malnutrition in limited resources settings to improve outcomes. Vray and associates embarked on alternative 'renutrition' strategies for the management of moderate acute malnutrition among children across Madagascar, Niger, Central African Republic, and Senegal ( 34).

Iron-containing micronutrients powders (MNP) are widely used in sub-Saharan Africa in the prevention of iron deficiency anemia and micronutrient deficiencies in infants ( 23). However there is concern that their iron content may have adverse effects in children simultaneously treated with antibiotics. Antibiotic use is remarkably common in impoverished communities in Kenya, with an average of 4.9 antibiotic courses per child year. In rural Tanzania, more than 50% of infants receive antibiotics by the age of 6 months, chiefly for diarrheal and respiratory diseases. In a controlled intervention trial, Paganini et al. gave small groups (n 6-8) healthy infants who were still being breast-fed various combinations of MNP with and without iron (5mg), and with and without antibiotics (amoxicillin 125 mg/day; ampicillin 125 mg/day + cloxacillin 125 mg/day; or trimethoprim 40 mg/ day + sulphamethoxazole 200mg/day). They were concerned to find that iron supplementation increased the appearance of pathogens such as pathogenic E. coli and decreased Bifidobacterium abundance. In other separate studies Jaeggi et al. and Tang et al. made similar observations that iron supplementation increased entero-pathogen levels and intestinal inflammation in weaning infants ( 24, 25). Notably, a randomized clinical trial investigating the effect of antibiotics on the gut microbiome diversity in Burkina Faso pre-school children also reported that the use of Azithromycin affected the composition of the intestinal microbiome ( 22). Although these findings discourage use of iron-containing micronutrient powders during antibiotic therapy, they raise concern over the empiric use of antibiotics and nutritional supplements in impoverished communities, where more attention should arguably be paid to improving food, sanitation and housing.

Malawi has exceedingly high rates of infant mortality from malnutrition ( 35). Consequently there is a desperate need for developing efficacious interventions to ameliorate SAM. To investigate this, Malawian infant twin pairs discordant and concordant for marasmus and kwashiorkor have been involved as microbiota donors in a series of longitudinal studies designed to understand underlying mechanisms of SAM ( 20, 31, 32). Remarkably, undernutrition-associated phenotypes such as stunting ( 29) and diet-dependent enteropathy ( 32) could be transferred to gnotobiotic mouse models through transplantation of fecal samples or culture-purified bacteria obtained from sick infants. Bearing in mind the previously described low efficacy of ready-to-use-therapeutic foods (RUTFs) ( 20), there is hope that identification of distinct microbial biomarkers that characterize different states of malnutrition, such as those indicative of stunting and enteropathy, as well as those that can ameliorate these pathologies, is indispensable in evaluating interventions, in different socio-economic settings and geographic locations ( 4, 32). Indeed, the gut microbiota maturity, defined using bacterial taxonomic biomarkers, discriminatory for age and predictive for growth, has been described ( 4). Its potential as a lead in studying the effects of host and environmental factors on the gut microbiota development and associated diseases, has been demonstrated ( 15, 32). Such studies portray the coupling of infant twin microbiota donors with gnotobiotic mouse models as powerful tools in investigating the role of gut microbiome in childhood undernutrition and its interventions.

Breast milk is a source of nutrients and bioactive substances required for normal growth and development of the infant ( 36). It contains pro-, and prebiotics such as milk oligosaccharides ( 37) that are viewed as potential microbiota-directed therapeutics for childhood undernutrition. These oligosaccharides are beneficial substrates to the gut microbiota contributing to enhanced gut bacteria function, protection from pathogen infection and improved immune response. Gordon and co-workers analyzed human milk oligosaccharides (HMOs) from breast milk of 6-month-postpartum mothers in two independent randomized controlled clinical trials of undernourishment in Malawi ( 29). The first birth cohort study tested the efficacy of lipid-based nutrient supplements (LNS) to prevent severe stunting among infants (LCNI-5 study), while the second investigated supplementing maternal and infant diet with micronutrient fortified LNS (iLiNS-DYAD-M study).

Initially, breast milk samples were selected from mothers in the LCNI-5 study whose children exhibited healthy growth (height-for-age Z score [HAZ] > 0; n=29) or severe stunting (HAZ < −3; n=59). The HMO abundance and composition were found to associate with infant growth since the breast milk from mothers whose children were severely stunted had significantly lower levels of total, sialylated, and fucosylated HMOs compared to that from mothers whose infants had healthy growth. Among the mothers lacking the FUT2 gene, i.e. unable to produce alpha-1,2-linked fucosylated HMOs ("non-secretor" phenotype), those whose infants were severely stunted produced milk HMOs deficient in fucosylated and sialylated components compared to milk HMOs from mothers of healthy infants. Similar observations were made in mothers enrolled in the iLiNS-DYAD-M study. However, in "secretor" mothers in the latter study, only the sialylated milk HMOs, neither total nor fucosylated, were elevated significantly in those with healthy infants (n=20) compared to the ones with stunted infants (n=40).

To investigate the role of sialylated milk HMOs in infant growth, the researchers used bacteria from fecal microbiota of a stunted infant donor to colonize germ-free mice and piglets feeding on prototypic Malawian diet (control) selectively supplemented with sialylated bovine milk oligosaccharides (S-BMOs) or inulin. Their objective was to determine preclinically if the sialylated HMOs are causally related to healthy growth. After colonizing 5-week-old male germ-free mice with a defined community of 25 bacterial strains, and monitoring body weight and composition for 5 weeks, weight and lean body mass gain were significantly increased by S-BMO supplementation and not inulin. Of the 25 bacterial strains, only Escherichia coli and Bacteroides fragilis responded transcriptionally to S-BMO supplementation in vivo, however, interaction with all the community members was necessary to mediate growth promotion. Further, observations of decreased levels of serum and liver acylcarnitines and increased concentrations of serum insulin, leptin and triglycerides in S-BMO-treated mice compared to controls, over the initial 5-week period, suggested that S-BMO supplementation modulated metabolism in host tissues. Overall, this study demonstrated the causal relationship between S-BMOs and growth as well as the potential of S-BMOs as supplements that have to be tested for improving growth outcomes. In a randomized trial, Davis et al. investigated the relationships between HMOs, microbiota, infant morbidity and growth in Gambian mother-infant dyads ( 26). Without providing causation mechanisms, the fucosylated HMOs were found to be associated with morbidity while sialylated HMOs were predictive of growth. Prevotella was associated with decreased morbidity, as had been observed in a previous Malawian children cohort study cited ( 38).

Westernized diseases and the gut microbiome

Nutrition and the gut microbiome have been implicated in the etiology of many westernized diseases ( 11, 39). However, the role of the gut microbiome in the rising incidences of colorectal cancer (CRC) in countries undergoing dietary and lifestyle transitions, typical of sub-Saharan Africa, is just unfolding. The age standardized incidence of CRC per 100,000 has been traditionally <5 ( 40), but, despite variations between African countries, larger incidences of >10 have been reported in some countries ( 41). In Zimbabwe, an observational study was recently undertaken to assess the link between CRC risk and dietary changes from traditional to Western during urbanization ( 41). Owing to retention of fiber intake in the urban population, the levels of butyrate and butyrogenic bacteria were similar between rural and urban participants, yet the levels of bile acids, indicative of high-fat diet were higher among urban participants. This study demonstrated the potential to prevent a CRC epidemic through retention of traditional high fiber foods, a sustained adjustment of diet that would reverse the pattern of metabolic markers associated with CRC risk.

In a previous comparative diet switch study of rural Africans to a high-fat, low-fiber diet, and African Americans to a high-fiber, low-fat diet, reciprocal changes in microbiota, its metabolic activity and mucosal biomarkers of CRC risk were observed within two weeks ( 42). In yet another comparative metagenomic study, not related to a disease, but attempting to understand how the microbiome has evolved to support hosts living in different environments, the gut microbiome of the Hadza hunter-gatherers of Tanzania was compared with that of the urban Italians ( 43). The Hadza gut microbiome was enriched with genes with the functional capacity to fermenting carbohydrates into short-chain fatty acids (SCFAs) and synthesize SCFAs from amino acids, while the urban Italian gut microbiome showed functional potential in xenobiotics metabolism ( 43, 44). It has been assessed that the current diet of the Hazda is rich in fiber, containing 75-100 grams of fiber per day mostly from pulp and seeds of baobab fruits ( 45). Their microbiome features reflected the diet, lifestyle and environment of the study participants, that is, the unindustrialized and traditional rural lifestyle and foraging diet of the hunter-gatherers versus the industrialized and westernized diet and lifestyle of urban Italians. Taken together, there is strong evidence that the gut microbiota metabolizes the plant- and animal-based diet into products that may respectively protect against and promote westernized diseases in African populations ( 42), and will shift compositionally and functionally in favor of the diet and environment at hand ( 43) thus affecting health.

Nutrition and the Gut Microbiome in USA and Canada

Nutrition can impact the general well-being of people of every age, race, and ethnicity. Notably, industrialized nations bear witness to an obesity epidemic, setting the stage for vast increases of serious chronic illnesses, such as non-alcoholic fatty liver disease leading to liver failure and metabolic syndrome, which predisposes individuals to diabetes and its multiple micro- and macro-vascular complications. While lifestyle changes through diet and exercise are encouraged to combat the metabolic syndrome, several researchers in Canada and the U.S. have focused on modulation of the gut microbiota as a viable strategy to manage weight and improve metabolic health. These studies are described below.

Prebiotics/Probiotics

Prebiotics, non-digestible fermentable oligo- and polysaccharides that act as a food source for probiotics (living microbes) were used as possible means of modulating the gut microbiota to manage obesity and improve metabolic health. Three studies investigated the effects of prebiotics administered in different formulations on body composition, appetite control, metabolic markers, and gut microbiota in adults and children. Reimer et al. studied the effect of 3 kinds of isocaloric snack bars, one containing the prebiotic, 8 grams inulin-type fructans (ITF), one containing whey protein, a control bar, and combination of ITF + whey protein bars administered twice daily for 12 weeks in 96 overweight or obese adults ( 46). In a separate study, a daily dose of prebiotic oligofructose-enriched inulin (OI) or an isocaloric amount of control maltodextrin as powder dissolved in water was consumed prior to the evening meal for 16 weeks in 38 overweight and obese but otherwise healthy children ( 47). ITF, whey protein, and the combination snack bars all improved long-term appetite control but only whey protein was associated with modest reduced body fat in the adult participants. There was no significant additive effect in weight loss or appetite regulation when ITF and whey protein were administered in combination. A significant increase in Bifidobacterium, was observed only with the ITF-containing snack bars. Among children who consumed the OI prebiotic, researchers observed normalized weight gain, reduced whole body and trunk body fat, and decreased primary fecal bile acids, cholic acid and chenodeoxycholic acid compared to placebo. However, there was no reduction in absolute body weight. Bifidobacterium also increased with OI intake compared to placebo. A criticism of the study in children is the distribution of race of the participants was 82% Caucasian and 18% African American and Hispanic. In the third prebiotic study, the effect of a daily dose of 15 grams of yellow pea fiber consumed prior to large meals for 12 weeks in overweight/obese adults with stable weight was examined ( 48). The consumption of the yellow pea fiber resulted in small improvements in body fat and glucose tolerance along with a reduction of body weight primarily as fat mass but no significant changes in microbiota were detected at this dose.

Probotics have been used to increase the proportion of intestinal microbes known to have beneficial effects on human gut mucosa. However, due to their short colonization time their beneficial effects are limited. In an attempt to produce a probiotic with long-term sustainability, Maldonado-Gómez et al. investigated orally administered Bifidobactrium longum ( 49). In this double-blind, placebo-controlled, human crossover study, 23 adults consumed a daily dose of 10 ¹⁰ viable cells of B. longum AH1206 or maltodextrin placebo in random succession with 1 to 3 weeks washout between 2 week treatments and 4 weeks test of persistence. In 30% of participants, the strain remained detectable in feces for at least 6 months without causing gastrointestinal symptoms or impacting the resident gut microbiota. The long-term persistence of AH1206 was dependent on individualized features of the resident gut microbiota. These results suggest that bacterial species can be established and sustained in the gut of certain individuals, given the opportunity and suitable environment. Krumbeck, et al. ( 50, 51) describe testing of a probiotic preparation involving an in vivo selection (IVS) method compared with commercially prepared probiotic administered with (synbiotic) and without a prebiotic. In the first study, researchers isolated a bacterial strain of Bifidobacterium (IVS-1) in fecal samples following 9-week administration of increasing doses of prebiotic galactooligosaccharides (GOS) to volunteers. A retrospective analysis of fecal microbiota in one participant demonstrated eight-fold enrichment in Bifidobacterium post intake. The autochthonist (bacteria already resident in the host) IVS-1 functionality was tested in rats administered the bacterial strain alone, the GOS prebiotic alone, or the combination of the pre- and probiotics. IVS-1 out-performed the resident Bifidobacterium in terms of replication in the presence of GOS. Investigators concluded that IVS can be used to successfully formulate a synergistic synbiotic that will overtake other strains naturally resident in the gut ( 50). In the second study, researchers used a randomized, double-blind, placebo-controlled, parallel arm clinical trial to evaluate IVS bifidobacterial strains and commercial bifidobacterial probiotic preparations with and without GOS prebiotic vs. placebo in improving intestinal permeability among 94 obese adults. Improvements in intestinal permeability were shown with both probiotic treatments and GOS. The treatment effects were primarily directed to permeability of the colon. This 6-arm study did not demonstrate a synergic effect in the two products containing both pre- and probiotics. However, authors stated that the IVS probiotic preparation was more effective than the commercial probiotic in establishing residence in the human gut ( 51). The latter two studies represent research examining autochthonist vs. commercially prepared probiotics and exploring potential synergism with specific prebiotics. Clearly, these investigators promote the use of individually-isolated probiotic strains naturally resident in the gut over the introduction of foreign strains that are commercially prepared. This practice would be closely aligned with holistic approaches to health care and traditional indigenous healing practices.

Traditional Foods and Ethnicity

While host genetics and lifestyle influence the gut microbiome, we know that diet is the major factor shaping it. Investigators in this study were interested in how seasonality affects the gut microbiome among Canadian Inuit people, assuming that variations in food sources available during different seasons would contribute to large shifts in gut microbiome composition ( 52).

Stool samples collected from toilet tissue were analyzed for microbiome composition among Canadian Inuit volunteers living in Resolute Bay, Nunavut and Canadian individuals of primarily European descent living in Montreal, Quebec. Important findings were that 45-61% (the greatest proportion) of variability in microbiome composition was due to individual identity. Examining both groups together, 11% of the variability over the course of 12 months was explained by diet. Among Inuit alone, 17% of the variability was due to diet. Sex explained 3-4% of the variability in microbiomes and geography contributed 3-5% to the variability. Microbiomes of women varied more than men and microbiomes among Nunavut residents were more varied than Montreal residents. Unexpectedly, there were no significant seasonal shifts in microbiome composition in either the Inuit in Nunavut or the European descent Montreal groups. Aside from the above results, the study revealed that Canada's indigenous population living in its northern remote areas is no longer solely reliant on "traditional" food items. Westernized foods are available year-around, which could be the reason why seasonality did not seem to affect microbiome composition in this study. However, the Inuit microbiome did vary over time more than the Montreal diet. Authors suspect greater food security in Montreal and the fact that all foods are available year-round in that area were the reasons for less variability over time in that group. Circumstances in Nunavut resemble those of other indigenous communities in the circumpolar north. Elders and other community residents report less reliance on subsistence lifestyle with the advent of big box stores (e.g., Costco, Walmart, Sam's Club) in more urbanized areas, increased mechanization and commercial air transport, internet orders through companies that provide free or substantially reduced shipping fees, and the availability of "westernized" prepared foods in the local community stores. A second important study outcome was the assessment of dietary intake measured as mean frequency of consumption (number of times eaten per participant) of each food category per day. The Nunavut group consumed substantially more eggs (mean frequency 0.91 vs. 0.18) than the Montreal group, while the Montreal group consumed more dairy products (mean frequency 1.9 vs. 0.88) and alcoholic beverages (mean frequency 0.96 vs. 0.22). There was also notably less consumption of fruits and vegetables (mean frequency 0.85 vs. 2.72) among the Nunavut group than the Montreal group. Importantly, the Nunavut group diet consisted largely of game meats - raw, cooked, and fermented. The foods traditionally fermented include walrus and whale meat, fish, seal, and caribou. The meat and fat that is caught in the summer is buried in the ground over the autumn and winter months ready for consumption in the next year. These traditional foods are similar to traditional foods consumed by indigenous peoples (Inupiat and Yup'ik) in northern circumpolar regions of Alaska. In Alaska, raw, cooked, and fermented game sources include moose, caribou, and marine mammals, such as whale meat and blubber, sea lion, walrus, seal and seal oil, wild birds and bird eggs, and multiple ocean and river fish. However, all communities have local markets, which stock "western" prepared/preserved foods with long shelf life, decreasing reliance on traditional indigenous food sources.

The developing gastrointestinal microbiota in the first years of life is important for immune function, nutrient metabolism and protection from pathogens ( 53, 54). Early evidence suggests that diet influences the infant gut microbiome ( 55). There is preliminary evidence that gut microbial composition in adults and children varies by age, dietary intake, ethnicity, geography, and adoption of western life-styles ( 56, 57). In 2017, Stearns et al. explored the effects of race/ethnicity separate from geographical region on the gut microbiota in early life ( 58). Participants from two prospective Canadian birth cohorts were included. Researchers used 1-year fecal samples from 173 Caucasian infants and 182 infants of South Asian ancestry living in Canada in the main analysis. Results demonstrated that the gut microbiome of infants is influenced by race/ethnicity, age, weight gain, and breastfeeding. South Asian mothers lived in Canada for an average of 8 years (vs. a lifetime for Caucasian mothers), were younger, more likely to be vegetarian, and more likely to be diagnosed with gestational diabetes than the Caucasian mothers. South Asian infants had higher abundance of several members of lactic acid bacteria (LAB) contained in the feces, specifically Bifidobacterium, Lactococcus, Streptococcus, and Enterococcus than in the Caucasian infants feces. LAB are responsible for the breakdown of carbohydrates to lactate and acetate ( 57, 59). The abundance of the Atopobium cluster of Actinobacteria was also higher in South Asian vs. Caucasian infants. This group of bacteria are saccharolytic and have been observed in abundance in the microbiome of individuals with a fiber-rich diet ( 60). Caucasian infants showed greater abundance of members of Firmicutes from the order Clostridiales, shown to increase in response to diets rich in animal protein and fat ( 61). This study demonstrates race/ethnicity and infant feeding practices play important roles in the development of the infant gut microbiome. While race/ethnicity are not modifiable, the infant diet is and its alteration can assist in promoting healthy gut microbiota.

Nutrition and the gut microbiome in Europe

Numerous recent clinical studies performed by research groups in Europe examine the effects of whole foods and additives on the gut microbiome and human health. While European diets are quite diverse, the general trend towards 'Westernization' of diet (e.g., high intake of fat and low consumption of milk) causes similar health problems in most European countries (e.g., rising incidences of obesity, cardiovascular diseases and colon cancer). In this context of nutrition, gut microbiome and human health, a selection of recent studies is discussed.

Nuts (walnuts in particular) are known to have health benefits in that their consumption was shown to lower plasma lipid levels ( 62). The aim of one study was to investigate how walnut intake alters the gut microbiome composition and diversity. In a randomized controlled trial (cross-over design) of 96 healthy participants, a walnut-enriched diet was administered for 8 weeks followed by a switch to nut-free diet. ( 63). A second group of 98 participants followed the dietary pattern in reverse order and fecal samples were collected for 16S rRNA gene sequencing analysis. No difference was found in alpha-diversity, but with regard to beta-diversity a distinct clustering of the walnut and control groups was observed. However, the walnut diet explained only about 5% of observed difference compared to the control diet. In the walnut group, a significantly increased abundance of Ruminococcaceae and Bifidobacteria coincided with a decrease in Clostridium sp. Cluster XIVa species compared to control diet. Thus, walnut intake may promote compositional shifts of the gut microbiota to potentially probiotic and SCFA-producing species that may account for health benefits associated with walnut consumption. However, the link to health-promoting, walnut-dependent metabolites remains speculative, since this study reported compositional differences and did not quantify actual microbial metabolites.

A vegetarian diet rich in vitamins and fibers has been shown to be beneficial to the immune system ( 64). The aim of another recent study was to investigate the effect of a 3-months lacto-ovo-vegetarian diet on the gut microbiota and the immune system in healthy omnivorous volunteers ( 65). Fifteen healthy omnivorous volunteers switched to a lacto-ovo-vegetarian diet for 3 months, and blood and fecal samples were collected pre- (month 0) and post-intervention (month 3). Control groups consisted of healthy volunteers staying on their omnivorous diet or vegetarian diet, respectively. All fecal samples were analyzed by metagenomic shotgun-sequencing. While no difference in alpha-diversity was detected, a few genus-level changes were associated with the vegetarian diet intervention. After 3 months of lacto-ovo-vegetarian diet, the abundance of Alistipes was reduced, coinciding with increased abundance of Roseburia inunilivorans, Ruminococcus lactis, Lactobacillus plantarum and Streptococcus thermophiles in the fecal microbiota. However, it needs to be noted that the authors did neither comment on compliance of study participants that switched from an omnivorous to a vegetarian diet nor provided details on how/if dietary intake was recorded, which are crucial parameters to evaluate the obtained results. An additional comparison of both control groups (long-term omnivores and vegetarians) revealed compositional differences at genus and species levels, supporting the idea that long-term dietary patterns are a major driver of gut microbiota assembly. In conclusion, a switch to the vegetarian diet had an impact on gut microbiota composition, but its functional relevance on gut microbial co-metabolism remains to be elucidated.

It is reported that Bifidobacteria can have functional benefits by cross-feeding other members of gut microbiota specialized on production of butyrate, an essential short chain fatty acid for colon epithelial cells ( 66). The aim of this recent study was to analyze how consumption of fermented dairy products (FDP) - a yogurt fortified with the probiotic Bifidobacterium animalis subsp. lactis, BB-12, may be associated with positive impact on human health ( 67). In this prospective intervention study, 150 healthy participants received FDP fortified with BB-12 twice a day for 30 days in total. Fecal samples were collected at day 0 and 30 and 16S rRNA gene sequencing analysis performed. While no change in alpha-diversity after FDP intake was shown, a correlation analysis of species occurring together identified 5 major microbial networks and distinct compositional shifts following FDP intake were observed. A paired comparison revealed that abundance of 39 taxa increased and 24 taxa decreased after FDP intake. An increased abundance after FDP intake was demonstrated for Coriobacteriaceae (ability to metabolize lactose to lactate), Bifidobacteriaceae (probiotic, anti-inflammatory), Staphylococcaceae, and Erysipelotrichaceae. Decreased numbers were demonstrated for Lachnoclostridium_unclassified (involved in bile acid metabolism) and Roseburia genera (potential SCFA producers), for example. When investigating changes in lactose-fermenting taxa (e.g., Bifidobacterium, Lactobacillus, Lactococcus), which are likely to be affected by altered FDP intake, the authors identified 2 clusters of study participants: cluster 1 showed a weaker increase in relative abundance of lactose-fermenting bacteria compared to the individuals from cluster 2 and and less changes in overall fecal microbiota composition. In contrast, a higher number of taxa in the fecal microbiota of individuals from cluster 2 was affected by FDP intake, suggesting that cluster 2 can be termed "responders". Interestingly, these responders showed a lower abundance of lactose-fermenting bacteria in the fecal microbiota at baseline compared to cluster 1 (or "non-responders"), which may explain the observed cluster-specific increase in lactose-fermenting bacteria. Overall, significant shifts in gut microbiota composition suggest changes induced by 30 days of FDP intake, but the effect on microbial metabolism, in particular with regard to human health, remains unclear.

According to the National Health and Nutrition Examination Survey of the U.S.A, dietary phosphate intake of Americans exceeds the daily recommended intake of 700 mg phosphorus for adults and the elderly ( 68). This is mainly a result of the increased consumption of food prepared or treated with phosphate additives, ranging from baked goods to cola beverages ( 69). A recent study by Trautvetter et al. aimed at analyzing the impact of high phosphorus intake on gut-related parameters ( 70). The randomized controlled trial, double-blinded intervention (monosodium phosphate with/without calcium carbonate supplements) with 62 healthy participants consisted of a pre-intervention phase (consumption of placebo for 2 weeks) and an intervention for 8 weeks (monosodium phosphate with or without calcium carbonate). Fecal samples were collected after placebo and intervention and 16S rRNA gene sequencing, fecal water cytotoxicity and targeted short-chain fatty acids were analyzed. Significantly higher levels of total short-chain fatty acids and acetate in feces were detected after 8 weeks on monosodium phosphate with calcium carbonate compared to monosodium phosphate without calcium carbonate. However, no differences in epithelial cell cytotoxicity and only minor differences in gut microbiota composition between men from both groups, but not women were found (e.g., higher abundance of Clostridium XVIII in men receiving the highest levels of monosodium phosphate and calcium carbonate compared to the other groups). These results suggest that there is no strong effect of a high phosphorus diet on gut microbiota composition and metabolism, despite small increases in short-chain fatty acid production.

Nutrition and the gut microbiome in Asia

Weight management, obesity, and metabolic disorders are also a concern in Asian populations as diet and life styles change. The following Asian studies break down the effects of food components and different diets on the gut microbiome and how they may influence health.

Fat

In China, the nutritional transition from a traditional low-fat, high-carbohydrate diet to a diet relatively higher in fat and lower in carbohydrate has been associated with a dramatic increase in the risk of obesity, type 2 diabetes, cardiovascular diseases and colon cancer in the past 30 years ( 71). Studies have shown that human gut microbiota diversity and richness are reduced when comparing high fat diets with more traditional diets of relatively higher proportions of carbohydrates ( 72, 73). Wan et al. performed a 6-month randomized controlled-feeding trial of 217 healthy young adults, varying the amounts of fat in isocaloric diets containing lower-fat (20% energy), moderate-fat (30% energy), and higher-fat (40% energy) ( 74). At the phylum level, the moderate and higher fat diets decreased the ratio of Firmicutes to Bacteriodetes after intervention. At the genus level, the higher fat diet decreased the abundance of Faecalibacterium, increased the abundance of Alistipes and Bacteroides, while the lower fat diet increased the Faecalibacterium and Blautia abundance after the intervention. Concentration of fecal butyrate was increased after the lower-fat diet intervention and decreased after the higher-fat intervention. The changes in relative abundance of Blautia was negatively associated with the changes in serum total cholesterol, low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol, whereas the change in Bacteroides abundance was positively correlated with the changes in these blood lipid markers. Higher-fat consumption by healthy young adults whose diet is in a state of nutrition transition appeared to be associated with unfavorable changes in gut microbiota, faecal metabolomic profiles and plasma proinflammatory factors, which might confer adverse consequences for long-term health outcomes ( 74). It should however, be noted that these diets were kept isocaloric, so it would be fair to replace low fat with high carbohydrate, and high fat with low carbohydrate. Further the low carbohydrate diet would have lower fiber. In this context, international studies that reflect different environmental conditions are important to identify the effects of diet composition on the gut microbiota. For example, Ocvirk et al. recently showed that the high fat, low carbohydrate and fiber diet of the Alaska Native people (AN) was associated with a very different colonic microbiota composition. In this study, the fecal microbiota showed a compositional predominance of Blautia and fecal levels of short-chain fatty acids were significantly lower compared to a low risk rural African population. The importance of this is that AN have the highest documented risk of colon cancer in the world, and the incidence of other westernized diseases such as obesity, diabetes, and cardiovascular diseases is also high. This highlights the concern about conclusions that dysbiotic signatures may play a causative role in westernized diseases ( 75).

Fiber

The need to determine whether associations between diet, the microbiome and westernized diseases were indeed causal led to very interesting human trial-experimental animal mechanistic studies reported by Zhao et al. in Science. In a randomized clinical study of Chinese patients with Type 2 diabetes mellitus, 43 patients received either the usual care based on the 2013 recommendations of the Chinese Diabetes Society (control) or a high-fiber diet (approximately 50 grams/day) composed of whole grains, traditional Chinese medicinal foods and prebiotics (WTP) for 84 days ( 76). Daily energy and macronutrients were similar across groups. Both groups received acarbose as the standardized medication (transforms part of the starch in the diet into a fiber by reducing its digestion and making it more available as fermentable carbohydrate in the colon). A group of 15 SCFA producing strains that were selectively promoted by the WTP diet were detected ( 76). Promoting this active group of SCFA producers not only enhanced a beneficial function but also maintained a gut environment that keeps detrimental bacteria such as indole- and hydrogen sulfide- producing strains at bay. Hemoglobin A1c (HbA1c) levels (primary outcome measure in this study) were significantly decreased in both groups from baseline in a time-dependent manner, but by day 28 of the study the decrease was greater in the WTP group, partly via increased glucagon-like peptide-1. There was a temporal difference in fasting blood glucose levels-only the WTP group achieved a significant reduction by day 28, although at the end of the intervention there was no difference between groups. The WTP group also showed greater reduction in body weight and better blood lipid profiles than the control group. In another Chinese study, Zhang et al. performed a hospitalized dietary interventional trial for 30 days of 40 children diagnosed with genetic (diagnosed with Prader-Willi syndrome (PWS)) and simple obesity. Some of the children in the PWS group continued on the diet intervention for 60 days. A WTP diet in combination with appropriate amounts of vegetables, fruits and nuts induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation ( 77). This dietary intervention shifted the dysbiotic gut microbiota to a healthier structure with relatively lower levels of bacteria that can produce potentially toxic metabolites from the fermentation of dietary fats and proteins, and higher level of bacteria that can produce potentially beneficial products from the fermentation of carbohydrates.

Chinese Traditional herbal formulas

A traditional Chinese herbal formula, Gegen Qinlian Decoction (GQD), is believed to alleviate type 2 diabetes. A 12 week randomized double-blinded placebo controlled clinical trial in 187 patients with type 2 diabetes by Xu et al. found that low (48 grams), moderate (144 grams), and high doses (240 grams) of GQD induced structural changes of the gut microbiota composition and enriched the amounts of 'beneficial' bacteria, such as Faecalibacterium spp., high butyrate producers, in a dose dependent manner ( 78). Another herbal formulation, the prebiotic Deshipu stachyose granules (DSG), a mixture of α-galacto-oligosaccharides derived from the dietary roots of Lycopus lucidus Turcz, was reported to facilitate intestinal peristalsis and defecation relieving constipation in mice ( 79). A study designed to investigate the effect of DSG on gut microbiota and bowel function in 100 adult volunteers found that DSG at a dosage of 5 grams per day for 14 days could instructively regulate the gut microbiota with significant increases in 'probiotic' species bifidobacteria and lactobacilli and a remarkable decrease in the potential pathobiont Clostridium perfringens. DSG also could effectively improve the bowel function of patients suffering from constipation with a marked increase in defecation frequency from 1.78 times per week to 3.02 times per week ( 80).

Green tea has been claimed to hold health benefits including anti-colorectal cancer activity and is characterized by the presence of large amounts of polyphenols, also known as catechins, such as epigallocatechin-3-gallate, epigallocatechin, epicatechin gallate, and epicatechin ( 81). Yuan et al. ( 82) investigated the effect of green tea liquid (GTL) consumption (400 ml per day for 2 weeks) on the gut and oral microbiome in 12 healthy volunteers. They found an increased FIR:BAC (Firmicutes to Bacteroidetes ratio), elevated SCFA producing genera, and reduction of bacterial LPS synthesis in feces following a 1 week washout period. GTL also altered the salivary microbiota and reduced the functional pathways abundance relevant to carcinogenesis and reduced the fecal levels of Fusobacterium.

Ketogenic Diets

A ketogenic diet (KD) consists of a diet very low in carbohydrates and high in fat. This reduction in carbohydrates puts the body in a state of ketosis due to the need to increase the mobilization and oxidation of fat for energy. A KD has been advocated for the treatment of chronic epilepsy. Xie et al. performed a comparison between 14 infants with epilepsy and 30 healthy control infants before and after KD treatment to explore if the gut microbiota of infants with refractory epilepsy differed with that of age-matched healthy infants ( 83). The therapeutic effect of the KD on refractory epilepsy and the changes in the gut microbiota were also studied. After being on the KD treatment for a week, 64% of epileptic infants showed an improvement with a 50% decrease in seizure frequency. The gut microbiome structure in epileptic infants differed dramatically from that in healthy infants. Proteobacteria, which was significantly higher in epileptic infants, decreased dramatically after the KD. Cronobacter predominated in the epileptic infants group and remained at a low level both in the healthy infants and in the epileptic infants after the KD. Bacteroides increased significantly in the epileptic infants after KD, in which Prevotella and Bifidobacterium also grew in numbers and kept increasing ( 83).

Summary

The studies discussed provide irrefutable evidence from around the world that the human microbiome can be modified by dietary change in children and adults. Whilst the associations between specific dietary components and health and disease are strong, a lot more work on causality is needed before specific microbes, or groups of microbes, can be used therapeutically. The evidence for a balanced diet and balanced microbiota being able to prevent westernized diseases and extend good quality lifespan is, however, compelling ².

Figure 1:

Illustration of some of the actions of butyrate released by colonic microbial fermentation of fiber on host metabolism, inflammation and carcinogenesis.

Figure 2:

From the study of Zhjao et al: 43 patients with T2DM were randomized for 84 days to a traditional Chinese high fiber diet. Eighty nine percent of the high fiber group showed normalization of their HbA1c compared to 29% of the control group. Shotgun sequencing identified 15 specific SCFA-producing strains (see above) that were promoted by dietary fiber which were also associated with better improvement in hemoglobin A1c levels and diminished indole and hydrogen sulfide producers.

Table 2:

Location of study and reference

Disease or condition

Age of participants

Number and/or nutritional status of participants

Study design

Study outcomes

Normal health

24-67 years (Inuit)
23-48 years (non-Inuit)

n=15 Inuit participants; n=9 non-Inuit participants

Observational study

Gut microbiota

Obesity

35.8± 4.2 (lean)
42.5±3.9 (overweight and obese)

n=22; 11 lean and 11 overweight and obese

Observational study

Rate SCFA absorption, gut microbiota, dietary intake

Table 3:

Location of study and reference

Disease or condition

Age of participants

Number and/or nutritional status of participants

Study design

Study outcomes

Normal health

39 ± 10.1; 34.7 ± 10.4; 33.5 ± 7.4

n=17 switched to vegetarian diet
n=14 control diets (7 omnivorous, 7 vegetarian)

Sub-study of a randomized trial

Gut microbiota, immune analysis

China
Li et al. 2017

Constipation

Adults under 65 years

n=100; n=50 (Deshipu stachyose granules), n=50 (control)

Non-blind randomized control trial

Gut microbiota, bowel function

Biography

Footnotes

Source and Selection of Articles Reviewed: The aim of this review is to summarize recently published research from human studies on the gut microbiota-modulating effects of diet. It includes sections on microbiome research of populations from around the globe in the USA, Canada, Europe, Asia, and Africa that address specific public health challenges. References for this review were identified through searches of PubMed for peer-reviewed articles published in English from 2014 to August 31, 2019 by use of the terms "Human Nutrition (or Nutrition) and the (Human) Microbiome in USA, Canada, Europe, Asia, and Africa," appearing in the title or abstract. Articles resulting from these searches, as well as relevant references cited in those articles, were reviewed. The conclusions highlight the future needs and implications for scientists and clinicians in this fast-developing field of research, and the need for high-quality, large-scale controlled human dietary intervention studies.

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

Bibliography

28. Million M, Tidjani Alou M, Khelaifia S, Bachar D, Lagier J-C, Dione N, et al. Increased gut redox and depletion of anaerobic and methanogenic prokaryotes in severe acute malnutrition. Sci Rep. 2016. May 17;6:26051. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]

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Diet and the Human Gut Microbiome: An International Review

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This review summarizes the key results of recently published studies on the effects of dietary change and nutritional intervention on the human microbiome from around the world, focusing on the USA, Canada, Europe, Asia, and Africa. It first ...

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website that may show some ideas for some types of resources to use in the class such as labelling activities and quiz

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Introducing the Digestive System

A Model of the Digestive System

https://www.youtube.com/watch?v=aemI64NAK08 Contributor: Aoife McDonnell Resource type: Audio / Video

A great hands-on activity to investigate the functions of each part of the digestive system. The video illustrates how a teacher can carry out the demonstration/ guide students in creating a similar model with explanations for each representation. The activity motivates students engaged with the topic along with aiding students memory skills in a fun interactive manner whereby students learn more about their key skills for learning together.

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How it maps to the curriculum

Strand: 5. Biological Science

Strand unit: 4. Human Organs & Systems

Suggestions for use: Teacher can watch the video/ give the link to students to watch for homework. In class, set class into groups. In groups students need to negotiate and research how they will demonstrate the model of the digestive system to the class. Allow time in class for students to organize their group presentation. In the next lesson, groups must be given individual time to present the model to the class. (Video can be used so groups can reflect on presentation skills). Ensure the class come up to the front and gather around the demonstration area while the group present their model to the class and explain the analogies to the class.

Key Skills: Being Creative Communicating Managing Information and Thinking Working with Others

https://www.scoilnet.ieuploads/resources/25511/25247.pdf Contributor: Aoife McDonnell Resource type: Worksheet

Worksheet for students to assess a model of the digestive system. Students can choose to assess the model within the given YouTube video or a model of their own choice. Students need to assess the strengths and limitations of the model and identify the processes/ parts the model represents.

View full description

How it maps to the curriculum

Strand: 5. Biological Science

Strand unit: 4. Human Organs & Systems

How it maps to the curriculum

Strand: 5. Biological Science

Strand unit: 4. Human Organs & Systems

Sample Models Create a Comic Strip

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Official education portal of the Department of Education and Skills in Ireland. Curriculum focused resources and support for primary and post primary teachers.

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Word wall can help the teacher to create certain assessment activities for their class

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can be used as a recap activity or other activities such as work sheet or quiz can be created from the content of the video.

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Digestive System - Junior Cycle Science - Revision Video