Viscera affectum anno: the gut beyond eating behaviours

Abstract

One of the most pleasurable, yet dangerous, activities of our daily life is eating. But once food has been swallowed, all we can do is to trust our gut. Several remarkable studies published in 2020 have expanded our knowledge on how the gut is intertwined with essential behaviours beyond food.

“The gut doesn’t get much respect” was the opening line of my human physiology class 12 years ago. The professor, a neuroscientist, proceeded to explain that, though this misunderstood organ is often judged merely by its products of digestion, it has more neurons than the spinal cord. Things have changed since then. In the past 10 years, discoveries on how the gut influences the brain have inspired neuroscientists, endocrinologists, microbiologists and scientists from many other disciplines to turn to the gut in the quest to understand the mind. According to PubMed, in the past 12 months, there were 761 scientific articles published on ‘gut–brain’ biology as of 25 November 2020. Here, I highlight three of these 2020 articles that expanded our knowledge and imagination on how the gut makes sense of its environment to guide brain functions and behaviour.

Seeking to identify bacteria that influence Caenorhabditis elegans behaviour, O’Donnell et. al.¹ screened for non-pathogenic bacteria that alter chemotaxis. In the laboratory, the worms are fed with Escherichia coli, but in the wild they forage on bacteria that live in rotting vegetation². One clear candidate emerged: Providencia alcalifaciens strain JUb39. Feeding C. elegans these Gram-negative bacteria decreased their avoidance of octanol, which is a volatile repellent avoided by worms on a laboratory diet. The effect requires Providencia to be eaten and remain alive in the digestive tract of the worm. Worms fed Providencia pre-treated with antibiotics find octanol repulsive. In fact, the more extensive the colonization of these rod-shaped bacteria, the less repulsive the worms find octanol. But what is the magic ingredient that these bacteria have? It turns out that the gut of the worm produces an array of monoamines³. One of those is tyramine, which is metabolized into octopamine. When released, octopamine acts on the OCTR1 receptor localized in the worm’s nociceptive ASH neurons, reducing the worm’s aversion. For comparison, to the worm, ASH neurons are what peripheral sensory neurons are to mammals. Although endogenous octopamine is essential, endogenous tyramine is dispensable so long as it is supplemented in the diet or by Providencia. Cleverly, these bacteria release tyramine to reduce the instinctive aversion of the worm to the repulsive odour of Providencia. One can only wonder whether bacteria in blue cheese do the same to our nose via the gut!

On a second sweet story, scientists have known for decades that sugar delivered directly into the gut has a strong reinforcing effect. In fact, genetic deletion of sweet taste receptors makes animals blind to sweeteners, but not to sugars⁴. Previously, it was shown that the electrogenic glucose transporter SGLT1 is necessary for sugar preferences in mice⁵. Building on these observations, Tan et al.⁶ found that blocking SGLT1 (via pharmacological inhibition) from the gut lumen prevented the development of such preference in mice. Moreover, intraduodenal perfusion of sugar (for example, glucose), but not sweetener (that is, acesulfame potassium) or water, causes a prominent activation of neurons in the caudal nucleus of the solitary tract (cNST). These cNST neurons receive synaptic inputs from a population of vagal nodose neurons responding to sugar but not to sweetener or to water. The activity of the cNST neurons is rapidly silenced when the vagal branches are severed, confirming previous observations that the vagus nerve conveys stimuli from sugars to the brain⁷. The vagal-to-cNST neural circuit responds to sugar and its non-metabolizable analogue methyl-α-D-glucopyranoside⁶, indicating that the trigger is the sugar molecule rather than its metabolic products. Silencing the cNST neurons abolished the development of sugar preferences as well, and activating them artificially is sufficient to develop a novel preference to an otherwise low-preference stimulus⁶. As stated by the authors, “It will be of interest to determine the identity of the intestinal cells mediating these responses”, as they represent the entry point to drive the animal’s choice for sugars and perhaps other nutrients from the gut.

Finally, before you fall asleep, remember that sleep is essential for life. Insufficient sleep is associated with an array of health disorders and premature death. Though the causes are unknown, oxidative stress due to reactive oxygen species (ROS) has been proposed as a theoretical culprit⁸. As sleep is generated by neurons, researchers have been examining the brain for explanations. But, in 2020, Vaccaro et al.⁹ found a culprit outside the brain. They continuously deprived fruit flies (Drosophila melanogaster) of sleep. After 10 days, flies began dying, and, by 20 days, all of them were dead. If sleep deprivation stopped before 15 days, surviving flies recovered and went on to have regular lives. A broad search for tissue damage showed all tissues being normal, except for one — the gut. The researchers found increased accumulation of ROS in the mid gut of sleep-deprived flies compared with non-sleep deprived flies. Similar effects were also observed in mice. Though the mechanisms by which ROS accumulates in the gut are far from established, there seems to be a connection to dopaminergic neurons controlling arousal. A mutation in the gene that encodes fumin, a dopamine transporter, makes flies sleepless without affecting their lifespan, and their guts show normal ROS levels. How ROS accumulation in the gut leads to death is also unclear. According to Vaccaro et al., neither gut permeability nor food intake seems to be an issue. To determine whether a reduction in ROS will prevent death, the investigators screened for antioxidant compounds and identified a few that allowed for “normal or near-normal” lifespan in flies, including melatonin. Supple mentation with melatonin reduced mortality in sleep deprived flies compared with sleep deprived flies that did not receive antioxidants. The effects were attributed to an antioxidant effect rather than sleep or circadian effects¹⁰. This study opened many questions and brings attention to the fact that the gut is closely associated with behaviours beyond food intake and choices. One question is how, under normal circumstances, sensory arousal elicited by gut stimuli could contribute to sleep — one essential pleasure of life (FIG. 1).

Fig. 1 |. A gut sense for subliminal choices.

Our knowledge of how the gut influences essential behaviours has expanded, beyond eating behaviours.

Our respect and fascination for the study of gut–brain biology has increased exponentially in 2020. Terms such as ‘gut feeling’, ‘go with your gut’ or ‘trust your gut’ are beginning to morph from the colloquial to the scientifically sound. The rapid accumulation of knowledge is testing the boundaries of language. For instance, although it is clear that the gut has a sensory system of its own, no word exists to describe a gut sense. Putting it in words might enable us to learn how sensations from the gut guide our emotions and to understand how the lack of such a sense derails our feelings. Words such as smell and anosmia or taste and ageusia have worked for the nose and the tongue, what will that word be for our intuitive gut sense?

Key advances.

• Bacteria can use neurobiomimicry to coerce worms to eat more of those same bacteria¹.

• The development of sugar preferences in mice depends on brain stem neurons receiving vagal inputs from the gut⁶.

• Death by lack of sleep in fruit flies and mice is due to cumulative oxidative stress in the gut⁹.