Gut-brain axis : a biological reality in which the gut communicates with the entire brain through cross-talking neurons

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You know that feeling in your gut?

We think of it as an innate intuition that sparks deep in the belly and helps guide our actions, if we let it. It’s also a metaphor for what scientists call the “gut-brain axis,” a biological reality in which the gut and its microbial inhabitants send signals to the brain, and vice versa.

It’s not a surprise that the brain responds to signals in the gut, initiating motor functions involved with digestion.

Directed by the brainstem, these types of basic biological actions are largely automatic.

But what if the higher brain – the thinking, emotional centers – were influenced by signals in the gut, too?

New University of Illinois research in rats shows the entire brain responds to the gut, specifically the small intestine, through neuronal connections.

To map the connections, researchers inserted neuron-loving viruses in the rats’ small intestines and traced the viruses as they moved from neuron to neuron along the Vagus and spinal nerves and throughout the brain.

The idea was virus movement mimicked the movement of normal signals through neurons from the gut to the brain and back.

“We saw a lot of connections in the brainstem and hindbrain regions. We knew these regions are involved in sensing and controlling the organs of the body, so there weren’t any big surprises there.

But things got more interesting as the viruses moved farther up into parts of the brain that are usually considered emotional centers or learning centers, cognitive places.

They have all these multifaceted functions. So thinking about how information from the small intestine might be nudging those processes a little bit is really cool,” says Coltan Parker, doctoral student in the Neuroscience Program at Illinois and lead author on a study published in Autonomic Neuroscience: Basic and Clinical.

The study represents the first complete map of neuronal connections between the small intestine – what Parker and his co-authors call an “underloved” part of the digestive system – and the entire brain.

The involvement of cognitive and emotional centers hints at how the thinking brain sometimes overrides our feeling of being full, provides fodder to explore relationships between depression and digestive troubles, and more.

“Now we’re actually finding the neuro-anatomy that might be involved in that ‘feeling in your gut,'” says Megan Dailey, study co-author and program administrator in the College of Agricultural, Consumer and Environmental Sciences at Illinois.

In addition to showing just how extensive the connections are between the small intestine and the brain, the study uncovered a rarely documented feature of the neurons themselves.

Scientists have long assumed sensations from the gut, or anywhere in the body, traveled to the brain along one set of neurons (the sensory neurons), with instructions from the brain traveling back along a separate set of neurons (the motor neurons).

But in their mapping study, Illinois researchers discovered some of the neurons – about half – were transmitting both sensory and motor signals.

They were capable of cross-talk within the same neuron.

“From the cortex to the brainstem, in pretty much every region we investigated, there was that 50% overlap of sensory-motor signals.

It was throughout the brain, consistently,” says study co-author Elizabeth Davis. Davis is a 2018 graduate of the Illinois Neuroscience Program and is currently studying as a postdoctoral scholar at the University of Southern California.

The same pattern – 50% of neurons having both sensory and motor signaling capabilities – had only been shown one other time, in a study mapping neuronal connections between fat tissue and the brain.

The researchers point out new evidence of the same crosstalk pattern could suggest a general architecture of neuronal networks between the body and brain.

“This study shows that sensorimotor feedback loops are abundant across all levels of the brain.

Up until now, it has really been unknown how information in the small intestine, about nutrients or anything else, can get up to the brain and affect cognitive-emotional processes, and then how those processes can come back down and affect the gut,” Parker says.

“With more research, we may finally begin to understand how hunger makes us ‘hangry,’ or how a stressful day becomes an irritable bowel.”

The article, “Central sensory-motor crosstalk in the neural gut-brain axis,” is published in Autonomic Neuroscience: Basic and Clinical.


The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis.

This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders.

The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans.

Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging.

Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson’s disease, and Alzheimer’s disease.

Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field.

Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.

… Also

The human gut microbiome can exert effects on mental and physical health through different routes including through the brain-gut-microbiome axis (BGMA [1]), intestinal activity [2], and the competitive exclusion of pathogenic bacteria [3].

BGMA signaling in particular has been shown to be bi-directional, where not only can gut bacteria influence health and behavior, but psychological states can alter gut health.

Perturbations to the BGMA have been associated with gastrointestinal disorders [4], depression and mental quality of life [5], Parkinson’s disease [6], increased anxiety [7], and decreased cognitive abilities [8]. While the mechanisms through which the gut microbiome and human body interface have yet to fully understood, previous work has shown that bacteria can influence neural [9], hormonal [10] and immune responses [11], and permeability of both the gut [12] and the blood brain barrier [13].

Accordingly, understanding how the BGMA functions to regulate human health and behavior is of importance.

Several bacterial metabolites have been identified as possible mechanisms through which bacteria communicate via the BGMA with their host. Chief amongst these are metabolites that interface with the immune system [14].

For example, short chain fatty acids (SCFA, e.g., butyrate, acetate) produced by fermenting bacteria can suppress pro-inflammatory cytokines, and interact with regulatory T cells to attenuate colitis [15]. The bacterial metabolite indole stimulates the production of interleukin-22 (IL-22),

which stimulates the production of anti-microbial peptides thus serving a protective role against pathogens [16].

Polysaccharide A downregulates the production of the pro-inflammatory IL-17, while upregulating the production of IL-10, which together serve to protect against colitis [17].

The production of IL-6 and IL-1β can be stimulated by the gut microbiome, which can lead to regulatory B-cell differentiation [18]. Overall, there are well-established links between the immune system and the gut microbiome in humans.

Sleep is a physiological state that is intrinsically linked to the immune system but is overall understudied in the context of BGMA.

In general, short sleep duration and poor sleep quality have been associated with several aspects of cognitive and neurobehavioral performance [1921], and several diseases including cancer [22], type II diabetes [23], and Alzheimer’s disease [24].

Notably, cytokines represent a potential critical interface between sleep physiology and gut microbiome composition. The acute phase pathway cytokines IL-1β and IL-6 in particular are strongly associated with sleep physiology. IL-1β is a major somnogenic factor [2527].

IL-1β administration in human and non-human animals increases spontaneous sleep and fatigue, and IL-1β increases with ongoing sleep loss [2728]. Unlike IL-1β, IL-6 is not a direct somnogenic factor, but sleep loss results in increased IL-6 levels [29].

In the gut, IL-6 and IL-1β mediated-inflammation fluctuate in response to stress and disease [3031]. For example intestinal mucositis results in increased expression of IL-6 and-IL-1β in the small intestine [3233] and in serum and colon tissue [34] in mice. In humans, chronic stress alone increases IL-6 and-IL-1β [35].

Fig 1. The interaction network between measures of sleep, microbiome diversity and cognitive performance.

Pearson correlation coefficients were used to generate the weight of each edge in the network. Heat map shown on image. Different colored circles indicate groupings of nodes with similar traits in the network (I = microbiome diversity, II = sleep, III = cognition). Raw data for correlations (outside of microbiome diversity control correlations) found in S1S4 Figs. Directionality of interactions is not implied in this figure.

https://doi.org/10.1371/journal.pone.0222394.g001

Despite the close relationship between cytokine activity, gut microbiome activity and sleep, only a handful of studies have examined sleep and gut-microbiome composition. In mice, periods of intermittent hypoxia, which serves to simulate obstructive sleep apnea [36], and sleep fragmentation, have been shown to alter the gut microbiome diversity [37].

In humans, previous research has shown that partial sleep deprivation can alter the gut microbiome composition in as little as 48 hours [38], however longer periods of sleep deprivation apparently do not have this effect [39].

A more recent study showed that high sleep quality was associated with a gut microbiome containing a high proportion of bacteria from the Verrucomicrobia and Lentisphaerae phyla, and that this was associated with improved performance on cognitive tasks [40].

In spite of these findings, the mechanisms through which the gut microbiome can affect sleep remains unresolved, and in particular, the molecules that interface between sleep and the gut microbiome remain unidentified.

To address this uncertainty, we investigated the relationship between gut microbiome diversity, sleep, cognition and the pro-inflammatory cytokines, IL-6 and IL-1β. To accomplish this, we used a multidisciplinary approach consisting of microbiome sequence, actigraphy, cognitive and neurobehavioral testing, and biochemical approaches to measuring immune system markers.


More information: Coltan G. Parker et al, Central sensory-motor crosstalk in the neural gut-brain axis, Autonomic Neuroscience (2020). DOI: 10.1016/j.autneu.2020.102656

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