Effects of the gut microbiome on control of organ and tissue function

Last four lectures for PHYL3004! These last few topics are a bit all over the place, but I guess that just adds to the fun I guess...?

So why are researchers looking at the gut microbiome? The gut microbiome has become of interest due to the actions of Toxoplasma gondii. Toxoplasma gondii is a single-celled gut parasite in cats. Rodents can become infected with T. gondii by contact with cat faecal matter. Once infected, rats lose their normal fear of cats and may even become sexually aroused by cat urine. This makes them more likely to spend time around cats, resulting in them becoming cat food and completing the life cycle of T. gondii.

The gut microbiome

As I've already written about here, we have a helluva lot of bacteria living on and in us. Usually, initial colonisation occurs at birth during vaginal delivery, as well as during breast feeding. In fact, babies delivered via a C-section have been found to have a higher risk of obesity and diabetes, and it has been suggested that the gut microbiome may have been a factor. The three main types of gut bacteria are Prevotella, Bifidobacteria and Bacteroidetes, and each has a preference for a different kind of food. Prevotella prefer carbohydrates, Bifidobacteria prefer dietary fibre, and Bacteroidetes prefer fats. Changes in diet can therefore change the relative proportions of these different bacterial species.

Effects of gut bacteria on eating behaviour

Competition for nutrients provides a selective advantage to bacteria that can influence their host to consume more of the food that they like. For example, if Bacteroidetes can influence us to eat more fat, that will help Bacteroidetes survive in the long term. Indeed, gut bacteria may manipulate our reward pathways, produce toxins that alter mood, alter our taste receptors and/or hijack vagal transmission in order to manipulate our eating behaviour. Many bacteria also manufacture peptides with very similar structures to hormones that regulate appetite, such as leptin and neuropeptide Y. They can also secrete short-chain fatty acids (SCFAs), which can activate enteric nerves.

Interestingly enough, obesity is associated with reduced bacterial species numbers and decreased genetic diversity of gut bacteria. Bacterial transfer experiments in mice have also shown that mice who are given fecal transplants from obese humans are more likely to gain weight than mice who are given fecal transplants from lean humans, even if food consumption doesn't change. One possible explanation is that certain bacteria can produce SCFAs from fibre, creating an increased amount of digestible fat and an increase in adiposity.

Thankfully, we can probably use this to our advantage. Mice who are fed probiotics ("good bacteria") are less likely to gain weight, regardless of whether they eat a high- or low-fat diet. Probiotic treatment may also improve glucose control in mice fed a high-fat diet. Probiotics appear to increase faecal secretion of SCFAs, such as butyrate. Butyrate also increases release of GLP-1, an incretin released from epithelial cells which can increase insulin release.

Effects of gut bacteria on other behaviours

As I mentioned earlier, the whole reason why we're looking at the effects of the microbiome is because it appears to have impacts on rats and their fear (or lack of) of cats. Some other studies involving germ free (GF) mice, which are specially raised to have no gut bacteria, have shown that these mice have a greater release of ACTH and corticosterone compared to controls. The stress response of GF mice is normalised once given a faecal transplant. Experiments with BALB/c mice (which are naturally more timid) and Swiss mice (which are naturally less timid) have also shown a link between gut bacteria and timid/anxious behaviour, as measured with a "step down test." In the "step down test," mice are put on a little step, and are timed to see how long it takes for the rat to step down and start exploring its surroundings.

Several possible explanations for the effects of gut bacteria on behaviour have been proposed. Gut bacteria can produce neurotransmitters such as serotonin, as well as neurotransmitter precursors such as tryptophan. They can also produce SCFAs which, as I've said before, have neuro-active properties. They may also be able to activate the vagus nerve directly, and in fact vagotomy can eliminate some of the behaviour-related changes induced by probiotics (which I'll mention in a bit). Gut bacteria can also modulate the immune system, and all of those cytokines may have effects on the CNS.

Just like with satiety and weight gain, probiotics can play a role in behaviour. Probiotic treatment with Lactobacillus rhamnosus has been found to decrease corticosterone levels and anxiety and depression-like behaviour in mice. There were also region-dependent alterations in GABA mRNA in the brain, which may explain the behavioural changes.

Possible role of gut bacteria in autism spectrum disorder (ASD)

Believe it or not, the role of the microbiome has also been investigated in patients with autism. Autism patients often have gastrointestinal symptoms, an altered gut microbiome, and alterations in SCFA production. In animals, high doses of SCFAs has been shown to produce "autistic-like" behaviour which can be reversed by probiotic treatment.

The main animal model for ASD is maternal immune activation (MIA), in which pregnant mice are injected with poly(I:C), which is structurally similar to viral dsRNA. Offspring have gut barrier defects and microbiota alterations, as well as a large elevation in 4-ethylphenylsulfate (4EPS). 4EPS is secreted by gut bacteria in these "ASD mice," and when injected into healthy mice, 4EPS seems to result in higher levels of anxiety. Treatment with the probiotic bacteria Bacteroides fragilis (BF) appeared to correct gut permeability problems and normalise some communicative behaviours, though social interaction didn't change. It is hypothesised that increased gut permeability, combined with increased 4EPS, may lead to increased 4EPS in the circulation and in the CNS, which in turn may lead to autistic behavioural traits. Obviously, however, this area of research is still in its infancy, and these experiments were only done on mice. Additionally, autism is thought to be a result of many factors, including genetics, and so it is unlikely that there is a simple solution for all cases of autism.