Transplanting Microbiota From Alzheimer’s Patients Leads to Changes in Brain Function

Post by Anastasia Sares 

The takeaway

The need to understand Alzheimer’s disease is becoming more urgent. This work establishes a causal role for changes to the gut microbiome in the development of Alzheimer’s.

What's the science?

The microbes living in our intestinal tract can produce compounds that either affect our body directly or are important precursors for the body’s functions. Studies have noted a correlation between Alzheimer’s disease and gut health, but this correlation is not enough to say with confidence that poor gut health actually contributes to Alzheimer’s disease. For that, a real experiment is needed. This week in Brain, Grabrucker, Marizzoni, Silajžić and colleagues transplanted fecal samples from people with and without Alzheimer’s into rats, which led to changes in their brain development and cognitive function.

How did they do it?

In order to show that gut bacterial composition caused changes in brain health, the authors took samples of human fecal matter from older adults with and without Alzheimer’s-type dementia and transplanted it into rats with a depleted microbiome (the depleted microbiome was achieved by giving the rats a cocktail of antibiotics before the fecal transplant). In essence, this procedure replaced a significant amount of the rats’ original gut bacteria with that of the human participants. In this way, rats were randomly subjected to “healthy” or “unhealthy” gut bacteria, and the authors could then measure the effects on the brain.

The rats were examined for changes in brain structure and function. Measures of brain structure included how many new neurons were generated in the hippocampus and the branching patterns of these new neurons. Measures of brain function included the ability to complete a maze and the ability to recognize and explore novel objects.

What did they find?

The human participants with Alzheimer’s disease had signs of inflammation in blood and fecal samples. Their microbiomes were also abnormal, with an increase in bacterial species that are thought to cause inflammation and pathology (Bacteriodetes and Desulfovibrio) and a decrease in species that are thought to produce beneficial compounds (Fimicutes, Verruocomicrobiota, Clostridium sensu stricto 1, and Coprococcus). Several of these microbial differences were observed in the rats who received the fecal transplants as well, along with alterations in the colon for the rats who received transplants from humans with Alzheimer’s (more fecal water content, fewer goblet cells, and a reduction in colon length). Not only that, but the rats with the Alzheimer’s microbiota performed worse on cognitive tests, like distinguishing between new and familiar objects or remembering where to go in a water maze. These rats also had fewer new neurons in their hippocampi at the end of the 50-day period, and these neurons had less complex branching structures.

What's the impact?

This work supports the idea of a causal role of gut health in the development of Alzheimer’s disease, which may lead to interventions that focus on gut health as a protective factor for the disease. This work also highlights how animal research can bring high-value insights, by uncovering new avenues for therapeutic approaches to devastating diseases like Alzheimer’s disease.

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Does the Gut-Brain Axis Play a Role In the Emergence of Psychiatric Disorders?

Post by Lani Cupo

The takeaway

The gut-brain axis undergoes many changes in adolescence, and these can, in turn, impact the nervous system. It is possible that environmental changes impacting the gut may influence the emergence of psychiatric disorders during adolescence, but more research is required on the topic.

What's the science?

Over the past two decades, the gut-brain axis has increasingly been investigated as important to mental, psychiatric, and neurological health. Most research, however, has focused on the first years of life or old age, with few studies investigating the period of adolescence where both the gut microbiome and brain undergo many changes and psychiatric disorders commonly emerge. This week in Biological Psychiatry, McVey and colleagues sought to synthesize the current knowledge base around the impact of the environment on the gut-brain axis and its role in the emergence of psychiatric disorders during adolescence.

What did they review?

The authors performed a review of the literature on adolescent development and plasticity — or changeability — of the gut microbiome and the brain in adolescence in both human and nonhuman animal studies. The gut-brain axis comprises several component parts investigated in this review. The gut microbiome includes the microorganisms that live in the intestines. The enteric nervous system (ENS) comprises neural and glial cells that directly control the digestive tract (from the esophagus to the anus). While it operates largely independently of the central nervous system, the vagal nerves carry signals to and from the brain to the ENS. Finally, the review examined brain development during adolescence in the context of psychiatric development and atypicality.

What did they find?

First, examining the gut microbiome during adolescence, the authors found that the diversity and stability of microorganisms in the gut were altered, with important sex differences. Specifically, they found that during puberty male gut microbiomes became less diverse, whereas female microbiomes remained stable. There was evidence of bidirectional influence of gut microbiome and sex hormones, meaning the microbiome influences sex hormones and sex hormones influence the microbiome. An altered diet during adolescence is known to impact the gut microbiome as well, drawing attention to the impact of the adolescent environment.

While the authors found there was a lack of studies examining the ENS during adolescence, there was some evidence pointing to changes to the neurons and glia of the ENS during adolescence. For example, in the duodenum, the ratio of neurons to glia was reduced, but in the colon, it was increased. Regarding the vagal nerve, there is some association between changes in vagal tone, measured via heart-rate variability (changes in the interval between heartbeats), and poorer psychological and physical outcomes. Specifically low (worse) vagal tone in adolescence has been associated with later life cardiovascular disease risk, adolescent asthma, emotional dysregulation in adolescents with autism spectrum disorders, and clinical depression.

Adolescence is a period defined by many brain changes, including in the frontal lobes, which continue to develop well after puberty. Two major areas of brain development include synaptic density (synapses are pruned through childhood and adolescence) and myelination (which increases during early life and adolescence). Both of these processes result in greater efficiency of brain networks from childhood to early adolescence. The authors draw attention to the psychiatric disorders that emerge in adolescence, including major depressive disorder, anxiety disorders, eating disorders, and alcohol use disorders, for all of which there is evidence pointing to the association of alterations in the gut microbiome.

The authors also summarize evidence from nonhuman animal studies linking alterations in communication between the microbiome, gut, and brain and clinical dysfunction. The work they highlight indicates the role of the gut microbiome in modulating the HPA axis activity in response to acute stress, as well as the possibility of moderating the gut microbiome, gene expression in the brain, and behaviors with diet.

What's the impact?

The results of this review first draw attention to the potential role the gut microbiome may play in moderating the emergence of psychiatric disorders in adolescence. Importantly, however, this review identifies a lack of studies that comprehensively investigate this topic, and therefore more research is needed to understand how the gut microbiome influences the development of psychiatric disorders.

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Glioma Tumors Hijack Healthy Mechanisms of Neuroplasticity in Order to Grow

Post by Trisha Vaidyanathan 

The takeaway

Healthy neurons can form synapses with glioma tumor cells. These neuron-to-glioma synapses undergo a form of synaptic plasticity similar to healthy neurons, that is dependent on the release of brain-derived neurotrophic factor (BDNF), allowing tumor cells to proliferate and tumors to grow. 

What's the science?

Gliomas are the most common form of brain cancer in children and adults and glioma tumor progression is highly regulated by the activity of surrounding neurons. However, it is not known precisely how neuronal activity regulates tumor progression. Neurons and glioma cells can interact through the secretion of signals and through direct neuron-to-glioma synapses. One hypothesis is that neuron-to-glioma synapses are strengthened through a form of neuroplasticity in which glioma cells increase their sensitivity to the excitatory neurotransmitter glutamate by recruiting more AMPA glutamate receptors to the membrane. This form of neuroplasticity can occur between two healthy neurons via the signaling molecule BDNF and the BDNF receptor, TrkB. This week in Nature, Taylor and colleagues used patient-derived glioma cells and mouse models to demonstrate that gliomas recruit BDNF signaling to strengthen the neuron-glioma connection and drive tumor proliferation and progression.

How did they do it?

First, the authors transplanted patient-derived glioma cells into mice, a process called xenografting. This allowed the authors to manipulate each component of the BDNF signaling pathway and assess the effect on tumor proliferation and animal survival. In a series of experiments, the authors (1) removed neuronal release of BDNF with a mutant mouse model, (2) used CRISPR to remove the BDNF receptor, TrkB, from the glioma cells, (3) administered a potential therapeutic drug (entrectinib) that blocks the family of Trk BDNF receptors, and (4) used pharmacology to block AMPA receptors.

Second, the authors directly tested whether BDNF drives plasticity in glioma cells by using patch-clamp electrophysiology to measure the glioma cell response to glutamate with or without BDNF and with or without the BDNF receptor.

Third, to assess whether glioma cell plasticity led to increased AMPA receptor signaling, the authors created cultures of the glioma cells and used a sophisticated method called cell-surface biotinylation to quantity the amount of AMPA receptor protein on the glioma membrane with and without BDNF exposure. Additionally, the authors used the pH-sensitive sensor, pHluorin, to visualize AMPA receptors moving to the membrane in real time after BDNF exposure.

Fourth, the authors assessed how well the glioma cells with or without the BDNF receptor were able to associate with the surrounding neuronal network by quantifying the number of neuron-to-glioma synapses with immuno-electron microscopy.

Lastly, the authors sought to validate their hypothesis that increased synapse strength led to higher tumor growth by stimulating glioma cells to varying degrees with optogenetics and measuring the resulting tumor growth.  

What did they find?

First, the authors found that disrupting any part of the BDNF neuroplasticity pathway – either removing neuronal release of BDNF, removing or blocking the BDNF receptor in glioma cells, or blocking AMPA receptors – increased the survival of the xenografted mice and reduced tumor proliferation. This demonstrated that BDNF signaling is a critical component of how neuronal activity promotes tumor growth.

Second, the authors demonstrated that BDNF was sufficient to increase the glioma cell response to a puff of glutamate. Further, BDNF could not elicit this response if the glioma cell lacked the BDNF receptor TrkB confirming the importance of the BDNF-TrkB signaling pathway for glioma plasticity.

Third, the authors found increased AMPA receptor protein at the membrane of glioma cell cultures that were exposed to BDNF. They also were able to visualize AMPA receptors moving to the membrane after BDNF exposure in real-time with their pH-sensitive sensor. This confirmed that BDNF signaling in glioma cells drives neuroplasticity by increasing the number of AMPA receptors at the membrane, the same mechanism used by healthy neurons.

Fourth, immuno-electron microscopy revealed that glioma xenografts that lacked the BDNF receptor TrkB had fewer neuron-to-glioma synapses than xenografts that had TrkB expression. These data revealed that BDNF-TrkB not only strengthens the synapse but also promotes the formation of synapses.

Lastly, the authors clearly demonstrated the importance of neuron-to-glioma synapse plasticity for tumor growth by showing that robust optogenetic stimulation to depolarize glioma cells resulted in more tumor proliferation than mild optogenetic depolarization.

What's the impact?

The finding that glioma tumor cells hijack a well-established method of neuroplasticity to strengthen their integration into neuronal networks and proliferate is critical to our understanding of how brain cancer both influences and is influenced by, the surrounding healthy tissue. This work will provide several novel targets that could result in effective treatment for brain cancer, some of which the authors have already started to explore in this paper. 

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