The Gut-Brain Axis Takes Center Stage

A rapid expansion of new discoveries and knowledge lays the foundation for a new era in medicine

We’ve known about the gut-brain axis for decades but there has recently been an unprecedented jump in our knowledge base that has transformed our expectations for its preeminence. In this edition of Ground Truths I’m going to review some of the recent advances that are shaping the field, particularly for a new era of gut hormones in medicine. But that’s only part of the expansion!

Background

To start with I’m going to simplify things because if I tried to diagram all the ways the gut and brain interact bidirectionally, it would be hard to follow. So here is my reductionist representation.

As seen above, there are 4 principal interactions by which the gut influences the brain. There are 2 types of neural pathways, the “second brain” referring to the enteric (gut) nervous system from the cells that line the intestine and communicate to the vagus nerve to the brain (and in the opposite direction, too). There are also connections via the sympathetic, parasympathetic nervous system (autonomic nervous system, ANS) branches and spinal cord innervation to the gut primarily through the ANS.

Cells in the gut produce hormones (enteroendocrine cells) such as glucagon-like peptide (GLP-1), gastric inhibitory peptide (GIP), peptide YY, secretin, gherlin, gastrin, and many others. Some of these regulate pancreatic hormones such as insulin, glucagon and amylin, which can be considered as gut hormones but derived from pancreatic cells rather than intestinal lining cells. The hormonal interaction between gut and brain also goes through the hypothalamus-pituitary-adrenal (HPA) axis.

The abundant and diverse bacteria in the gut microbiome of tens of trillion of cells of more than 3,000 species. These gut bacteria and their metabolites have an outsized impact by producing or stimulating different neurotransmitters (5HT, GABA) and metabolites (e.g. short chain fatty acids, SCFAs) that communicate with the brain and the immune system. For example, see my previous Ground Truths on how a gut bacteria and its metabolites can drive sugar cravings.

The interaction with the immune system is critical to maintain integrity of the gut lining (avoiding “leaky gut syndrome”) and the blood-brain-barrier.

The graphic below does more justice to the complexity of the gut-brain axis compared to what I’ve oversimplified.

New Discoveries and Advances

Inflamed Gut T cells—> Inflamed Brain

The precise way by which the gut can induce inflammation in the brain has remained unclear. In the journal Nature this week it was shown that inflamed gut-derived CD4+ T cells can infiltrate the brain, leading to neuroinflammation and neurological damage in the experimental model. The graphic below shows the intermediate steps and mediators in this process which, in part, involves molecular mimicry, that is to say bacteria derived proteins (antigens) looking like host derived proteins, inciting an immune response.

This was the second of 2 recent discoveries centered around gut-derived immune cells that get into the brain. Newly identified specialized CD4+ T cells from the gut and white adipose tissue establish residence in the brain’s subfornical organ and regulate feeding behavior.

A Bacterial Protein Blocks Pathogenic Amyloid Formation

Remember the bacterium that Barry Marshall discovered that caused gastric ulcers and was awarded (with Robin Warren) by a Nobel Prize 2005? It was Helicobacter pylori. Well it turns out the H. pylori can do good things too! As in blocking the formation of amyloid protein formation. This week in Science Advances it was demonstrated that H. pylori releases the protein CagA (cytotoxin-associated gene A) which potently inhibits pathogenic amyloid assemblies, via blocking multiple steps (primary nucleation, secondary nucleation, and elongation) for formation in Alzheimer’s disease, Parkinson’s disease and type 2 diabetes. As the authors aptly point out: “Bacteria, often underestimated due to their microscopic scale, offer a vast reservoir of ingenious strategies spanning a myriad of scientific and technological domains” such as the CRISPR genome editing story.

While it remains to be seen whether this discovery in vitro can be translated to a therapeutic, i.e. preventive strategy vs. misfolded proteins, it is certainly worthy of further assessment.

It is notable that this is only one of many recent discoveries for gut microbiome bacteria unexpectedly producing or affecting key biological processes. Like producing sex hormones or playing a critical role in glucose regulation, or metabolites influencing our response to immune checkpoint inhibitors for cancer treatment.

A Plethora of New Gut Hormones

This week there were multiple publications, simultaneous with presentations at the American Diabetes Association annual meeting. Several new gut hormone clinical trials, beyond the ones that are widely used—semaglutide (Ozempic) and tirzepatide (Zepbound, Mounjaro), were unveiled.

Amycretin

There were the randomized trials of subcutaneous (injectable) and oral Amycretin, a molecule that combines a GLP-1 domain with another gut hormone, amylin, as receptor agonists mimicking the natural hormones of both. Below are the results with the pill form for 12 weeks vs placebo for body weight loss. (ETD-estimated treatment difference).

Here is the coverage of the Amycretin results at WSJ

Ecnoglutide

There was a randomized trial of ecnoglutide, a novel GLP-1 receptor, conducted in 36 medical centers in China, with very good results for weight loss as seen below, similar to Amycretin.

CagriSema

There were also 2 Phase 3 triasl reports of the combination of semaglutide and cagrilintide for obesity (shown below) and for obesity plus diabetes.

Beyond these, results for Maritide, a combined GLP-1 agonist and GIP antagonist injectable. given monthly were presented.

Orforglipron

Add to that Orforglipron, a GLP-1 small molecule (non-peptide) pill, which had a favorable effect on hemoglobin A1c in a 40 week trial of Type 2 diabetes. When the preliminary results were announced in April, it was accompanied by this cover of TIME magazine and this article. That may have seemed a stretch for a trial with its primary endpoint of HbA1c reduction. The weight loss achieved (the trial acronym was ACHIEVE) was deemed similar to that of semaglutide, but that isn’t clear from the data below and the trial was not head-to-head. There is an oral semaglutide (Rybelsus) that is approved for Type 2 diabetes and being assessed for obesity. And for Alzheimer’s disease, as discussed below.

Primary endpoint of ACHIEVE

Secondary endpoint of ACHIEVE for weight loss

There were many other new GLP-1 family of drugs and combinations presented without publications in NEJM or The Lancet or are in development. These include the triple receptor drug retatrutide (targets GLP-1, GIP and glucagon), cotadutide, mazdutide, and servodutide (all 3 are combined GLP-1 and glucagon target), and many others.

As I hope you can see, the number of gut hormone drugs has exploded, no less their potential combinations along with the move to oral, small molecule agents. .Through randomized trials, their broad impact has been unequivocally proven for diabetes, obesity, and for treating related conditions of heart failure (with preserved ejection fraction), kidney disease, liver disease, sleep apnea, along with unexpected suppression of addiction to alcohol, cigarette smoking, nail biting and gambling. Add a surprising impact that we’re starting to see for autoimmune diseases.

Even before there is weight loss with these drugs, there is evidence from experimental models of reduced systemic (body-wide) and brain inflammation. What is surprising is that drugs like semaglutide have little direct penetrance to the brain, but exert their effect chiefly through the gut-brain axis. New molecules in this class will have enhanced brain penetrance.

Will They Work For Alzheimer’s Disease?

Meanwhile the most important extension of the benefits of these drugs is for Alzheimer’s disease.

Previously, a Phase 2 randomized trial of an older, less potent GLP-1 drug, Liraglutide in 200 participants, was presented at the 2024 Alzheimer’s Association annual conference but has not yet been published. In participants with mild Alzheimer’s disease after 1 year of treatment there was a reported 18% less cognitive decline and 50% reduced brain shrinkage compared to placebo.

The pending EVOKE and EVOKE Plus trials of daily oral semaglutide participants aged 55–85 years with mild cognitive impairment or mild dementia due to Alzheimer’s disease with confirmed amyloid abnormalities by PET scan or cerebrospinal fluid biomarkers The only difference in the 2 trials is with respect to entry criteria with EVOKE Plus that allows for small vessel pathology. Both trials (study design below), each with ~1840 participants, are expected to be completed (104-week treatment, and there is a 52-week extension) this September with announcement of the results soon thereafter.

I hope you can detect a major weakness in these trials which will reduce the likelihood of their success. The treatment is too late. The participants, with cognitive impairment or dementia are quite far along in the process of brain inflammation, as I recently reviewed. If the trials show efficacy that I’m not expecting (the primary endpoint is the same as used for the approved beta-amyloid monoclonal antibody drugs, change in Clinical Dementia Rating – Sum of Boxes score) that would be great. The right trial would be in people without any cognitive impairment but at high-risk as defined by family history, high polygenic risk score, APOE4 carrier or homozygotes, high levels of p-Tau217 and other blood biomarkers. The other concern about the EVOKE trials is that oral semaglutide is relatively weak compared with tirzepatide (from a head-to-head randomized trial of the injectables), retatrutide, and other molecules, no less the issue of direct brain accessibility.

Here’s a list of naturally occurring gut-derived hormones that can be mimicked with receptor agonists or antagonists, along or in combination

Concluding Remarks

The extensive work reviewed here has brought the gut-brain axis to the spotlight, just the beginning of a new era of medicine. Even though about 12% of American adults are already taking GLP-1 drugs, that portends a much bigger story ahead. As more evidence mounts for their potent anti-inflammatory effect, especially in the brain, and more pills emerge that reduce the cost, there will be much higher uptake. While it’s not exactly an epiphany or eureka moment, the realization to keep in mind is that the gut talks to the brain and the immune system. We have so many ways now and more in the future to modulate that. In context, we have not had potent ani-inflammatory drugs that exploit the gut-brain axis in the past. Perhaps the old saying, “the way to a man’s heart is through his stomach” will be revised to “ the way to a human’s brain and immune system is through the gut.”

Recall from my prior post on organ clocks that it is our brain and immune system clocks that are most predictive of healthspan and survival (Figure below). If we’re going to extend our healthspan, it will require more attention to preserving the health and slow the aging process for these 2 organs (one is a system).

Our enhanced understanding of the gut-brain axis, and its modulation via GLP-1 drugs, manipulating the gut microbiome and its metabolites (reviewed here), or through neural pathways, holds exceptional promise for a new era of medicine largely unforeseen—that is centered on our gut!

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For a deeper look into the topic, I wrote about the gut-brain axis and a whole chapter on the GLP-1 drugs (which includes the concerns and downsides of these drugs) in SUPER AGERS. Thanks to many of you subscribers who helped put it on the NYT bestseller list 3 weeks in a row. And for the positive feedback on the audio version that I narrated. It took a week to do the recording, but it seems well worth it from your comments.

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