The Alzheimer’s gut-brain link: How butyrate could curb amyloid-β buildup and inflammation

A) Immunoblot profile of synthetic Aβ preparation containing monomers, dimers, trimers, tetramers and high molecular weight oligomers. B) IF staining of HuC/D, Tuj1 (green) and Aβ (red) in Ctrl and Aβ-treated pure enteric neurons isolated from WT rat. Scale bar, 20 μm. Credit: Molecular Psychiatry (2026). DOI: 10.1038/s41380-026-03522-6.

Alzheimer’s disease (AD) is a neurodegenerative disease that causes progressive memory loss and a significant decline in mental functions. Past studies have shown that people with AD exhibit a buildup of a protein called amyloid-β (Aβ), forming deposits known as amyloid plaques that disrupt communication between neurons.

The accumulation of Aβ in the brain can start during early stages of the disease, before patients start exhibiting severe symptoms. Interestingly, past findings showed that people diagnosed with AD often also experience digestive symptoms, from years before the first symptoms emerge.

Researchers at Nantes University in France have carried out a study investigating the possibility that Aβ accumulates both in the brain and in the gut of patients with AD, which can also damage connections that promote healthy digestion, contributing to the progression of the disease. Their findings, published in Molecular Psychiatry, support this hypothesis, while also identifying a gut molecule that reduced Aβ production and slowed down memory loss in a mouse model of AD.

“Besides the severely handicapping brain symptoms, AD patients display early gastrointestinal (GI) manifestations such as upper and lower GI dysmotility, in particular constipation,” wrote Rodrigue Brossaud, Thibauld Oullier and their colleagues.

“Although there is increasing evidence of Aβ accumulation in the gut, its pathogenic effects on enteric nervous system (ENS) connectivity and gut function as well as underlying pathophysiological mechanisms are poorly understood. Furthermore, studies have reported a gut to brain transmission of Aβ that causes memory deficits in mice.”

Aβ affects ENS connectivity and GI function in mouse and human models. Credit: Molecular Psychiatry (2026). DOI: 10.1038/s41380-026-03522-6

How butyrate could protect the gut and brain

In recent years, many research groups have tried to identify treatments that could prevent or reduce the buildup of Aβ when AD is still in its early stages. These treatments could significantly slow down the onset of the disease or reverse its progression before Aβ plaques cause irreversible damage to both the gut and brain.

Brossaud, Oullier and his colleagues have also been working toward this goal, by studying the molecular processes underpinning the production of Aβ. As part of their recent study, they first examined mice that naturally develop Alzheimer-like symptoms, referred to as SAMP8 mice.

They first measured Aβ levels in their gut, brain and blood, while also checking for the presence of enzymes that produce or remove the protein. The team also studied connections in the enteric nervous system (ENS), the network of nerves and neurons that controls digestion.

“We investigated the capacity of the short-fatty acid butyrate to restore Aβ-driven alteration of ENS connectivity and gut-brain functions in the SAMP8 mouse model of AD,” wrote the authors.

“We show that SAMP8 mice display a gut amyloid pathology, an alteration of ENS connectivity and gut defects prior to memory decline. BACE1, an Aβ-producing enzyme, expression and activity are increased, whereas neprilysin, an Aβ-degrading enzyme, is decreased in the gut of SAMP8 mice, indicating a rise in Amyloid Precursor Protein (APP) holoprotein processing and a reduction of Aβ clearance which promote an amyloidosis.”

Brossaud, Oullier and his colleagues also explored the effects of Aβ on gut tissue extracted from humans and stem-cell-derived organoids (i.e., organs grown in the lab). Finally, they investigated the effects of butyrate, a small molecule produced by gut bacteria while digesting fiber, on the gut and brain function of the SAMP8 mice.

“In primary ENS cultures, Aβ causes a degradation of synaptic-associated proteins EphB2 and synaptophysin, leading to an alteration of ENS connectivity,” wrote the authors.

“In wild-type mice, intra-colon delivery of Aβ alters ENS connectivity and causes subsequent GI symptoms, recapitulating the phenotype of the SAMP8 mouse model of aging and AD. Moreover, Aβ impairs ENS connectivity in human induced pluripotent stem cell (iPSC)-derived intestinal organoids and explant cultures of the human colon, indicating that Aβ causes ENS lesions in models of the human gut.”

When the researchers treated the mice with butyrate, they found that it significantly reduced the production of Aβ, protecting nerve connections in the gut and lowering inflammation. Notably, mice who were administered butyrate also did not present the memory deficits observed in those who did not receive it.

“Butyrate reduces Aβ secretion and preserves enteric neuronal connectivity in vitro and in vivo, and blocks Aβ accumulation in the gut, brain and plasma in SAMP8 mice,” wrote the authors. “In addition, butyrate ameliorates neuroinflammation and prevents gut dysfunction and memory deficit.”

Toward more effective treatments for Alzheimer’s disease

The findings of this recent study highlight the key role of the gut in the emergence and progression of memory deficits in a mouse model of AD. While the results need to be validated in humans before they can be applied in clinical settings, they hint at a possible therapeutic target that could slow down or even prevent the onset of AD.

“Collectively, these findings suggest that Aβ promotes gut symptoms through alteration of ENS connectivity and butyrate counteracts these impairments with an amelioration of neuroinflammation and memory function in the AD model,” wrote Brossaud, Oullier and their colleagues.

The efforts of this research team could soon inspire additional studies exploring the molecular mechanisms underpinning the early digestive symptoms associated with AD. Moreover, they could prompt other molecular and medical scientists to assess the potential of butyrate for preventing Aβ accumulation and slowing down AD-associated cognitive decline.