Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model

Abstract

Emerging evidence has demonstrated that intestinal homeostasis and the microbiome play essential roles in neurological diseases, such as Parkinson's disease. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Currently, there is no effective treatment. Most patients die within 3–5 years due to respiratory paralysis. Although the death of motor neurons is a hallmark of ALS, other organs may also contribute to the disease progression. We examined the gut of an ALS mouse model, G93A, which expresses mutant superoxide dismutase (SOD1G93A), and discovered a damaged tight junction structure and increased permeability with a significant reduction in the expression levels of tight junction protein ZO-1 and the adherens junction protein E-cadherin. Furthermore, our data demonstrated increased numbers of abnormal Paneth cells in the intestine of G93A mice. Paneth cells are specialized intestinal epithelial cells that can sense microbes and secrete antimicrobial peptides, thus playing key roles in host innate immune responses and shaping the gut microbiome. A decreased level of the antimicrobial peptides defensin 5 alpha was indeed found in the ALS intestine. These changes were associated with a shifted profile of the intestinal microbiome, including reduced levels of Butyrivibrio Fibrisolvens, Escherichia coli, and Fermicus, in G93A mice. The relative abundance of bacteria was shifted in G93A mice compared to wild-type mice. Principal coordinate analysis indicated a difference in fecal microbial communities between ALS and wild-type mice. Taken together, our study suggests a potential novel role of the intestinal epithelium and microbiome in the progression of ALS.

Salmonella enteritidis Effector AvrA Stabilizes Intestinal Tight Junctions via the JNK Pathway

“…For JNK and p-JNK, it is known two bands will be detected: 46 and 54 kDa. All bands detected on blots were consistent with production information from the companies and other scientific reports which studied particular protein with antibodies ZO-1 (20,(51)(52)(53), E-Cadherin (20,39,52,53), Claudin-1 (20,53,54), 54), Occludin (52), Villin (45,55,56), JNK, p-JNK (40, 53, 57, 58), and ␤-actin (59). AvrA-e forward CAGGCCACAAAAGAAAAC AvrA-e reverse ATAACAGCCGCATCAAAC AvrA-r forward CCCAAGCTTATCTACCTCCCGGTGTCA AvrA-r reverse CGGGATCCTTGCGGGCGTCTATCTGT AvrA-cm forward…”

The bowel and beyond: the enteric nervous system in neurological disorders

“…In contrast to Prp-TDP43 Ala315Thr mice, however, the defect consists of abnormal tight junctions between enterocytes and increased mucosal permeability 135 . The SOD1 Gly93Ala mucosa, moreover, has increased numbers of Paneth cells, but decreased expression of the antibacterial peptide defensin-5, which Paneth cells produce.…”

Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression

“…Indeed, it has been proposed that gut microbes are important in the progression of some other neurological diseases [103,104]. In the SOD 1 mouse model of ALS, abnormal intestinal permeability associated with increased inflammatory cytokines in the gut and an altered gut microbiome have been observed [105]. While gut microbes have not been studied in ALS patients, it is plausible that the dietary changes that occur in ALS [13,76] could contribute to adaptations in the gut microbiome.…”