1: Identification of trypsin-degrading commensals in the large intestine.
Science of the Month - January 2023
Nature.
2022;609(7927):582-+. [Article]
Li YX, Watanabe E, Kawashima Y, Plichta DR, Wang ZJ, Ujike M, Ang QY, Wu RR, Furuichi M, Takeshita K, Yoshida K, Nishiyama K, Kearney SM, Suda W, Hattori M, Sasajima S, Matsunaga T, Zhang XX, Watanabe K, Fujishiro J, Norman JM, Olle B, Matsuyama S, Namkoong H, Uwamino Y, Ishii M, Fukunaga K, Hasegawa N, Ohara O, Xavier RJ, Atarashi K, Honda K.
In this study, we performed a comprehensive proteomic analysis of host proteins in mouse intestinal contents and found that the intestinal bacterium *Paraprevotella clara* (*P. clara*), present in the large intestine, promotes the degradation of trypsin in the gut. Since trypsin degrades IgA antibodies, which are essential for infection defense, we found that *P. clara*'s promotion of trypsin degradation maintains luminal IgA levels, leading to the elimination of orally ingested pathogens. Furthermore, as trypsin is also involved in promoting coronavirus infection, it was revealed that mice with *P. clara* in their intestines show resistance to mouse coronavirus (MHV). In fact, a metagenomic analysis of stool samples from COVID-19 patients, collected with the support of the COVID-19 Keio Donner Project, showed that individuals with a higher abundance of *P. clara* genes involved in trypsin degradation did not require oxygen inhalation and had milder diarrhea symptoms. From these findings, we have clarified that by promoting trypsin degradation in the gut, *P. clara* helps defend against infection by pathogens such as bacteria and viruses.
(Kenya Honda, Department of Microbiology and Immunology, Class of 1973)
2: Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery.
Science Advances.
2022 Sep 23;8(38):eabq0866. doi: 10.1126
Ken Hiratsuka, Tomoya Miyoshi, Katharina T Kroll, Navin R Gupta, M Todd Valerius, Thomas Ferrante, Michifumi Yamashita, Jennifer A Lewis, Ryuji Morizane
Autosomal recessive polycystic kidney disease (ARPKD) is a genetic disorder caused by mutations in the *PKHD1* gene, leading to kidney cyst formation, decreased renal function from birth, and progression to end-stage renal failure. It has been difficult to obtain a phenotype for this disease in animal models, and there have been no approved therapeutic drugs. In this study, we created an ARPKD disease model by culturing kidney organoids—derived from human disease iPS cells and *PKHD1*-mutated stem cells created with CRISPR gene editing—under fluid flow on a chip fabricated with a 3D bioprinter (Organoid-on-a-chip). Through this, we elucidated the mechanism by which mechanical stress from urine flow causes tubular dilation in segments distal to the renal distal tubule. We also demonstrated that RAC1 and FOS, molecules involved in mechanosensing, could be novel therapeutic targets, and that drugs targeting them—which are FDA-approved for other diseases or have been used in clinical research—have a cyst-reducing effect (Figure). The kidney Organoid-on-a-chip model can reproduce the in vivo microenvironment, serving as a novel platform for elucidating disease pathophysiology and discovering new therapeutic targets.
(Ken Hiratsuka, Department of Nephrology, Endocrinology and Metabolism, Class of 1987)
3: Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes.
Nat Commun.
2022. doi: 10.1038/s41467-022-33605-1.
Shin-Ichi Ikeda, Toshihide Kurihara, Xiaoyan Jiang, Yukihiro Miwa, Deokho Lee, Naho Serizawa, Heonuk Jeong, Kiwako Mori, Yusaku Katada, Hiromitsu Kunimi, Nobuhiro Ozawa, Chiho Shoda, Mari Ibuki, Kazuno Negishi, Hidemasa Torii, Kazuo Tsubota
The essence of the pathology of myopia is the elongation of the eye's anteroposterior axis (axial length). It is becoming clear that the physical stress on the posterior part of the eyeball due to this morphological change is related to visual impairment, and there has been a demand for elucidating the mechanism of pathological axial elongation associated with myopia and creating effective and safe intervention methods. In this study, we revealed that in myopic eyes, endoplasmic reticulum (ER) stress occurs in the sclera, which maintains the shape of the eyeball. We found that suppressing scleral ER stress by administering chemical chaperones such as phenylbutyrate inhibited pathological axial elongation, without affecting the physiological axial elongation of the eyeball that occurs with growth. It was also clarified that inducing ER stress in the sclera can induce myopia. Furthermore, we revealed that among the ER stress response pathways, both the PERK and ATF6 pathways control axial elongation through the regulation of scleral collagen expression. This finding not only clarifies the mechanism of pathological axial elongation but also indicates that intervention in scleral ER stress can effectively and safely inhibit myopia progression, which is expected to have a significant impact on the development of drugs to control myopia.
(Toshihide Kurihara, Department of Ophthalmology, Class of 1980)
Other Published Papers
1: A combined stem-cell-gene therapy strategy for ALS.
2: Transplantation of neural progenitor cells into the human CNS.
3: Neuroendocrine neoplasms of the lung and gastrointestinal system: convergent biology and a path to better therapies.
Nat Rev Clin Oncol.
2022 Oct 28. doi: 10.1038/s41571-022-00696-0.
Kenta Kawasaki, Natasha Rekhtman, Álvaro Quintanal-Villalonga & Charles M. Rudin
4: Longitudinal monitoring of circulating immune cell phenotypes in large vessel vasculitis.
5: AJM300 (carotegrast methyl), an oral antagonist of alpha 4-integrin, as induction therapy for patients with moderately active ulcerative colitis: a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.
Lancet Gastroenterology & Hepatology.
Matsuoka K, Watanabe M, Ohmori T, Nakajima K, Ishida T, Ishiguro Y, Kanke K, Kobayashi K, Hirai F, Watanabe K, Mizusawa H, Kishida S, Miura Y, Ohta A, Kajioka T, Hibi T.