gut feeling'
Opioids can control gut immune responses and thereby reduce colonic inflammation, indicating their potential in the treatment of immune diseases


Date:
September 30, 2021
Source:
Tokyo University of Science
Summary:
Opioid receptors play key roles in regulating our senses and
emotions.

Recently, their discovery outside the nervous system raised several
questions about the effects of opioids on the immune system. Now,
researchers have shown that KNT-127 -- a drug that targets delta
opioid receptors -- can reduce pro-inflammatory signals in the
colon. Their research highlights the immunomodulatory properties of
opioids and indicates their therapeutic potential in inflammatory
bowel disease and other related disorders.



FULL STORY ========================================================================== Opioids are a class of substances that control sensations such as pain
and emotions in animals. While plant-derived opioid narcotics such
as morphine are the most well-recognized, other opioid molecules like endorphins can also be synthesized by the body or artificially developed
in laboratories. Opioids exert their actions by binding to opioid
receptors present on the surface of cells. While opioid receptors were
earlier thought to be limited to the central nervous system (CNS), their
recent discovery in other parts of the body has prompted questions about
their effects in other parts of the body, including the immune system.


==========================================================================
In a recent study published in Frontiers in Immunology, Prof. Chiharu Nishiyama, Kazuki Nagata, and Ayumi Okuzumi from the Tokyo University of Science and Prof. Hiroshi Nagase from the University of Tsukuba attempted
to understand the effects of opioids on the immune system. They tested the effects of KNT-127 -- an artificially synthesized opioid that activates
delta opioid receptors -- on immune responses in live animal and cell
culture experiments.

When mice with inflammatory bowel disease (IBD) were treated with KNT-127,
they showed a reduction in the severity of colitis -- a form of colon inflammation - - indicated by lower weight loss and colon atrophy and
improved disease activity scores. Similar results were also obtained in
a recovery model, confirming the beneficial effects of KNT-127 against
colonic inflammation.

Although these results were promising, an important caveat still loomed.

"Before proceeding with additional experiments, we had to rule out the
role of CNS opioid receptors in the anti-inflammatory effects of KNT-127,"
says Prof.

Nishiyama, the lead researcher on the study. To address this, the
researchers performed similar experiments with YNT-2715, a peripheral
KNT-127 that cannot cross over from the blood to the brain. The results
were similar to those observed with KNT-127, confirming that its anti-inflammatory effects were indeed CNS-independent.

Encouraged by this, the group examined other immune-related effects
of KNT-127 treatment in the colitis model. They found that during
disease progression, the opioid reduced the serum levels of IL-6, a pro-inflammatory factor, while also decreasing the number of macrophages
in the mesenteric lymph nodes (MLNs).

Interestingly, they also observed an increase in the number of regulatory
T cells (Tregs) in MLNs. Together, their results showed that KNT-127
suppresses the inflammation caused by macrophages during disease
progression and enhances the anti-inflammatory response due to Tregs
during recovery.

Finally, to understand the direct effects of KNT-127 on immune cells,
the researchers performed in vitro experiments in which they treated macrophages derived from bone marrow or T cells from spleen with the
drug. The results were consistent with those from animal experiments,
revealing increased secretion of the pro-inflammatory signals as well
as enhanced development of Tregs in response to KNT-127 treatment.

Altogether, the findings demonstrated that KNT-127 can directly act on
immune cells and reduce the severity of inflammation, making it a good candidate for the treatment of IBD. "Several people around the world
suffer from diseases related to colon inflammation, and so far, optimal treatment strategies are lacking. Our findings show that KNT-127 and other activators of opioid receptors could be promising therapeutic options for
such diseases," comments Prof. Nagase, the chief drug developer behind the synthetic opioid, while also cautioning of the road ahead. "Of course,
before these drugs are used clinically, additional experiments will be
required to elucidate how they exert their immunomodulatory functions
and what their effects on other immune diseases are," he adds.

Nevertheless, Prof. Nishiyama and her team are confident that their
study represents an important milestone, not only towards the treatment
of IBD but also towards our understanding of the "brain-gut axis"
-- the interrelationship between brain and gut function -- which has
received increasing attention in recent years. "Today, we know that
poor mental health has physical manifestations. For example, stress
worsens inflammation in the gut, which in turn affects the health of
the brain. Our results on the immune-related effects of opioids, which
commonly act on the brain, is a step toward unraveling the biological mechanisms that govern the reciprocative relationship of gut health and
the immune system with the CNS," mentions Prof. Nishiyama, excited about
what the future holds.

========================================================================== Story Source: Materials provided by Tokyo_University_of_Science. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Kazuki Nagata, Hiroshi Nagase, Ayumi Okuzumi, Chiharu
Nishiyama. Delta
Opioid Receptor Agonists Ameliorate Colonic Inflammation by
Modulating Immune Responses. Frontiers in Immunology, 2021; 12 DOI:
10.3389/ fimmu.2021.730706 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210930171011.htm

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