Herbs And Phytochemicals: Antioxidant Rosmarinic Acid From The Herb Rosemary Alleviates Intestinal Inflammatory Damage In IBD By Regulating Gut Microbiota

Herbs And Phytochemicals: Inflammatory Bowel Disease (IBD) is a debilitating gastrointestinal disorder characterized by chronic inflammation, affecting millions of people worldwide. Despite extensive research, the exact cause of IBD remains elusive. It is now widely accepted that the interplay between genetic, immunological, and environmental factors is at the heart of this heterogeneous disease. Recent studies have shed light on the pivotal role of the gut microbiota in triggering and exacerbating chronic inflammation within the intestinal tract.


                                                     Rosemary
 
Furthermore, IBD can disrupt the normal smooth muscle contractions of the intestine and contribute to a variety of health issues.
 
One of the key components in maintaining gut health is the intestinal flora, a complex ecosystem of microorganisms that reside in our gastrointestinal tract. This microbial community, consisting of up to 100 trillion microorganisms from 1,800 different genera, plays a vital role in maintaining the host's immune system and ensuring overall internal balance. Disruptions in this delicate balance can lead to numerous diseases, including IBD, obesity, diabetes, cardiovascular problems, cancer, and neurodegenerative disorders.
 
However, the good news is that nature has provided us with potential remedies in the form of natural polyphenolic compounds. One such compound, known as rosmarinic acid (RA), has garnered significant attention due to its numerous pharmacological properties, including its antioxidant, anti-cancer, anti-inflammatory, anti-apoptotic, and anti-fibrotic effects. Recent Herbs And Phytochemicals research by scientists from Northeast Agricultural University, Harbin, Heilongjiang-China has indicated that rosmarinic acid (RA) might hold the key to alleviating the symptoms of IBD, protecting the gut from inflammation, and regulating the microbiota that call it home.
 
Rosmarinic Acid: A Natural Wonder
Rosmarinic acid, named after the herb rosemary (Salvia rosmarinus Linn.), is a polyphenolic constituent found in various herbs, including rosemary, perilla, sage, mint, and basil. Its wide distribution in nature has prompted researchers to explore its potential therapeutic applications, and the results have been promising.
 
Rosmarinic acid’sunique properties have made it a subject of interest for its potential to address various diseases, including acute IBD. It has demonstrated a protective effect on the intestinal tract in mouse models, reducing inflammation, repairing intestinal flora imbalances, alleviating endoplasmic reticulum stress, inhibiting cell death, and restoring smooth muscle contractions to normalcy.
 
Protective Effects of Rosmarinic Acid
The results of this study have shed light on the incredible protective effects of rosmarinic acid on the small intestine of mice in the context of IBD. Through a series of experiments, researchers established a clear link between RA and its ability to counteract the damaging effects of IBD.
 
One significant outcome of the study was the observation that rosmarinic acid (RA) significantly alleviated the symptoms of IBD induced by dextran sulfate sodium salt (DSS). Mice treated with DSS exhibited severe intestinal damage, including the shortening of small bowel length, weight loss, diarrhea, and the presence of blood in stool. In contrast, mice treated with RA showed remarkable protection against these symptoms, with a lower Disease Activity Index (DAI) and a healthier intestinal morphology.
 
Regulation of Gut Microbiota
An essential aspect of rosmarinic acid (RA)'s protective effects is its influence on the gut microbiota. To gain a comprehensive understanding of this, the researchers employed 16S rRNA high-throughput sequencing, which allowed them to explore the changes in species composition within the intestinal flora.
 
The results were striking. Rosmarinic acid (RA) induced a shift in the abundance of certain bacterial genera within the gut microbiota. Lactobacillus johnsonii and Candidatus Arthromitus sp SFB-mouse-NL increased in abundance, while Bifidobacterium pseudolongum, Escherichia coli, and Romboutsia ilealis decreased. This shift is significant because Lactobacillus johnsonii is known to reduce inflammation and endoplasmic reticulum stress, while Candidatus Arthromitus sp SFB-mouse-NL plays a crucial role in innate and adaptive immune functions.
 
On the other hand, Escherichia coli has been implicated in causing acute diarrhea, and Romboutsia ilealis is considered a potentially harmful bacterium in the gut. Bifidobacterium pseudolongum, known for its protective effect on the intestinal barrier, was also found to decrease in abundance with DSS treatment, highlighting the significance of maintaining the balance of these bacterial species.
 
Repairing the Intestinal Barrier
One of the primary consequences of IBD is the disruption of the intestinal barrier, leading to a cascade of inflammatory responses. RA's intervention here was clear. It mitigated tight junction dysregulation, inflammation, and endoplasmic reticulum stress, thus preserving the integrity of the intestinal barrier.
 
At the gene and protein levels, rosmarinic acid (RA) effectively downregulated the expression of key molecules associated with inflammation, including E-cadherin, Occludin, ZO-1, ZO-2, and ZEB. These molecules are critical in maintaining the integrity of tight junctions, and their dysregulation is often associated with intestinal inflammation.
 
Inflammatory factors, including NF-κB, IκBα, IL-6, IL-1β, and TNF-α, also saw their expression levels increase with DSS treatment, while the anti-inflammatory factor IL-10 decreased. However, RA treatment significantly reversed this trend, reducing the expression of inflammatory factors and increasing IL-10 levels.
 
Endoplasmic reticulum stress (ERS) plays a significant role in IBD, and here too, rosmarinic acid (RA) demonstrated its protective effects. ERS-related molecules, including GRP78, IRE1, PERK, ATF6, and CHOP, were upregulated in the DSS group. RA effectively downregulated their expression, reducing endoplasmic reticulum stress in the small intestine.
 
Mitigating Cell Death
IBD often triggers cell death in the intestinal tissues, and RA effectively mitigated this phenomenon. In the DSS group, the expression of genes associated with cell death pathways, such as Caspase8, RIPK1, RIPK3, MLKL, Bax, Cytc, Caspase12, Caspase9, and Caspase3, increased significantly, while the anti-apoptotic Bcl-2 gene decreased. At the protein level, a similar trend was observed.
This suggested that DSS primarily induced apoptosis rather than necrosis in small intestinal cells. The molecular pathways associated with necrotizing apoptosis, mitochondrial apoptosis, and endoplasmic reticulum stress-mediated apoptosis were all activated. RA's intervention effectively reduced these cell death pathways and increased Bcl-2 levels, indicating a shift towards a more anti-apoptotic state.
 
Normalizing Smooth Muscle Contraction
The DSS-induced imbalance in the gut microbiota was also associated with abnormal contractions of the small intestinal smooth muscle. Rosmarinic acid (RA) was found to restore the balance by downregulating the expression of key genes and proteins associated with smooth muscle contraction, including CaM, MLC, MLCK, RhoA, and ROCK.
 
In the DSS group, these molecules were significantly upregulated, leading to abnormal muscle contractions. However, in the RA + DSS group, these expressions were significantly decreased, indicating that rosmarinic acid (RA) could normalize the smooth muscle contractions in the small intestine.
 
Conclusion
This research showcases the exceptional potential of rosmarinic acid in mitigating the symptoms of IBD and protecting the gut from inflammation. Through its multifaceted effects on the intestinal flora, preservation of the intestinal barrier, reduction in endoplasmic reticulum stress, mitigation of cell death pathways, and normalization of smooth muscle contractions, RA holds the promise of a more holistic approach to IBD treatment.
 
The results are not only promising for IBD patients but also provide a novel perspective on the utilization of natural polyphenolic compounds for therapeutic purposes. The relationship between the gut microbiota and the development of IBD is becoming increasingly clear, and RA's effects in regulating this complex ecosystem offer hope for more effective treatments and possibly even prevention in the future.
 
Nature, once again, has shown us that within its vast treasury of compounds, there are potential solutions to some of the most complex health problems we face today. Rosmarinic acid, found in the unassuming rosemary herb, has unveiled its healing powers in the realm of IBD. As research continues, it might open new avenues for treating not only IBD but also other diseases rooted in inflammation and microbiota imbalance.
 
The study findings were published in the peer reviewed journal:
https://journals.asm.org/doi/10.1128/spectrum.01914-23
 
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