Introduction

Ulcerative colitis (UC) is the major form of inflammatory bowel disease (IBD). UC is a relapsing and remitting mucosal inflammation that starts from the rectum and spreads continuously to the proximal segments of the colon [1]. The prevalence of UC has been rising in the newly industrialized countries in Africa, Asia, and South America [2]. For example, it is about 11.6 per 100,000 people in China [3]. Additionally, the incidence of colorectal cancer in Asian patients with UC has been also increasing [4]. This situation imposes a great need for effective UC treatment, but the current therapy methods cannot meet the expectations due to the unsustainable efficacy [5].

The maladjustment of the immune system affected by heredity, environment, and gut microbiota is closely related to the progress of UC [6]. The intestinal immune microenvironment consists of intestinal epithelial cells, macrophages, dendritic cells (DCs), regulatory T cells (Tregs), and inflammatory T cells, which collaboratively maintain immune homeostasis [7]. The inflammatory microenvironment can be a target for UC treatment. Macrophages (MΦ) are pivotal in coordinating the progress of UC [8]. Macrophages are characterized by their diversity and plasticity in response to environmental signals and are traditionally classified into M1Φ with pro-inflammatory/anti-microbial activity and M2Φ with anti-inflammatory activity/tissue repair [9]. An increase of M1Φ amount in the pathological site of colitis predicts the worsening disease stage [10]. Re-education from M1 to M2 phenotype is a potential strategy for UC treatment [11].

In addition to the aggravated inflammatory immune responses in colitis, excessive proliferation of fibroblasts and myofibroblasts contributes to the deposition of extracellular matrix (ECM) and the fibrosis of the intestinal wall. Severe intestinal fibrosis may result in intestinal obstruction and require surgical intervention [12]. Traditional treatments mainly focus on alleviating the symptoms of UC through anti-inflammatory approaches (e.g., 5-aminosalicylic acid, corticosteroids, immunosuppressants, or monoclonal antibodies), but their clinical application has been restrained because of unsustainable therapeutic effect, the recurrence after drug withdrawal, and off-target systemic side effects [1]. Moreover, these medications are of little help in solving the intestinal fibrosis problem that is a complication of UC [12]. Therefore, the synergy of immune regulation and anti-fibrosis may be a new strategy for UC treatment.

To address this issue, we proposed a combination therapy strategy using an oral nanomedicine for co-delivering patchouli alcohol (PA) and simvastatin (SV), a “two-birds-one-stone” nanotherapeutic strategy. We previously revealed that patchouli alcohol, a natural tricyclic sesquiterpene isolated from a Chinese herb Guang Huo ** a safe and effective drug for UC. The interaction between the inflammatory immune microenvironment and colitis-related fibrosis during the progression of UC has not been fully demonstrated yet, and further investigation and understanding will be helpful to better depict the underlying mechanisms and seek effective drug combinations.