Acute pancreatitis (AP) is a common gastrointestinal disease. In recent years, the
hospitalization rate and related costs of AP have increased significantly. About 15% -
20% of patients will develop acute severe pancreatitis, namely SAP. SAP is a serious
abdominal disease with many complications and high mortality. The global average annual
incidence rate is about 6.75 cases/100000 people. Systemic inflammatory response syndrome
(SIRS), multiple organ dysfunction syndrome (MODS), and sepsis are often associated with
it. SIRS and MODS may be caused by the release of inflammatory cytokines in the early
stage of AP, and intestinal dysfunction and pancreatic necrosis in the later stage. Some
studies have shown that 59% of AP patients are accompanied by intestinal barrier injury,
and increased permeability of intestinal mucosa, resulting in intestinal bacterial
translocation, pancreatic tissue necrosis and infection, and multiple organ dysfunction
syndrome. Most of the bacteria causing necrotic infection of pancreatic tissue to come
from intestinal flora, such as Escherichia coli and Enterococcus. Therefore, intestinal
flora may play an important role in the occurrence and development of AP.

As the largest organ of the human body, the gastrointestinal tract provides a broad
colonization surface for biological flora. Intestinal bacteria present in the human
gastrointestinal tract are essential components for the development of the mucosal immune
system, the promotion of food digestion and absorption, and the regulation of glucose
metabolism. In addition, it also has the function of protecting the intestinal barrier
and mediating host immunity and metabolism. The host and microbe reach the
micro-ecological balance in the state of health, which is called internal environment
stability, and the host maintains normal physiological functions. However, external
factors (such as infection, toxin, diet change, disease, etc.) may change or destroy the
balance between them, and the disorder of intestinal flora will in turn induce or
accelerate the disease's progress. As one of the research hotspots in recent years, the
imbalance of intestinal flora has always attracted people's attention. The current study
found that the ecological imbalance of intestinal microbiota during AP was defined as the
decrease of intestinal microbial diversity and the change of the balance between
symbiotic microbiota and pathogenic microbiota. The change of intestinal flora occurred
in the early stage of AP, which may be involved in the aggravation of the disease. Not
only that but also early intestinal flora disorder was found in SAP research. In addition
to intestinal bacteria, their metabolites such as short-chain fatty acids (SCFAs) also
affect the progress of AP. Moreover, more and more studies have found that changes in
intestinal flora during the development of AP may be related to the severity of the
disease. In the process of AP occurrence and development, the abnormal secretion of
trypsin and the destruction of pancreatic structure leads to the abnormal secretion of
the pancreas, which can cause changes in intestinal homeostasis and intestinal flora. In
addition, the study also found that intestinal microbiota is an important medium during
AP, and its imbalance is closely related to the severity of AP. At present, many
experimental data have shown that the diversity of intestinal microorganisms and the
relative abundance of specific bacterial groups have changed during the AP process.

Based on the relationship between intestinal flora imbalance and the occurrence and
development of AP, the possible mechanisms of intestinal microbial imbalance in AP are
mainly as follows: (1) intestinal motility disorder: gastrointestinal motility disorder
often exists in AP and plays a role in disease progression. Intestinal motility disorder
can also lead to the accumulation of harmful substances and inhibit the growth of
probiotics. (2) Ischemia-reperfusion injury (IRI): pro-inflammatory cytokines such as
TNF- α during AP, the release of insulin can cause intestinal mucosal IRI and disrupt
intestinal microcirculation. One of the main causes of intestinal microcirculation damage
is the destruction of sugar calyx. (3) Oxidative stress: severe oxidative stress and
intestinal-activated caspase-3 pathway was found during AP. Oxidative stress not only
accelerates the disorder of intestinal barrier function but also participates in the
disorder of intestinal microbiota. (4) Immune dysfunction: intestinal immunosuppression
can be observed in the early stage of acute pancreatitis, which is related to the damage
of the clearance of proliferative pathogens.

In AP, the change of intestinal microflora is closely related to its occurrence and
development, and the metabolites of intestinal microflora will also affect the serum
metabolic indicators of AP patients. Intestinal microflora has high metabolic activity
and can transform host sources and dietary components into different metabolites. Some
metabolites are beneficial and some are harmful. Metabolites beneficial to the host
include lactic acid, bile acid (BA), SCFA, and bacteriocin. These substances are
generally considered antibacterial factors and play a key role in the prevention of
pathogenic infection. In addition, there are also related intestinal flora and several
specific products produced that may have a certain impact on SAP. In human intestines,
bifidobacteria and lactobacillus are probiotics that can stimulate anti-tumor properties
and immunity. The main products of bifidobacterium metabolism are lactic acid and acetic
acid, which reduce the pH value in the intestine and inhibit the growth of harmful
microorganisms. This mechanism is particularly evident in the cecum and ascending colon.

At present, the continuous pandemic of coronavirus disease (COVID-19) in 2019 caused by
severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) poses a serious threat
to global public health, and millions of people in more and more countries are at risk.
This pandemic has not only affected the medical system but also affected the global
socioeconomic balance. COVID-19 was soon designated as a global pandemic by the World
Health Organization, because as of January 2021, there were about 98 million confirmed
cases and about 2 million confirmed deaths. Nevertheless, since the outbreak of COVID-19,
our understanding of it has increased significantly, and a variety of treatment methods
and drug interventions have been tested or are currently being developed to reduce its
risk factors. Recently, some candidate vaccines have shown about 95% clinical efficacy
and are currently being approved for emergency use in different countries. Therefore,
vaccination as one of the effective means of protection is worth promoting worldwide.
Some studies have confirmed that several intestinal microflorae have the potential to
improve the immune response and reduce adverse events after COVID-19 vaccination and that
intestinal microflora has the potential to supplement the effectiveness of the vaccine.
Combined with several recent studies, intestinal flora plays a key role in regulating the
immune response to vaccination and is related to the severity of COVID-19 patients.
However, the comprehensive evaluation of host response, especially the role of intestinal
flora in antibody production, is limited. Therefore, the specific role of intestinal
flora in the development of COVID-19 needs further study.

The composition of intestinal microflora and the severity of acute infection (including
COVID-19) have a two-way relationship with the lung, which is called the "gut-lung axis".
Intestinal ecological imbalance, that is, the emergence of viral pathological organisms,
changes the signal transduction of intestinal epithelial cells and produces
proinflammatory reactions, which can lead to impaired immune response and make COVID-19
patients vulnerable to serious diseases. A variety of inflammatory and infectious
diseases are associated with symbiotic disorders. Several studies have shown that the
stool virus shedding of COVID-19 patients will continue for a long time after the
respiratory symptoms subside. This shows that the gastrointestinal tract is the site of
virus replication, and has caused concern about fecal and oral transmission. This was
further confirmed by a small study of 30 COVID-19 patients. The study showed that the
decrease in biological diversity increased along with the increase of opportunistic
bacteria, including Streptococcus, Rochella, Verona, Clostridium erysipelas, and
actinomycetes. The abundance of fecal bacteria, Clostridium mycobacterium and Clostridium
hartwickii was associated with severe COVID-19 disease. The abundance of beneficial
Bacteroides and Alisma orientalis was negatively correlated with the severity of the
disease. Many studies have explored the relationship between intestinal ecological
disorders, severe COVID-19, and elevated inflammatory markers. Bacteroides Donovan and
Akermann myxophila and IL-1 β、 IL-6 are positively correlated with CXCL8. Similarly,
IL10, TNF- α, and chemokines (such as CXCL10 and CCL2) are negatively correlated with
beneficial microbiota (such as Bifidobacterium adolescents, Eubacterium rectum and
Faecalis procterii), which maintain a low level in fecal samples collected one month
after the disease. In another study involving a small group of COVID-19 patients, butyric
acid producers (for example, Fecal Procter, Clostridium butyricum, Clostridium parvum,
and Eubacterium rectum) were significantly reduced, and conditional pathogens such as
Enterococcus and Enterobacteriaceae were abundant in severe patients with adverse
outcomes. Changes in intestinal microflora were observed in children with acute and
non-acute Kawasaki disease, which further suggested that MISC in SARS-CoV-2 might be
associated with ecological disorders. Limited studies on patients with COVID-19 have
shown intestinal ecological disorders. A small report at the beginning of the pandemic
showed that the levels of lactobacilli and bifidobacteria in COVID-19 patients were low.
Zuo et al. showed that COVID-19 virus RNA in the feces of almost half of the sampled
patients was positive, which lasted for a long time after the respiratory tract was
cleared. In addition, the authors found that patients with viral RNA had higher levels of
opportunistic pathogens. To better clarify the role of probiotics in the treatment of
COVID-19, several studies are currently underway. The clear recommendations on probiotics
and COVID-19 treatment still need further evidence, although there are biological
rationality and reasons to hope that they may play a beneficial role.

In the current era of the continuous prevalence of COVID-19, many patients are faced with
COVID-19 infection and AP at the same time, which poses new challenges to the diagnosis
and treatment of clinicians. Based on the key role of intestinal flora imbalance in AP
and COVID-19 infection and the unique advantages of metabonomics in the diagnosis and
prognosis of infectious diseases. Therefore, our research is based on the fact that the
imbalance of intestinal flora plays an important role in the development of COVID-19
infection and AP while considering the impact of intestinal flora and its metabolites on
the serological indicators of patients. The purpose of this study was to explore the
complex relationship between the changes in the intestinal microbiome and serum
metabolite in patients with novel coronavirus infection and acute pancreatitis, hoping to
provide help for clinical diagnosis and treatment of patients with novel coronavirus
infection and acute pancreatitis.