Finally , adenylyl cyclase is activated by Gs α protein and catalyzes the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP ) . The concentration of cAMP increases significantly , triggering protein kinase A (PKA) to destroy the cystic fibrosis transgene. The membrane-regulated conduction (CFTR) channel allows a large amount of chloride ions and water to flow out into the intestinal lumen , exceeding the normal absorption capacity , that is, secretory diarrhea occurs  [21]. Heat-resistant enterotoxin has a similar diarrheal pathway as heat-sensitive enterotoxin and cholera toxin, but the difference is that after heat-resistant enterotoxin binds to the ganglioside GM1 receptor of intestinal epithelial cells, it activates the intestinal epithelial cells. Ulate cyclase increases the level of guanosine triphosphate (cGMP) in the cytoplasm, eventually causing secretory diarrhea [22].

Secretory diarrhea caused by heat-sensitive enterotoxin, cholera toxin and heat-resistant enterotoxin is often accompanied by severe dehydration. In particular, heat-sensitive enterotoxin and cholera toxin are the most severe diarrhea-causing toxins discovered so far. After the animal becomes ill, if it is not treated in time, it will It is extremely easy for dehydration, body weight loss, and even death to occur.

Shigella and Salmonella cause secretory diarrhea mainly by increasing intracellular Ca2+ concentration .

After Shigella or Salmonella invades intestinal epithelial cells, it stimulates immune cells to secrete IL-6, IL-8 and tumor necrosis factor, causing an increase in intracellular Ca2+ concentration. The increase in Ca2+ concentration not only causes calcium to activate chloride channels in large quantities The secretion of chloride ions will also inhibit the sodium hydrogen exchange protein (NHE3) and reduce the absorption of sodium ions. Eventually, a large amount of electrolytes will be lost, water will flow out, and secretory diarrhea will occur [23]. Rotavirus also causes secretory diarrhea mainly by increasing intracellular Ca2+ concentration . After rotavirus enters the cell, its non-structural protein 4 (NSP4) recognizes integrin α1β2 and increases the Ca2+ concentration under the action of enteric nerves. The increase in Ca2+ concentration not only causes calcium-activated chloride channels to secrete a large amount of chloride ions and inhibits NHE3 In addition, it also inhibits the sodium-glucose co-transporter (SLC5A1), reducing sodium ion absorption. Eventually, electrolytes and water are lost massively, leading to secretory diarrhea [24]. In addition, stimulated by various factors, including endogenous neprilysin in the intestine, vasoactive peptide (VIP) and 5-hydroxytryptamine (5-HT) produced during inflammation, calcium-calmodulin, substance P, etc., It can also indirectly increase the concentration of cAMP, cGMP or Ca2+, causing secretory diarrhea. For example, endogenous enkephalin (an intestinal endogenous opioid peptide with pro-absorptive and anti-secretory effects in the small intestine) binds to intestinal basement membrane delta receptors and directly inhibits the activity of adenylyl cyclase , but can be rapidly degraded into leuko-enkephalin and egg-enkephalin by the endogenous metalloprotease-enkephalinase. The degraded products lose their absorption-promoting and anti-secretory effects, leading to secretory diarrhea [25]. 03 | The relationship between diarrhea and secretory diarrhea in weaned piglets. Diarrhea is caused by the fact that the gastrointestinal tract and immune function of piglets are not fully developed after weaning, and factors such as feed changes, group transfers, and stress affect the integrity and normal function of the intestines, that is, Non-infectious diarrhea [26]; more importantly, diarrhea occurs due to infection with ETEC as the representative pathogen, that is, infectious diarrhea. The process by which ETEC causes diarrhea can be roughly divided into two processes :  the first step ▷   The fimbriae (adhesin) of ETEC can recognize intestinal epithelial cell receptors and adhere to the intestinal epithelial cells; the  second step ▷ The intestinal   epithelium is produced during the growth of ETEC. Toxins, especially heat-sensitive enterotoxins, can rapidly trigger secretory diarrhea. Adhesins, endotoxins and enterotoxins are considered to be the three elements that cause diarrhea in ETEC. Adhesins themselves are not toxic and mainly serve to adhere fimbriae to intestinal epithelial cells to facilitate proliferation; endotoxins can only be released in the presence of intestinal damage. Absorbed into the blood, inflammation is induced only when the detoxification ability of the liver is exceeded; enterotoxins directly act on intestinal epithelial cells to cause diarrhea, and the effect is severe [27-28]. Therefore, infectious diarrhea in weaned piglets is mainly secretory diarrhea . 04 | Current status of clinical drugs for secretory diarrhea. At present, the drugs used by humans and veterinarians to treat secretory diarrhea include loperamide, octatrile, phenothiazine, chlorpromazine, glyburide, and oral rehydration solution. salt (ORS), racecadotril, etc. Among them, loperamide, ORS, and racecadotril are the most widely used. Proanthocyanidins are new drugs approved by the FDA for anti-secretory diarrhea  [17,25]. Loperamide mainly acts by inhibiting intestinal motility and prolonging absorption time; octatrile mainly acts on neuroendocrine tumors by inhibiting the release of secretagogues (such as VIP and 5-HT); phenothiazine and chlorpromazine Mainly by inhibiting calcium-calmodulin, thereby inhibiting the cAMP effect stimulated by hormones; glyburide can act on chloride channels and reduce secretion. These types of drugs are valuable in different treatment options for secretory diarrhea, but they carry the risk of serious side effects and toxicity, and have great limitations in terms of indications and suitable populations. ORS can effectively replenish the body's lost water and electrolytes to treat dehydration. It is the most important clinical auxiliary treatment and can reduce diarrhea mortality by about 70%. However, it cannot reduce body fluid loss, stool volume or shorten the course of the disease .