A Literature Review— Khaya senegalensis , Anacardium ouest L., Cassia sieberiana DC., Pterocarpus erinaceus , Diospyros mespiliformis , Ocimum gratissimum , Manihot esculenta , Vernonia amygdalina Delile, Pseudocedrela kotschyi and Daniellia oliveri Possess Properties for Managing Infectious Diarrhea

The rise in antimicrobial resistance increases researchers’ interest in medicinal plants used for traditional treatment of infectious diseases. The study is based on ten (10) medicinal plants mostly cited in the treatment of diarrhea in West Africa: Khaya senegalensis, Anacardium ouest L., Cassia sieberiana DC., Pterocarpus erinaceus, Diospyros mespiliformis, Ocimum gratissimum, Manihot esculenta, Vernonia amygdalina Delile, Pseudocedrela kotschyi, Daniellia oliveri. The objective is to make a review on ethnopharmacological, pharmacological, toxicological

them in the fight against infectious diarrhea.

Definition
Diarrhea is defined as "the passage of three or more loose or liquid stools per day (or more frequent passage than the normal for the individual)" [1]. It is simply a modified movement of ions and water along an osmotic gradient. Under normal conditions, the gastrointestinal tract absorbs large amounts of fluids and electrolytes. It is estimated that 100 to 200 ml of fluids and electrolytes are excreted in the stool from the 8 to 9 litres of fluid presented in the intestine each day. Pathogens in the intestine (bacteria, viruses, parasites, etc.) can, for one reason or another, contribute to altering this balance towards a net secretion: this is called diarrhoeal disease [22]. Most of these pathogens responsible for diarrhoeal diseases are spread by faeces contaminated water.

Causes and Pathophysiology of Infectious Diarrhea
Infections are more frequent when there is a lack of sanitation and/or hygiene and safe water [1]. Infection with bacteria such as enterotoxigenic and enteropathogenic E. coli, Salmonella, Shigella and V. cholerae, is one of the main causes of diarrheal diseases in developing countries [5]. Rotavirus, Escherichia coli, cryptosporidium and Shigella species are among the most reported pathogens [1] [23]. In a study performed in Bangui, including 333 cases and 333 controls, the most attributable cases of hospitalized diarrhea were due to rotavirus, Shigella/EIEC, Cryptosporidium parvum/hominis, astrovirus and norovirus [2].
Two or more pathogens may be involved at the same time: this is called polymicrobial infection. For a micro-organism to be pathogenic, several conditions must be met: 1) the need to ingest a minimal inoculum infecting; 2) fighting the barrier flora with which it competes; 3) crossing the mucus film and adhering to enterocytes (by various ways) [24]. After this step, the enteric pathogens, in depending on the genetic information they have, will interfere with the physiologically normal mechanisms for regulating the movement of water and electrolytes by taking over intracellular control of the regulation of the concentration of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), intracellular Ca 2+ ion concentration, or by modifying the architecture of the enterocyte cytoskeleton. In addition, there are several particularities depending on the microorganisms involved [25].

Escherichia coli
Escherichia coli represents 80% of the aerobic intestinal flora of humans. It is both a commensal bacterium and an enteropathogenic bacterium through the expression of acquired and/or constitutive virulence factors. There are six E. coli pathovars capable of enteropathogenic potential: 1) Enterotoxigenic E. coli (ETEC) responsible for childhood diarrhea in developing countries and trav-eler's diarrhea; 2) Entero-invasive E. coli (EIEC), responsible for dysentery close to shigellosis, 3) Enterohemorrhagic E. coli (EHEC), found in hemorrhagic colitis and typical hemolytic uremic syndrome (HUS), 4) Enteropathogenic E. coli (EPEC) are the cause of persistent childhood diarrhea which is often epidemic in developing countries, 5) Diffuse adhesion E. coli (DAEC) and 6) E. coli enteroaggregative (EAggEC) which cause persistent watery diarrhea in children [26].

Salmonella spp.
Non-typhoid Salmonella species are invasive bacteria that use a type III secretion system to deliver a variety of effectors into intestinal epithelial cells [27]. They are one of the 4 main causes of diarrhoeal diseases in the world [28].

Shigella spp.
Shigella produces Shiga toxins and stimulates an inflammatory infiltrate and watery and/or bloody diarrhea [29].
Shigella species cross the epithelial barrier by M cells. After elimination of the microphages, they bind lipoprotein to TLR2 (a Toll-like receptor encoded by the TLR2 gene and involved in bacterial recognition), resulting in the production of IL-1β (a chemo-attractor). Following translocation through M cells, LPS can bind to basolateral TLR4, resulting in the production of IL-6 and IL-8. IL-8 is a potent chemo-attractor for polymorphonucleocytes (PMN). PMNs are responsible for the secretion of Cl − and can also cause ulceration of the epithelium, resulting in a decrease in the surface area for absorption but also maximizing permeability and allowing easy access of the intestinal flora to the basolateral surface of the cells, thus promoting inflammation [30] [31] (Figure 1).

Vibrio cholerae
V. cholerae causes diarrhea using its major virulence factor (cholera toxin (CT)), which binds to apical GM1 receptors on host epithelial cells, thereby allowing translocation of the toxin into the cell [32]. One of the sub-units of the TC causes the production of cAMPs. cAMP activates PKA which phosphorylates the cystic fibrosis transmembrane conductance regulator (CFTR) domain. There is then an increase in Cl secretion, a decrease in Na + absorption, where the activity of NHE2 and NHE3 (both apical sodium transporters) is reduced together, resulting in increased levels of NaCl in the intestinal lumen, either by increasing secretion or decreasing absorption [33] [34] [35] [36] ( Figure 2).

Clostridium difficile
C. difficile often causes debilitating diarrhea. C. difficile produces toxins A and B (TcdA and TcdB), as well as an additional toxin called binary toxin [37]. TcdA alters the cytoskeleton and disrupts tight junctions, resulting in loss of epithelial barrier function. TcdA and TcdB thus pass easily through the epithelium with the preferential binding of TcdB to the basolateral cell membrane. They induce the production of pro-inflammatory cytokines, increased vascular permeability, recruitment of monocytes and neutrophils, apoptotic cell death of epithelial cells and connective tissue degradation. All this leads to pseudomembrane formation and diarrhea. In addition, the toxin-induced release of certain neuropeptides stimulates the central nervous system to induce fluid secretion, which is responsible for diarrhea [22] (Figure 3).

Viral Diarrhea
Viral diarrhoea is watery and often leads to dehydration that needs to be compensated for with oral rehydration solutions [38]. The main pathogens responsible  for infectious diarrhea are rotaviruses, noroviruses, sapoviruses, adenoviruses, and astroviruses. Among them, rotaviruses are the most important, causing severe diarrhea and mortality in children worldwide [5] [39]. They probably account for 50% of viral causes [38].

Parasite-Mediated Diarrhea
Parasite such as Entamoeba histolytica, Giardia lamblia, and Cryptosporidium parvum are common causes of water-borne diarrhea. For example, Giardia tropozoites use a ventral adhesive disc to adhere strongly to the epithelial surface of the intestine. In this way, they decrease the surface area for absorption. Absorption of NaCl and glucose due to this are therefore minimized, resulting in diarrhea [22] [40].

Management of Infectious Diarrhea
The management strategy for diarrhea must give priority to the assessment of the level of dehydration and its correction, using oral rehydration solutions with low osmolarity. Zinc supplementation is recommended for children with gastroenteritis living in poor conditions. It is only for moderate to severe bloody diarrhoea that antimicrobial therapy is sought in children. Breastfeeding is fundamental for the prevention of infectious diarrhoea but also during diarrhoea [23].
According to "Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea", the empiric antimicrobial therapy in adults should be either a fluoroquinolone such as ciprofloxacin, or azithromycin, depending on the local susceptibility patterns and travel history (strong, moderate). Empiric therapy for children includes a third-generation cephalosporin for infants < 3 months of age and others with

Involvement of Medicinal Plants in the Management of Infectious Diarrhea
In the African context, traditional medicine can be defined as a set of knowledge, preparation techniques and uses of natural substances. It is based on the socio-cultural and religious foundations of African communities, more specifically the experience of using and transmitting knowledge from generation to generation. It is used for the diagnosis, prevention or treatment of an imbalance in physical, mental or social well-being [42]. Diarrheal infections are among the many diseases treated by traditional medicine.  [20] and Daniellia oliveri [21] are ten plants from West African Pharmacopoeia, cited in several works for their usefulness in the treatment of infectious diarrhea.

Toxicity Study
According to Nwosu et al. [7], the aqueous extract of the leaves of Khaya senegalensis is not toxic. According to a study carried out by these authors in Nigeria on rats, the LD50 of the extract is higher than 3000 mg•kg −1 body weight. Although other studies revealed that chronic treatment rather induces an increase of these parameters [47]. Long treatments also cause elevation of serum creatinine and blood urea [7] which reflects renal dysfunction. Adakole and Balogun suspected a risk of acute ecotoxicity of crude (ethanol and aqueous) leaves of K. senegalensis [8]. The study focused on the sensitivity of chironomid larvae to extracts in the aquatic environment. LC 50 of 1.39 g/L and 1.20 g/L were obtained (for aqueous and ethanol extracts, respectively). In addition, deformations of mouthparts and other morphological changes were observed [48].

Antibacterial Properties
Scientific data reported that leaves and stem-bark of K. senegalensis were used for the cure of diarrhea [49]. Extracts were active on Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus spp., Salmonella spp. flavonoids, and phenols [13] [56]. Glycosides were absent in both extract while terpenoids and steroids were absent in aqueous and methanol extract respectively [13].

Toxicity Study
Tittikpina carried out a cytotoxicity assay of the raw extract on a human non-cancerous cell (namely MRC-5) and reported that the extracts were not toxic to MRC-5 cells [57]. Olafadehan [58] reported that a dietary tannin concentration of 60 g/kg and intake of 1.4 g/kg b.m. have no threat on animal health.

Antibacterial Properties
Pterocarpus erinaceus is used Nigeria and in other African savanna countries for traditional treatment of diarrhea, urethral discharges, fever and dysentery [59].
According to Tittikpina [57], All extracts and fractions tested show good activity against Gram-positive bacteria (including methicillin-resistant Staphylococcus aureus, MRSA) and Pseudomonas aeruginosa with MIC values ranging from 32 µg/mL to 256 µg/mL Methanol extract caused a significant (p < 0.01) reduction in wet faeces in mice in castor oil-induced diarrhea [14].

Toxicity Study
The effects of medium term administration of crude Diospyros mespiloformis root extracts on some biochemical parameters were investigated in mice [61].
The outcomes are early indications that long term consumption of D. mespiliformis could predispose to adverse tissue effects.

Antibacterial Properties
Leaf decoctions are used against fever, whooping cough and wounds [62]. Barks and roots are used to treat malaria, pneumonia, syphilis, leprosy, dermatomycoses, diarrhea, facilitation of delivery and as psycho-pharmacological drug [63].

Toxicity Study
According to Ajayi et al [65] the phenolic extract of O. gratissimum leaf had no cytotoxic effect against brine shrimp eggs and CHO-k1 cells.

Antibacterial Properties
Ocimum gratissimum leaves are used in the treatment of diarrhea and respiratory tract infections [66]. The essential oils extracted from fresh leaves of Ocimum gratissimum showed strong antibacterial activities against Salmonella enterica serotype Oakland and Salmonella enterica serotype Legon [67]. Essential oil also inhibited Klebsiella sp, Salmonella enteritidis, Shigella flexineri and Escherichia coli [68].

Antibacterial Properties
Vernonia amygdalina belongs to the vegetable species most cited and used by traditional healers in the treatment of bacterial diarrhoea [43]. Extracts were active on Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Staphylococcus aureus and bacillus [69].

Toxicity Study
Cassava (Manihot esculenta Crantz) contains cyanogenic glycosides. The toxic effects of the ingestion of cassava leaves are due to the action of cyanide released from these cyanogenic glycosides [18].

Antibacterial Properties
Various studies reported that M. esculenta leaves extract can be used as antibacterial agent [70].

Toxicity Study
The 28-day acute oral toxicity study of P. kotschyi demonstrated a lack of methanol extract toxicity. Behavioral, biochemical, hematological and weight data showed no toxicity [71].

Antibacterial Properties
The root bark of P. kotschyi is used in management of gastro-intestinal diseases, fever and rheumatism in Togo and [72]. In Nigeria, the roots and leaves are used in the treatment of rheumatism and dysentery. The results of the antimicrobial activity showed that the ethyl acetate extract was effective on Staphylococcus aureus, Salmonella Typhi, Streptococcus pyogenes, Candida albicans and Escherichia coli [20].

Toxicity Study
The acute toxicity studies for the N-butanol extract in mice (i.p) was found to be 1141.4 mg/kg and >4000 mg/kg D. oliveri [21].

Antibacterial Properties
Among the Hausa people in northern Nigeria, D. oliveri Hutch and Dalz (Fabaceae) is used for the treatment of diarrhoeal infections. Experimentally, in castor-oil-induced diarrhoea, variable protection between 80% and 60% has been observed for several doses. The antidiarrheal activity was comparable to that of loperamide at 5 mg/kg [21].

Conclusion
Due to their low toxicity, their antibacterial activity and their chemical composition, the ten plants studied have a definite potential for the fight against infectious diarrhea. However, more in-depth work is needed. It is necessary to evaluate the efficacy of the plants selected for diarrheal infections and propose galenitic formulations from the most effective plants, for the medical management of infectious diarrhea.