Administration of a Probiotic Mixture Ameliorates Cisplatin-Induced Mucositis and Pica by Regulating 5-HT in Rats.

Probiotic-based therapies have been shown to be beneficial for chemotherapy-induced mucositis. Previous research has demonstrated that a probiotic mixture (Bifidobacterium brevis, Lactobacillus acidophilus, Lactobacillus casei, and Streptococcus thermophilus) can ameliorate chemotherapy-induced mucositis and dysbiosis in rats, but the underlying mechanism has not been completely elucidated. We aimed to determine the inhibitory effects of the probiotic mixture on cisplatin-induced mucositis and pica and the underlying mechanism, focusing on the levels of 5-hydroxytryptamine (5-HT, serotonin) regulated by the gut microbiota. A rat model of mucositis and pica was established by daily intraperitoneal injection of cisplatin (6 mg/kg) for 3 days. In the probiotic+cisplatin group, predaily intragastric injection of the probiotic mixture (1 × 109 CFU/kg BW) was administrated for 1 week before cisplatin injection. This was then followed by further daily probiotic injections for 6 days. Histopathology, pro-/anti-inflammatory cytokines, oxidative status, and 5-HT levels were assessed on days 3 and 6. The structure of the gut microbiota was analyzed by 16S rRNA gene sequencing and quantitative PCR. Additionally, 5-HT levels in enterochromaffin (EC) cells (RIN-14B cell line) treated with cisplatin and/or various probiotic bacteria were also determined. The probiotic mixture significantly attenuated kaolin consumption, inflammation, oxidative stress, and the increase in 5-HT concentrations in rats with cisplatin-induced intestinal mucositis and pica. Cisplatin markedly increased the relative abundances of Enterobacteriaceae_other, Blautia, Clostridiaceae_other, and members of Clostridium clusters IV and XIVa. These levels were significantly restored by the probiotic mixture. Importantly, most of the genera increased by cisplatin were significantly positively correlated with colonic 5-HT. Furthermore, in vitro, the probiotic mixture had direct inhibitory effects on the 5-HT secretion by EC cells. The probiotic mixture protects against cisplatin-induced intestine injury, exhibiting both anti-inflammatory and antiemetic properties. These results were closely related to the reestablishment of intestinal microbiota ecology and normalization of the dysbiosis-driven 5-HT overproduction.

The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling.

The cytokine, GDF15, is produced in pathological states which cause cellular stress, including cancer. When over expressed, it causes dramatic weight reduction, suggesting a role in disease-related anorexia. Here, we demonstrate that the GDF15 receptor, GFRAL, is located in a subset of cholecystokinin neurons which span the area postrema and the nucleus of the tractus solitarius of the mouse. GDF15 activates GFRALAP/NTS neurons and supports conditioned taste and place aversions, while the anorexia it causes can be blocked by a monoclonal antibody directed at GFRAL or by disrupting CCK neuronal signalling. The cancer-therapeutic drug, cisplatin, induces the release of GDF15 and activates GFRALAP/NTS neurons, as well as causing significant reductions in food intake and body weight in mice. These metabolic effects of cisplatin are abolished by pre-treatment with the GFRAL monoclonal antibody. Our results suggest that GFRAL neutralising antibodies or antagonists may provide a co-treatment opportunity for patients undergoing chemotherapy.

Common TMPRSS6 mutations and iron, erythrocyte, and pica phenotypes in 48 women with iron deficiency or depletion.

BACKGROUND: TMPRSS6 A736V is associated with lower transferrin saturation (TS), hemoglobin (Hb), and mean corpuscular volume (MCV) levels in general adult populations. We sought to identify relationships of TMPRSS6 K253E, A736V, and Y739Y to iron, erythrocyte, and pica phenotypes in women with iron deficiency or depletion. METHODS: We tabulated observations on 48 outpatient non-pregnant women who had iron deficiency (serum ferritin (SF) <14pmol/L and TS <10%) or iron depletion (SF<112pmol/L). We performed direct sequencing of TMPRSS6 exons 7 and 17 in each patient. We used age, TS, SF, Hb, MCV, pica, and TMPRSS6 allele positivity (dichotomous) or mutation genotypes (trichotomous) as variables for analyses. RESULTS: Forty-six women were white; two were black. 58.3% had iron deficiency. 45.8% had pica (pagophagia, each case). Allele frequencies were 41.7% (K253E), 36.5% (A736V), and 39.6% (Y739Y). K253E frequency was greater in women with TS ≥10% (p=0.0001). Y739Y was more frequent in women with TS <10% (p=0.0135). Mean TS was also lower in women positive for Y739Y (6±4% vs. 13±16%, respectively; p=0.0021). In multiple regressions, neither K253E, A736V, nor Y739Y genotypes were significantly associated with other variables. CONCLUSIONS: TMPRSS6 K253E frequency was greater in women with TS ≥10%. Frequency of Y739 was greater in women with TS <10%. Mean TS was lower in women with Y739Y. We observed no other significant relationship of TMPRSS6 K253E, A736V, or Y739Y with iron, erythrocyte, or pica phenotypes.

[Pica as a harbinger of schizophrenia]. / Pica im Vorfeld einer schizophrenen Psychose.

The author reports the case of a youth who first became salient by self-neglect and finally was hospitalized for heavy drug abuse. In the closed ward, he suddenly displayed pica behavior but, in the further course, developed a typical schizophrenic syndrome. The diagnostic criteria are presented as well as all subtypes of pica. The author goes into the question of the aetiology of this enigmatic disorder. Finally, he points out the typical complications of pica and the therapeutical possibilities which are determined most of all by the underlying disease.