microorganisms Review Microbiomics in Collusion with the Nervous System in Carcinogenesis: Diagnosis, Pathogenesis and Treatment Rodney Hull 1 , Georgios Lolas 1,2 , Stylianos Makrogkikas 3 , Lasse D. Jensen 4 , Konstantinos N. Syrigos 2 , George Evangelou 2 , Llewellyn Padayachy 1,5 , Cyril Egbor 1,5 , Ravi Mehrotra 1,6,7 , Tshepiso Jan Makhafola 1,8 , Meryl Oyomno 1,9 and Zodwa Dlamini 1, *   Citation: Hull, R.; Lolas, G.; Makrogkikas, S.; Jensen, L.D.; Syrigos, K.N.; Evangelou, G.; Padayachy, L.; Egbor, C.; Mehrotra, R.; Makhafola, T.J.; et al. Microbiomics in Collusion with the Nervous System in Carcinogenesis: Diagnosis, Pathogenesis and Treatment. Microorganisms 2021, 9, 2129. https://doi.org/10.3390/ microorganisms9102129 Academic Editor: Elisa Bona Received: 19 August 2021 Accepted: 27 September 2021 Published: 11 October 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 SAMRC Precision Oncology Research Unit (PORU), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa; Rodney.hull@up.ac.za (R.H.); glolas@med.uoa.gr (G.L.); lc.padayachy@up.ac.za (L.P.); cyrilagbor0772@gmail.com (C.E.); ravi.mehrotra@gov.in (R.M.); tshepisomakhafola5@gmail.com (T.J.M.); meryl.oyomno@up.ac.za (M.O.) 2 Department of Medicine, National & Kapodistrian University of Athens, 11527 Athens, Greece; ksyrigos@med.uoa.gr (K.N.S.); grgevangelou@med.uoa.gr (G.E.) 3 FALCONBIO PTE, Ltd., 32 Carpenter Street, SGInnovate, Singapore 059911, Singapore; stelios279@falconbio.org 4 Division of Cardiovascular Medicine, Department of Health, Medicine and Caring Sciences, Faculty of Medicine, Linköping University, 581 83 Linköping, Sweden; lasse.jensen@liu.se 5 Department of Neurosurgery, University of Pretoria, Hatfield 0028, South Africa 6 Centre for Health Innovation and Policy (CHIP) Foundation, Noida 201301, India 7 Datar Cancer Genetics, Nashik 422010, India 8 Centre for Quality of Health and Living, Faculty of Health and Environmental Sciences, Central University of Technology, Bloemfontein 9300, South Africa 9 Department of Surgery, Faculty of Health Sciences, Steve Biko Academic Hospital, University of Pretoria, Pretoria 0007, South Africa * Correspondence: Zodwa.Dlamini@up.ac.za Abstract: The influence of the naturally occurring population of microbes on various human diseases has been a topic of much recent interest. Not surprisingly, continuously growing attention is devoted to the existence of a gut brain axis, where the microbiota present in the gut can affect the nervous system through the release of metabolites, stimulation of the immune system, changing the permeability of the blood–brain barrier or activating the vagus nerves. Many of the methods that stimulate the nervous system can also lead to the development of cancer by manipulating pathways associated with the hallmarks of cancer. Moreover, neurogenesis or the creation of new nervous tissue, is associated with the development and progression of cancer in a similar manner as the blood and lymphatic systems. Finally, microbes can secrete neurotransmitters, which can stimulate cancer growth and development. In this review we discuss the latest evidence that support the importance of microbiota and peripheral nerves in cancer development and dissemination. Keywords: microbiota; gut–brain axis; metabolites; neurogenesis; neurotransmitters; immunity; carcinogenesis 1. Introduction It has been estimated that the microbiota in a human body consists of approximately 3000 different species of microbes with 40,000,000,000,000 (40 trillion) individual microbial cells. The vast majority of these are gastrointestinal bacteria [1]. One of the first microbial based treatments proposed for cancer was found in the Eber’s Papyrus, written by the Egyptian physician Imhotep around the year 2600 BCE [2]. He proposed that infection of the area affected by the cancer through an open wound covered by a poultice could have therapeutic potential. At that time Germ theory was unknown [3]. This treatment was revived in the 1800s by William Coley who “vaccinated” cancer patients with live or heat-killed Streptococcus and Serratia species [2]. Coley documented 4 cases of sarcoma Microorganisms 2021, 9, 2129. https://doi.org/10.3390/microorganisms9102129 https://www.mdpi.com/journal/microorganisms